Melanoma Molecular Maps Projects

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Familial melanoma



Population-based studies have shown that 1% to 13% of patients with melanoma report the occurrence of the same disease in at least one first-degree relative. Cancer registry studies have shown that the relative risk to offspring of an affected parent is in the order of around 2, the risk to a sibling is around 3 and the relative risk where both a parent and a sibling are affected is around 9 [1]. The increased risk in relatives of melanoma patients probably reflects both shared genes and shared environmental exposures.

In some melanoma families, susceptibility is consistent with autosomal dominant inheritance of a single major gene (see next paragraph entitled "High risk/familial melanoma genes"). However, this does not appear to account for the bulk of familial clustering of melanoma, as demonstrated by the fact that segregation analysis in a large population-based sample of families failed to show a single gene being responsible for melanoma transmission [2]. Therefore, the majority of familial melanomas are likely due to a polygenic mode of inheritance.

The genetic variation, which is associated with melanoma risk is established to be related to the inheritance of variation in both high risk genes (such as CDKN2A [3]) and lower risk genes such as the gene coding for the melanocortin 1 receptor MC1R [4]. In understanding the impact of these genes, they are usually grouped therefore into genes associated with “high risk or familial melanoma” or those associated with lower risk clustering. Although this is a “false” distinction as risk associated with inherited genetic variation is likely to represent a continuum, the distinction does make the discussion easier to manage.


High risk/familial melanoma genes

The best understood melanoma susceptibility gene is CDKN2A on chromosome 9. Hereditary mutations in this gene underlie susceptibility to melanoma in 40% of families with 3 or more cases of melanoma [5]. The probability of identifying a mutation in a melanoma case from a family varies by continent but is generally increased if one of the cases has multiple primaries, or if there is onset at or under the age of 40 years [5]. In most populations there is also a strong relationship between gene mutation status and pancreatic cancer [6].

Specialist genetic risk and dermatological counselling is important for patients with 3 or more melanoma cases in the family, but there is debatable value in gene testing currently [7]. In countries with lower background population incidence rates, specialist counselling may be appropriate for 2 cases families. The relative lack of information to predict pancreatic cancer risk in particular families and a lack of proven screening for pancreatic cancer limit the value of testing for CDKN2A mutation positive families. For the majority of families (particularly in high incidence areas) there is no detectable mutation and there must be other hereditary mutations yet to be discovered. In these families therefore gene testing is unhelpful.

The CDKN2A locus is biologically of note as it codes for two alternatively spliced products: p16 and p14ARF. P16 binds to CDK4 and is a cell cycle inhibitor [3] having effects on cellular senescence. p16 is established specifically to play a role in the induction of senescence of melanocytes [8]. p14ARF is also a tumor suppressor gene, and mutations at the CDKN2A locus may lead to melanoma susceptibility if they impact on p16 alone, p14ARF alone [9,10], or both p16 and p14ARF.

Hereditary mutations are seen at this locus in less than 2% of apparently sporadic melanoma patients [11], which is in unselected melanoma patients.

Very rare families exist (2% of families with detectable mutations) who have hereditary mutations in the CDK4 gene which code for the p16 binding site [12,13].

The co-existence of melanoma and atypical nevi within families has been described and the syndrome has also been named B-K mole syndrome [14], the Dysplastic Nevus Syndrome or the Familial Atypical Multiple Mole and Melanoma (FAMMM) [15].

The lifetime risk (i.e. penetrance) of melanoma in CDKN2A mutation carriers is high, but variable, ranging from 58% in Europe to 91% in Australia by the age of 80 years [16], which underscores the importance of the environment (geographical location) even in familial melanoma.

Linkage studies suggest that approximately half of the melanoma families link to 9p21, although a CDKN2A mutation could not be found in all families that link to 9p21. The 9p21 locus is therefore supposed to harbour a second melanoma susceptibility gene, which is supported by several loss of heterozygosity (LOH) studies in melanoma patient material.

There is published evidence of familial melanoma genes at 1p36 [17] and 1p22 [18] but no causal genes have so far been identified.


Other familial cancer susceptibility genes

Cancer susceptibility syndromes are characterized by the genetic inheritance of a high likelihood of developing a variety of tumors. Some of these syndromes, such as Li-Fraumeni syndrome, Xeroderma pigmentosum, and Hereditary retinoblastoma confer a significant risk of melanoma development. For more details, see the "Risk factors" section (http://www.mmmp.org/MMMP/import.mmmp?page=riskfactors.mmmp).


Lower risk susceptibility genes

The most well understood common melanoma susceptibility gene to date is the MC1R gene which is established as a determinant of susceptible phenotypes such as red hair [19], sun sensitivity in the absence of red hair [20], and freckles [21]. The gene is also a melanoma susceptibility gene [22].

Other pigmentary genes (tyrosinase, TYR; TYR related protein 1, TYRP1; agouti signalling protein, ASIP) have also more recently been identified as melanoma susceptibility genes [23].

Additional candidate polymorphisms for melanoma susceptibility are listed in the MMMP Biocard #32 entitled: Gene Polymorphisms and Melanoma Risk.


References

[1] Hemminki K et al, Familial and attributable risks in cutaneous melanoma: effects of proband and age. J Invest Dermatol 2003, 120:217-223.

[2] Aitken JF et al, Segregation analysis of cutaneous melanoma in Queensland. Genet Epidemiol 1998, 15:391-401.

[3] Kamb A et al, A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994, 264:436-440.

[4] Suzuki I et al, Binding of melanotropic hormones to the melanocortin receptor MC1R on human melanocytes stimulates proliferation and melanogenesis. Endocrinology 1996, 137:1627-1633.

[5] Goldstein AM et al, Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet 2007, 44:99-106.

[6] Goldstein AM et al, High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res 2006, 66:9818-9828.

[7] Kefford R et al, Genetic testing for melanoma. Lancet Oncol 2002, 3:653-654.

[8] Sviderskaya EV et al, p16/cyclin-dependent kinase inhibitor 2A deficiency in human melanocyte senescence, apoptosis, and immortalization: possible implications for melanoma progression. J Natl Cancer Inst 2003, 95:723-732.

[9] Randerson-Moor JA et al, A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. Hum Mol Genet 2001, 10:55-62.

[10] Rizos H et al, A melanoma-associated germline mutation in exon 1beta inactivates p14ARF. Oncogene 2001, 20:5543-5547.

[11] Orlow I et al, CDKN2A germline mutations in individuals with cutaneous malignant melanoma. J Invest Dermatol 2007, 127:1234-1243.

[12] Goldstein AM et al, Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations. J Natl Cancer Inst 2000, 92:1006-1010.

[13] Zuo L et al, Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genetics 1996, 12:97-99.

[14] Clark WH et al, Origin of familial malignant melanomas from heritable melanocytic lesions. 'The B-K mole syndrome'. Arch Dermatol 1978, 114:732-738.

[15] Bergman W, Gruis NA, Frants RR (1992) The Dutch FAMMM family material: Clinical and genetic data. Cytogenet Cell Genet 59:161-164.

[16] Bishop DT et al, Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst 2002, 94:894-903.

[17] Bale SJ et al, Mapping the gene for hereditary cutaneous malignant melanoma-dysplastic nevus to chromosome 1p. N Engl J Med 1989, 320:1367-1372.

[18] Gillanders E et al, Localization of a novel melanoma susceptibility locus to 1p22. Am J Hum Genet 2003, 73:301-313.

[19] Raimondi S et al, MC1R variants, melanoma and red hair color phenotype: a meta-analysis. Int J Cancer 2008, 122:2753-2760.

[20] Healy E et al, Melanocortin-1-receptor gene and sun sensitivity in individuals without red hair. Lancet 2000, 355:1072-1073.

[21] Bastiaens M et al, The melanocortin-1-receptor gene is the major freckle gene. Hum Mol Genet 2001, 10:1701-1708.

[22] Valverde P et al, The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma. Hum Mol Genet 1996, 5:1663-1666.

[23] Gudbjartsson DF et al, ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat Genetics 2008, Epub ahead of print.


Author(s)

Julia A Newton Bishop, University of Leeds, UK (update: May 2008)

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Melanoma News

3-MARKER PROGNOSTIC SIGNATURE
The expression of 3 biomarkers (NCOA3, SPP1, RGS1) independently predicts survival of patients with melanoma.
Source: Kashani-Sabet M, Clin Cancer Res 2009, 15:6987-92

5-MARKER PROGNOSTIC SIGNATURE
The expression of 5 biomarkers (ATF2, p21/WAF1, p16/INK4A, beta-catenin) independently predicts survival of patients with melanoma.
Source: Gould Rothberg BE, J Clin Oncol 2009, 27:5772-80

GMCSF AND ONCOLYTIC VIRUS
In a phase II clinical trial of a GMCSF-encoding oncolytic herpesvirus, promising tumor response (26%) and survival (52% at 2 years) rates were observed.
Source: Senzer NN, J Clin Oncol 2009, 27:5763-71

BRAF V600E AND MAP2
Oncogenic BRAF V600E induces expression of neuronal differentiation marker MAP2 in melanoma cells by promoter demethylation and downregulation of transcription repressor HES1.
Source: Maddodi N, J Biol Chem 2010, 285:242-54

ROLE OF Treg CELL DEPLETION
In a RET transgenic mouse model of melanoma, depletion of CD25+Foxp3+ regulatory T cells with anti-CD25 mAb does not prevent tumor development.
Source: Kimpfler S, J Immunol 2009, 183:6330-7

ELESCLOMOL PLUS PACLITAXEL
In a phase II randomized trial (n=81), elesclomol (oxidative stress inducer) improved the therapeutic activity of paclitaxel in terms of progression free survival.
Source: O'Day S, J Clin Oncol 2009, 27:5452-8

VITAMIN D3 SERUM LEVELS
In a cohort of 872 patients, serum levels of vitamin D3 correlated with primary melanoma thickness and patients' survival.
Source: Newton-Bishop JA, J Clin Oncol 2009, 27:5439-44

LOCOREGIONAL RELAPSE AND NODE STATUS
The rate of locoregional (including in transit) metastases in patients with tumor-positive sentinel node (n=141) and patients with palpable nodal involvement (n=178) is similar.
Source: Veenstra HJ, Ann Surg Oncol 2009, Epub ahead of print

NFKB IN UVEAL MELANOMA
NFKB is expressed in both primary and metastatic uveal melanoma and its inhibition shows therapeutic potential in vitro.
Source: Dror R, Invest Ophthalmol Vis Sci 2009, Epub ahead of print

CONJUNCTIVAL MELANOMA INCIDENCE
In a Swedish study, the incidence of conjunctival melanoma significantly increased during the period 1960 to 2005.
Source: Triay E, Br J Ophthalmol 2009, 93:1524-8

STAT3 INHIBITION
In a xenograft model, STAT3 inhibition by antisense technology suppresses melanoma growth in vivo.
Source: Yang L, Cancer Biol Ther 2009, 8:2065-72

HYPERTENSION DRUGS AND MELANOMA RISK
In a case-control study (cases=1272), the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was not significantly associated with melanoma risk.
Source: Koomen ER, Cancer Epidemiol 2009, 33:391-5

SKIN SELF-EXAMINATION (SSE)
In a retrospective study (n=321), SSE was associated with decreased tumor thickness (adjusted ratio, 0.75; 95% CI: 0.66-0.85 for ever versus never use).
Source: Pollitt RA, Cancer Epidemiol Biomarkers Prev 2009, 18:3018-23

SENTINEL NODE TUMOR BURDEN
The EORTC Melanoma Group has released the recommendations on the measurement of sentinel node tumor burden for prognostic purpose.
Source: van Akkooi AC, Eur J Cancer 2009, 45:2736-42

SURGERY FOR LIVER METASTASIS
A non randomized study (n=255) showed longer survival for patients undergoing radical versus non radical hepatic resection for melanoma metastasis.
Source: Mariani P, Eur J Surg Oncol 2009, 35:1192-7

BIOMARKERS OF RESPONSE TO IL-2
Serum VEGF and fibronectin can predict clinical response to high dose interleukin-2 (n=59).
Source: Sabatino M, J Clin Oncol 2009, 27:2645-52

RANTES + GP100 VACCINE
In a gene therapy model, vaccination with chemokine RANTES and melanoma antigen gp100 is more effective than with gp100 alone.
Source: Aravindaram K, Gene Ther 2009, 16:1329-39

MODIFIED HEPARINS
Modified heparins inhibit integrin alpha(IIb)beta(3) mediated adhesion of melanoma cells to platelets in vitro and in vivo.
Source: Zhang C, Int J Cancer 2009, 125:2058-65

CDKN2A MUTATION RATE IN FAMILIAL MELANOMA
An Italian study showed that CDKN2A is mutated in 68/204 (33%) families with at least two members affected with melanoma.
Source: Bruno W, J Am Acad Dermatol 2009, 61:775-82

D2-40 DOES NOT PREDICT SENTINEL NODE STATUS
D2-40/S-100 dual immunohistochemistry increases the sensitivity of detection of lymphatic invasion in melanoma but does not predict sentinel lymph node involvement (n=27).
Source: Petitt M, J Am Acad Dermatol 2009, 61:819-28

D2-40 PROGNOSTIC AND PREDICTIVE VALUE
Expression of D2-40 (lymphatic invasion biomarker) in primary melanoma predicts sentinel lymph node status and correlates with survival (n=60).
Source: Petersson F, J Cutan Pathol 2009, 36:1157-63

ROLE OF MMP-13
Stromal expression of matrix metalloproteinase-13 is required for melanoma invasion and metastasis, as demonstrated in a gene knockout model.
Source: Zigrino P, J Invest Dermatol 2009, 129:2686-93

KIT EXPRESSION AND MUTATION
In a series of 173 melanomas, eighty-two percent (12 of 14) of cases positive for KIT mutation showed KIT expression in more than 50% of the cells.
Source: Torres-Cabala CA, Mod Pathol 2009, 22:1446-56

IGFBP7 AND MUTATED BRAF
In melanomas carrying oncogenic mutated BRAF, IGFBP7 is epigenetically silenced; systemically administered recombinant IGFBP7 suppresses the growth of BRAF-positive primary tumors in xenografted mice.
Source: Wajapeyee N, Mol Cancer Ther 2009, 8:3009-14

ADJUVANT IFN FOR UVEAL MELANOMA
In a non randomized trial, low dose adjuvant interferon alpha provides no survival benefit to patients with high risk uveal melanoma.
Source: Lane AM, Ophthalmology 2009, 116:2206-12

PHORBOL ESTER PARADOXICAL ACTIVITY
The tumor-promoting phorbol ester TPA inhibits melanoma growth by inactivation of STAT3 through a PKC activated tyrosine phosphatase.
Source: Oka M, J Biol Chem 2009, 284:30416-23

ADAM10 and L1-CAM
ADAM10 is overexpressed in metastatic as compared to primary melanoma; it is associated with melanoma invasiveness and releases L1-CAM, which is responsible for chemoresistance.
Source: Lee SB, J Invest Dermatol 2009, Epub ahead of print

EAPB0203 PRECLINICAL ACTIVITY
In a xenografted mouse in vivo model, EAPB0203 (a novel imidazo[1,2-a]quinoxaline derivative) is more effective than fotemustine against melanoma.
Source: Khier S, Eur J Pharm Sci 2009, Epub ahead of print

RAPAMYCIN PRECLINICAL ACTIVITY
In a mouse syngeneic model, mTOR inhibitor rapamycin inhibits lung metastasis through downregulation of alpha V integrin expression and upregulation of apoptosis signaling.
Source: Yang Z, Cancer Sci 2009, Epub ahead of print

NESTIN, SOX9 AND SOX10
SOX9 and SOX10 are highly expressed in melanoma and seem to have a regulatory role in Nestin expression; nestin and SOX9 may be negative prognostic markers.
Source: Bakos RM, Exp Dermatol 2009, Epub ahead of print

INDUCIBLE NITRIC OXIDE SYNTHASE (iNOS)
In patients with uveal melanoma (n=90), iNOS expression is not an independent prognostic factor at multivariable survival analysis.
Source: Johansson CC, Int J Cancer 2009, Epub ahead of print

CAFFEIC ACID PHENETYL ESTER (CAPE)
In an mouse melanoma model, CAPE shows anti-melanoma activity in vivo.
Source: Kudugunti SK, Invest New Drugs 2009, Epub ahead of print

BRAF, NFAT AND COX2
Oncogenic BRAF V600E activates NFAT2 and NFAT4 via MEK/ERK signaling, which leads to COX2 upregulation in metastatic melanoma.
Source: Flockhart RJ, Br J Cancer 2009, 101:1448-55

US-GUIDED FNAC AND SNB
Ultrasound-guided fine needle aspiration cytology of sentinel nodes is highly accurate and can lead to significant reduction of SN biopsy procedures.
Source: Voit CA, J Clin Oncol 2009, 27:4994-5000

PARKINSON DISEASE AND MELANOMA
A cohort study (n=157,036) showed a significant association between a positive family history of melanoma and risk of PD (multivariate relative risk = 1.85; 95%CI = 1.2-2.8).
Source: Gao X, Neurology 2009, 73:1286-91

ADH-1 FOR ISOLATED LIMB INFUSION
In a phase I trial (n=16), isolated limb infusion with melphalan combined with ADH-1 (a N-cadherin inhibitor) yielded a high complete response rate (50%).
Source: Beasley GM, Cancer 2009, 115:4766-74

PHOTOACUSTIC FLOW CYTOMETRY
Two color photoacustic flow cytometry with diode laser can reliably detect up to 1 melanoma cell per ml, which can be relevant for searching circulating melanoma cells.
Source: Galanzha EI, Cancer Res 2009, 69:7926-34

SNF5 TUMOR SUPPRESSOR GENE
SNF5, the core subunit of SWI/SNF complex, is downregulated in melanoma, which correlates with poor patients' prognosis; in vitro, SNF5 knockdown causes chemoresistance.
Source: Lin H, Clin Cancer Res 2009, 15:6404-11

MC1R VARIANTS AND MELANOMA RISK
In this case-control study (n=1,185), red hair color (RHC) and non-RHC melanocortin receptor 1 (MC1R) variants were the major contributors for melanoma risk in the German and Spanish population, respectively.
Source: Scherer D, Int J Cancer 2009, 125:1868-75

YM155 PHASE II TRIAL
In this trial (n=34), YM155 (a survivin inhibitor) failed to demonstrate significant anti-melanoma activity.
Source: Lewis KD, Invest New Drugs 2009, Epub ahead of print

MELANOMA THICKNESS TRENDS
An analysis of the SEER database revealed that over the past 20 years the proportion of melanoma in situ has increased, while thick melanoma proportion has remained substantially unchanged.
Source: Criscione VD, J Invest Dermatol 2009, Epub ahead of print

MIR-15B AND MELANOMA
MicroRNA-15b represents is an independent prognostic factor and increases melanoma cell proliferation and survival.
Source: Satzger I, Int J Cancer 2009, Epub ahead of print

LACUNARITY ANALYSIS
Lacunarity analysis (a simple statistical measure used for the analysis of fractal and multi-scaled images) of digitized dermoscopic images could help clinicians to diagnose cutaneous melanoma.
Source: Gilmore S, PLoS One 2009, 4:e7449

CD40L PLUS TLR AGONISTS
In an in vivo mouse melanoma model, nanoparticle-delivered multimeric soluble CD40L DNA show synergistic therapeutic effect combined with toll-like receptor (TLR) agonists.
Source: Stone GW, PLoS One 2009, 4:e7334

EXCISION MARGINS META-ANALYSIS
According to a Cochrane meta-analysis of randomized controlled trials, primary melanoma excision margins (wide vs narrow) do not affect patients' overall survival.
Source: Sladden MJ, Cochrane Database Syst Rev 2009, CD004835

WARNING ON PI-103
In an in vivo mouse melanoma model, PI-103 - a dual PI3K (p110alpha)/mTOR inhibitor - has no synergistic effect with sorafenib (BRAF/CRAF inhibitor), may cause immunosuppression, inhibit apoptosis and ultimately favor tumor growth.
Source: López-Fauqued M, Int J Cancer 2009, Epub ahead of print

KIT AND HIF-1 alpha
c-Kit mutant melanocytes show activation of PI3K pathway that is not sufficient for transformation; combination with HIF-1 forced expression leads to Ras/Raf/Mek/Erk pathway activation and melanocyte transformation.
Source: Monsel G, Oncogene 2009, Epub ahead of print

TYRO3 AND MITF
The receptor protein tyrosine kinase TYRO3 is an upstream regulator of MITF expression; its knockdown shows antimelanoma activity in a xenograft model and acts as a chemosensitizer.
Source: Zhu S, Proc Natl Acad Sci USA 2009, 106:17025-30

ROR2 AND WNT5A
The orphan tyrosine kinase receptor ROR2 mediates Wnt5A signaling in metastatic melanoma and its silencing shows antimelanoma activity in an in vivo mouse model.
Source: O'Connell MP, Oncogene 2009, Epub ahead of print

PAEP FUNCTIONAL CHARACTERIZATION
Silencing of PAEP (progestagen-associated endometrial protein) shows anti-melanoma activity in a xenograft model.
Source: Ren S, J Cell Mol Med 2009, Epub ahead of print

EPAC AND MIGRATION
Silencing of EPAC (an effector molecule of cAMP) inhibits melanoma cell migration.
Source: Baljinnyam E, Am J Physiol Cell Physiol 2009, 297:C802-13

MT1 MELATONIN RECEPTOR
MT1 melatonin receptor is expressed in primary melanoma and correlates with tumor thickness.
Source: Danielczyk K, Anticancer Res 2009, 29:3887-95

MITF AND BRAF V600E
In an in vitro model of human melanoma, silencing of MITF synergically increases the cytotoxic effect of BRAF V600E silencing.
Source: Kido K, Cancer Sci 2009, 100:1863-9

TREMELIMUMAB + VACCINE
In a phase I-II trial (n=16), MART-1 peptide-pulsed dendritic cells and tremelimumab resulted in objective and durable tumor responses at the higher range of the expected response rate with either agent alone.
Source: Pandha HS, Clin Cancer Res 2009, 15:6158-66

ONCOLYTIC REOVIRUS
In a murine in vivo melanoma model, oncolytic Reovirus increases the antitumor activity of cisplatin.
Source: Pandha HS, Clin Cancer Res 2009, 15:6158-66

ADJUVANT RADIOTHERAPY
In a retrospective study (n=77), adjuvant radiotherapy after lymph node dissection yields a high locoregional control rate, although distant metastases remain the major cause of mortality.
Source: Conill C, Clin Transl Oncol 2009, 11:688-93

SNB RECOMMENDATIONS
The European Association of Nuclear Medicine (EANM) and the EORTC have jointly released the recommendations for sentinel node biopsy in melanoma.
Source: Chakera AH, Eur J Nucl Med Mol Imaging 2009, 36:1713-42

HSV2 MUTANT DeltaPK
The growth defective herpes simplex virus type 2 mutant deltaPK shows significant antitumor activity in a xenograft model of human melanoma.
Source: Colunga AG, Gene Ther 2009, Epub ahead of print

MELANOMA INHIBITORY ACTIVITY (MIA)
MIA protein is highly expressed and secreted by malignant melanoma cells and plays an important role in melanoma development, progression and tumor cell invasion.
Source: Schmidt J, Int J Cancer 2009, 125:1587-94

CAVEOLIN-1
In an in vitro model, caveolin-1 promotes human melanoma progression as indicated by enhanced proliferation, migration, invasion and foci formation in semisolid medium.
Source: Felicetti F, Int J Cancer 2009, 125:1514-22

ARTEMISININ
Artemisinin (an antimalarial drug) reduces human melanoma cell migration by downregulating alpha V beta 3 integrin and metalloproteinase-2.
Source: Buommino E, Invest New Drugs 2009, 27:412-8

FAMILIAL MELANOMA IDENTIFICATION
In this review article, the Authors found that CDKN2A germline mutations (responsible for about 2% of melanomas) are more frequent in individuals with 3 or more primary invasive melanomas.
Source: Leachman SA, J Am Acad Dermatol 2009, 61:677.e1-14

MOESIN AND INVASION
In a 3D model, moesin orchestrates cortical polarity of melanoma cells, which may drive tumor vertical migration instead of superficial spreading.
Source: Estecha A, J Cell Sci 2009, 122(Pt 19):3492-501

MELANOMA REPROGRAMMING
Mouse melanoma cells can be reprogrammed into induced pluripotent stem cells, which suggests that cancer cells remain susceptible to transcription factor-mediated reprogramming.
Source: Utikal J, J Cell Sci 2009, 122(Pt 19):3502-10

PET VERSUS CT FOR STAGING
In a prospective comparison (n=251), PET and CT were equivqlent in upstaging; treatment changed in 19% of patients (79% using both scans, 17% only by PET, 4% only by CT).
Source: Bastiaannet E, J Clin Oncol 2009, 27:4774-80

WT1 AND MELANOMA DIAGNOSIS
Wilms' tumor 1 (WT1) protein expression is not helpful for the diagnosis of skin melanoma in a series of 45 cases.
Source: Rosner K, J Cutan Pathol 2009, 36:1077-82

SILIBININ AND MITOMYCIN-C
In an in vitro model, silibinin (a flavonoid from plant-derived silymarin) protects melanoma cells from mitomycin-C cytotoxicity.
Source: Jiang YY, J Pharmacol Sci 2009, 111:137-46

MELANOMA SPONTANEOUS REGRESSION
A review of the literature on the phenomenon of metastatic melanoma spontaneous regression reveals a total of 76 reported cases since 1866.
Source: Kalialis LV, Melanoma Res 2009, 19:275-82

ESTROGENS AND TUMOR THICKNESS
A retrospective Dutch study (n=687), use of estrogens is not associated with primary melanoma thickness.
Source: Koomen ER, Melanoma Res 2009, 19:327-32

GALLIUM COMPLEX KP46
In an in vitro model, gallium complex KP46 shows strong anti-melanoma activity.
Source: Valiahdi SM, Melanoma Res 2009, 19:283-93

GALECTIN-3 AND PROGNOSIS
Serum levels of galectin-3 may have an independent prognostic value in stage III-IV melanoma patients.
Source: Vereecken P, Melanoma Res 2009, 19:316-20

LAMININ-421 AND MIGRATION
In an in vitro model, antibody blockage of lymphatic endothelial cell laminin-421 inhibits migratory ability of melanoma cells.
Source: Saito N, Pigment Cell Melanoma Res 2009, 22:601-10

FOLATE RECETOR ALPHA AND METHOTREXATE
In an in vitro model, folate receptor mediated sequestration of methotrexate (MTX) in melanosomes may be targeted to overcome melanoma resistance to MTX.
Source: Sánchez del Campo L, Pigment Cell Melanoma Res 2009, 22:588-600

CREB AND CYR61
In an in vivo model, stable silencing of cAMP-response element-binding protein (CREB) expression in human metastatic melanoma cell lines suppresses tumor growth and experimental metastasis by downregulating cysteine-rich protein 61 (CCN1/CYR61) expression.
Source: Dobroff AS, J Biol Chem 2009, 284:26194-206

INDUCING MELANOMA DIFFERENTIATION
Induction of terminal differentiation in melanoma cells by downregulation of beta-amyloid precursor protein (APP) impairs cell proliferation and improves chemosensitivity.
Source: Bothelho MG, J Invest Dermatol 2009, Epub ahead of print

MART1 + P40 VACCINE
In a pilot study (n=14), vaccination with Melan-A/Mart-1 peptide and Klebsiella protein P40 as an adjuvant induced ex vivo detectable tumor antigen specific T cell responses in 6 patients.
Source: Lienard D, J Immunother 2009, Epub ahead of print

NEW MELANOMA ANTIGEN MELOE-2
An additional open reading frame (ORF) on meloe cDNA encodes a new melanoma antigen, MELOE-2, recognized by melanoma-specific T cells in the HLA-A2 context.
Source: Godet Y, Cancer Immunol Immunother 2009, Epub ahead of print

LOSARTAN PRECLINICAL ACTIVITY
In an in vivo murine melanoma model, inhibition of angiotensin II receptor 1 (AT1) by losartan limits tumor angiogenesis and growth.
Source: Otake AH, Cancer Chemother Pharmacol 2009, Epub ahead of print

EARLY VS LATE ONSET MELANOMA
Using the SEER database, investigators found epidemiological differences between early and late onset melanomas.
Source: Anderson WF, Cancer 2009, 115:4176-85

CAR-T CELLS PRECLINICAL ACTIVITY
In a xenograft model, immunotherapy of metastatic human melanoma using chimeric antigen receptors (CAR) engineered ganglioside GD2-specific T cells increases the survival of tumor-bearing animals.
Source: Yvon E, Clin Cancer Res 2009, 15:5852-60

GPIbalpha AND METASTASIS
In a mouse in vivo model, platelet glycoprotein Ib alpha (GPIbalpha) inhibition promotes melanoma metastasis.
Source: Erpenbeck L, J Invest Dermatol 2009, Epub ahead of print

PET META-ANALYSIS
A meta-analysis of 24 sudies shows that (18)F-FDG positron emission tomography is not useful to detect regional metastases, but could be useful to detect distant metastases.
Source: Jiménez-Requena F, Eur J Nucl Med Mol Imaging 2009, Epub ahead of print

ERBB4 MUTATIONS
ERBB4/HER4 mutations were found in 19% of individuals with melanoma (n=79); melanoma cells expressing mutant ERBB4 had reduced cell growth after shRNA-mediated knockdown of ERBB4 or treatment with ERBB inhibitor lapatinib.
Source: Prickett TD, Nat Genet 2009, 41:1127-32

SYNTAXIN-7
Using an antibody-based proteomics approach, investigators found that Syntaxin-7 (STX7) is selectively expressed in melanocytes and melanoma.
Source: Strömberg S, J Proteome Res 2009, 8:1639-46

OBESITY AND PROGRESSION
In a mouse melanoma model, obesity enhances melanoma growth in vivo, possibily by upregulation of VEGF pathways.
Source: Brandon EL, Cancer Biol Ther 2009, Epub ahead of print

MENADIONE AND SIAH2
Menadione is a specific inhibitor of SIAH2 ubiquitin ligase; in vivo, it inhibits the growth of xenograft melanoma.
Source: Shah M, Pigment Cell Melanoma Res 2009, 22:799-808

POSITIVE NON-SENTINEL LYMPH NODE (NSLN)
Among node-positive melanoma patients (n=429), presence of a positive NSLN is a highly significant poor prognostic sign, which warrants completion lymph node dissection after a positive SLN.
Source: Ghaferi AA, Ann Surg Oncol 2009, 16:2978-84

DNA REPAIR GENE POLYMORPHISMS
A meta-analysis (cases=4,195) reveals that XPD/ERCC2 single nucleotide polymorphism rs13181 is associated with risk of melanoma development.
Source: Mocellin S, Carcinogenesis 2009, 30:1735-43

MELANOSOMES AND CHEMORESISTANCE
In an vitro model, melanosome dynamics (e.g. biogenesis, density, status and structural integrity) modulates the drug resistance of melanoma cells.
Source: Chen KG, J Natl Cancer Inst 2009, 101:1259-71

PAR1, PAFR AND METASTASIS
Protease-activated receptor-1 (PAR1) and platelet-activating factor receptor (PAFR) induce melanoma cell adhesion molecule (MCAM/MUC18) expression and favor melanoma metastasis.
Source: Melnikova VO, J Biol Chem 2009, 284:28845-55

FKBP51 AND RADIOSENSITIZATION
Inhibition of FK506-binding protein 51 (FKBP51, an immunophilin with isomerase activity) greatly enhances radiotherapy efficacy in a xenograft melanoma model.
Source: Romano S, Cell Death Differ 2009, Epub ahead of print

NEW TNM STAGING SYSTEM
The latest version of the AJCC TNM staging system for cutaneous melanoma has been released (based on 30,946 cases). Main changes: 1) mitotic rate (added); 2) Clark level (removed). Main limit: no molecular biomarker has been implemented. The details are available in the TNM Staging section of the MMMP website.
Source: Balch CM, J Clin Oncol 2009, Epub ahead of print

SYNDECANS AND WNT5A
Heparan sulfate proteoglycans syndecan 1 and 4 are key components of the Wnt5A autocrine signaling, the activation of which leads to increased metastasis of melanoma.
Source: O'Connell MP, J Biol Chem 2009, 284:28704-12

US SCAN FOR PRIMARY THICKNESS
In a small study (n=53), preoperative 10-MHz sonography could discriminate thick (> 1 mm) from thin melanomas with promising accuracy.
Source: Vilana R, AJR Am J Roentgenol 2009, 193:639-43

CHEST X-RAY QUESTIONED
In 248 patients undergoing SNB, preoperative chest X-ray did not identify pulmonary metastasis and did not change planned treatment strategies.
Source: Vermeeren L, J Surg Res 2009, Epub ahead of print

NOVEL PET RADIOTRACER
A new melanoma positron emission tomography (PET) imaging radiotracer has been developed with high tumor-to-body contrast ratio and rapid renal clearance.
Source: Greguric I, J Med Chem 2009, 52:5299-302

4-HYDROXYCOUMARIN PRECLINICAL ACTIVITY
Anticoagulat 4-hydroxycoumarin (4-HC) resulted effective against melanoma in an in vivo mouse model.
Source: Salinas-Jazmín N, Cancer Chemother Pharmacol 2009, Epub ahead of print

LUMCORIN AND MIGRATION
In an in vitro study, lumcorin (a peptide derived from human lumican) inhibits melanoma migration.
Source: Zeltz C, FEBS Lett 2009, 583:3027-32

MELANOMA DETECTION ABILITY
An Australial study showed that the ability of skin cancer clinics to detect melanoma is similar to that of mainstream general practice and worse than specialist practice.
Source: Hansen C, J Am Acad Dermatol 2009, 61:599-604

WHOLE BRAIN RADIOTHERAPY (WBRT)
A small retrospective study (n=51) suggests that patients with brain metastases from melanoma receiving WBRT alone may benefit from dose escalation beyond 10x3 Gy.
Source: Rades D, Int J Radiat Oncol Biol Phys 2009, Epub ahead of print

MELANOMA EPIDEMIC
In a study conduced in East Anglia, melanoma incidence increased from 9.39 to 13.91 cases/100,000/year, while overall mortality only increased from 2.16 to 2.54 cases/100,000/year.
Source: Levell NJ, Br J Dermatol 2009, 161:630-4

DTIC +/- PF3512676
In a phase II-III RCT, the addition of CpG oligodeoxynucleotide PF-3512676 does not add significant tumor response advantage to dacarbazine alone.
Source: Weber J, Cancer 2009, 115:3944-54

HLA MOLECULES EXPRESSION
Investigators have assessed the expression of HLA class I and II molecules in a large panel of human melanoma cell lines.
Source: Mendez R, Cancer Immunol Immunother 2009, 58:1507-15

ADHESION MOLECULES EXPRESSION
Investigators have assessed the expression of adhesion molecules and ligands for receptors involved in cell-mediated cytotoxicity in a large panel of human melanoma cell lines.
Source: Casado JG, Cancer Immunol Immunother 2009, 58:1517-26

IPILIMUMAB PLUS BUDESONIDE
A phase II RCT showed that budesonide (an oral non-absorbed corticostroid) does not prevent dyarrhea in patients taking anti-CTLA4 ipilimumab.
Source: Weber J, Clin Cancer Res 2009, 15:5591-8

CXCL8 AND ITS RECEPTORS
In a human melanoma preclinical model, CXCL8 induces cell proliferation and angiogenesis; inhibition of its receptors (CXCR1 and CXCR2) shows promising therapeutic potential.
Source: Gabellini C, Eur J Cancer 2009, 45:2618-27

NBDHEX PRECLINICAL ACTIVITY
6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) induces JNK activation and apoptosis, and appears effective against human melanoma in both in vitro and in vivo preclinical models.
Source: Pellizzari Tregno F, Eur J Cancer 2009, 45:2606-17

TIL AND SENTINEL NODE STATUS
An Italian study (n=404) showed a significant correlation between the presence of tumor infiltrating lymphocytes (TIL) and sentinel node status.
Source: Mandalà M, Eur J Cancer 2009, 45:2537-45

IMIDAZO[1,2-a]QUINOXALINE ANALOGUES
New imidazo[1,2-a]quinoxaline analogues have been synthesized that inhibit human melanoma growth in vitro more than imiquimod and fotemustine.
Source: Deleuze-Masquefa C, Eur J Med Chem 2009, 44:3406-11

PD1 BLOCKADE
In an in vitro human model, programmed death-1 (PD-1) blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells.
Source: Wang W, Int Immunol 2009, 21:1065-77

OBATOCLAX AND TUNICAMYCIN
Human melanoma cells under endoplasmic reticulum stress (induced by tunicamycin) are more susceptible to apoptosis induced by the BH3 mimetic obatoclax.
Source: Jiang CC, Neoplasia 2009, 11:945-55

US-BASED THICKNESS PREDICTION
A review of the literature showed that high resolution ultrasound imaging correctly predicts excision margins in 72% of cases.
Source: Machet L, Ultrasound Med Biol 2009, 35:1411-20

PIGMENTATION GENE POLYMORPHISMS
In an Australian study, multiple pigmentation gene polymorphisms account for 12% of risk of skin melanoma.
Source: Duffy DL, J Invest Dermatol 2009, Epub ahead of print

RET G691S POLYMORPHISM
This germline RET polymorphism is frequently found in melanoma and responds to GDNF (glial cell line-derived neurotrophic factor), which promotes melanoma progression.
Source: Narita N, Oncogene 2009, 28:3058-68

ADJUVANT RADIOTHERAPY
Patients with clinically advanced, high-risk, lymph node-metastatic melanoma may benefit from adjuvant radiotherapy.
Source: Agrawal S, Cancer 2009, Epub ahead of print

MCL-1 AND ABT-737
In an in vitro melanoma models, RNA silencing of Mcl-1 enhances apoptosis induced by ABT-737 (a small-molecule inhibitor of Bcl-2, Bcl-XL and Bcl-W).
Source: Keuling AM, PLoS One 2009, 4:e6651

PAR-1 AND CONNEXIN-43
Protease-activated receptor-1 (PAR-1) promotes melanoma progression by enhancing connexin-43 expression.
Source: Villares GJ, Cancer Res 2009, 69:6730-7

DEK: A CHEMORESISTANCE ONCOGENE
Inhibition of DEK (a gene often overexpressed in advanced melanoma due to gain of chromosome 6p) expression by RNA interference restores melanoma sentitivity to chemotherapy agents.
Source: Khodadoust MS, Cancer Res 2009, 69:6405-13

NKG2D LIGANDS AND PROGNOSIS
At multivariable survival analysis, serum levels of ULBP2 (a NKG2D ligand able to neutralize cytotoxic lymphocytes) correlate with the prognosis of melanoma patients (n=200).
Source: Paschen A, Clin Cancer Res 2009, 15:5208-15

SNB IN YOUNG ADULTS
In an Australian study, SLN positivity rate was higher in young melanoma patients (n=55) than in adults (25% vs 17%), while non-SLN positivity and melanoma-specific death rates were lower.
Source: Howman-Giles R, Ann Surg Oncol 2009, Epub ahead of print

CD28/CTLA4/ICOS SNPs
In a large German study (cases=763), the SNPs of three immune related genes (CD28, CTLA4 and ICOS) do not appear to be associated with melanoma risk or prognosis.
Source: Bouwhuis MG, Cancer Immunol Immunother 2009, Epub ahead of print

METRONOMIC CYCLOPHOSPHAMIDE (mCP)
In a small retrospective study (n=13) of oral mCP in elderly patients with unresectable melanoma, the control rate (partial + stable disease) was 46% and the median survival was 8 months.
Source: Borne E, Invest New Drugs 2009, Epub ahead of print

PI3K/AKT, mTOR AND BRAF
Co-inhibition of PI3K/AKT and BRAF (but not mTOR) synergically inhibits human uveal melanoma cells proliferation in vitro.
Source: Babchia N, Invest Ophthalmol Vis Sci 2009, Epub ahead of print

PIGMENT EPITHELIUM-DERIVED FACTOR (PEDF)
In a mouse ocular melanoma model, constitutive overexpression of PEDF inhibits tumor growth and metastasis.
Source: Yang H, Invest Ophthalmol Vis Sci 2009, Epub ahead of print

dsRNA MIMIC TO KILL MELANOMA
In a mouse model, polyinosine-polycytidylic acid - a double strand RNA mimic - induces melanoma autophagy downstream of an exacerbated endosomal maturation program.
Source: Tormo D, Cancer Cell 2009, 16:103-14

FISH AND MELANOMA DIAGNOSIS
By detecting chromosomal alterations, fluorescence in situ hybridization (FISH) can be helpful for the diagnosis of melanoma.
Source: Gerami P, Am J Surg Pathol 2009, 33:1146-56

MICROMORPHOMETRY OF SLN METASTASIS
In 116 patients with tumor-positive sentinel lymph nodes (SLN), invasion depth and diameter of the metastasis correlate best with additional nodal disease; invasion depth best predicts overall survival.
Source: van der Ploeg IM, Ann Surg 2009, 250:301-4

SPARC AND OCULAR MELANOMA
SPARC (secreted protein acidic and rich in cysteine) is expressed in human uveal melanoma and its abrogation reduces tumor cell proliferation in vitro.
Source: Maloney SC, Anticancer Res 2009, 29:3059-64

OCULAR MELANOMA METASTASIS
In a large series of ocular melanomas (n=8033), the main factors predictive of metastasis by multivariate analysis included age, ciliary body location, increasing tumor diameter and thickness.
Source: Shields CL, Arch Ophthalmol 2009, 127:989-98

MELANOMA INCIDENCE FROM CHOROIDAL NEVUS
An analysis of 2514 consecutive cases of choroidal nevi showed that transformation into melanoma occurs in 2%, 9% and 13% of eyes at 1, 5 and 10 years, respectively.
Source: Shields CL, Arch Ophthalmol 2009, 127:981-7

NECK LYMPH NODE DISSECTION AND RADIOTHERAPY
In a retrospective study, regional disease control rate is higher with extended (vs selective) neck dissection and with (vs without) adjuvant radiotherapy.
Source: Hamming-Vrieze O, Arch Otolaryngol Head Neck Surg 2009, 135:795-800

VITAMIN D RECEPTOR (VDR) SNP
In a Polish study (n=763), four VDR signle nucleotide polymorphisms (rs1544410, rs731236, rs10735810, rs4516035) are not associated with melanoma risk.
Source: Gapska P, Cancer Epidemiol 2009, 33:103-7

RENAL TRANSPLANT AND MELANOMA
In an Australian study, immunosuppression after kidney transplant increases the risk of melanoma.
Source: Vajdic CM, Cancer Epidemiol Biomarkers Prev 2009, 18:2297-303

PHASE I TRIAL OF INO-1001 + TMZ
Myelosuppression and elevation of transaminases are the dose-limiting toxicities of INO-1001 (a PARP inhibitor) + temozolomide in patients with unresectable stage III-IV melanoma.
Source: Bedikian AY, Cancer Invest 2009, 27:756-63

ROLE OF TEM-8
In a mouse melanoma model, tumor growth is enhanced in tumor endothelial marker 8 (TEM8)-deficient animals.
Source: Cullen M, Cancer Res 2009, 69:6021-6

METRONOMIC THERAPY
Combination metronomic chemotherapy regimens are an effective treatment of advanced human melanoma metastasis in immunodeficient mice.
Source: Cruz-Munoz W, Clin Cancer Res 2009, 15:4867-74

AUTOLOGOUS VACCINE AND SURVIVAL
In a small trial (n=47), 2,4-dinitrophenyl-conjugated autologous melanoma cell vaccine is capable of inducing effective antimelanoma CD4 T-cell activity associated with improved survival.
Source: Lotem, M, Clin Cancer Res 2009, 15:4968-77

TARGETED RADIONUCLIDE THERAPY
In a preclinical study, the quinoxaline derivative ICF01012 is selectively uptaken by malignant cells and is active against murine and human melanoma.
Source: Bonnet-Duquennoy M, Int J Cancer 2009, 125:708-16

MICRORNA-155
In vitro, mir-155 ectopic expression inhibits melanoma cell proliferation and promotes apoptosis.
Source: Levati L, Int J Oncol 2009, 35:393-400

RIG-I AND MDA-5
Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated antigen 5 (MDA-5) helicases sense viral RNA in infected cells and initiate antiviral responses; in human melanoma cells they also initiate a proapoptotic signaling pathway independently of type I interferons (IFN).
Source: Besch R, J Clin Invest 2009, 119:2399-411

LYMPHOSCINTIGRAPHY AND SLN STATUS
A significant association exists between the lymphoscintigraphy pattern of 88 patients with melanoma and the status of their sentinel lymph nodes (SLN).
Source: Solari N, Melanoma Res 2009, 19:243-51

PHYSICAL ACTIVITY AND MELANOMA RISK
In a Canadian study, occupational physical activity is associated with melanoma risk: it is unclear whether sunlight exposure can explain these findings.
Source: Lee TK, Melanoma Res 2009, 19:260-6

PHASE II TRIAL OF DHA-PACLITAXEL
The efficacy of docosahexaenoic acid (DHA)-paclitaxel as a first-line therapy for metastatic melanoma does not exceed that seen with other single-agent chemotherapies such as dacarbazine.
Source: Homsi J, Melanoma Res 2009, 19:238-42

NUCLEAR PTEN
In an in vitro melanoma model, nuclear PTEN is involved in G2 progression possibly through the modulation of CDC2.
Source: Jacob AI, Melanoma Res 2009, 19:203-10

GERM-LINE MDM2 MUTATION
In a small series of patients with melanoma (n=28), MDM2 polymorphism G309 may be responsible for MDM2 overexpression and p53 suppression.
Source: Gluck I, Melanoma Res 2009, 19:199-202

DESATINIB AND KIT-MUTATANT MELANOMA
Two patients with advanced melanoma harboring the c-KIT L576P mutation (the most common KIT mutation in mucosal, acral lentiginous and chronically sun-damaged melanomas) showed >50% tumor response to tyrosine kinase receptor inhibitor desatinib.
Source: Woodman SE, Mol Cancer Ther 2009, 8:2079-85

NEW MELANOMA RISK LOCUS
In a large European study based on 317K tagging SNP, genome-wide screening identified the 9p21 locus as a novel melanoma risk biomarker.
Source: Bishop DT, Nat Genet 2009, 41:920-5

PDGFR-alpha GENE THERAPY
In a mouse melanoma model, platelet-derived growth factor receptor alpha gene therapy inhibits tumor growth in vivo.
Source: Faraone D, Neoplasia 2009, 11:732-42

PD0325901 PRECLINICAL ACTIVITY
PD0325901, a novel MEK inhibitor, inhibits human melanoma growth in vivo (xenograft model) independently of BRAF mutational status.
Source: Ciuffreda L, Neoplasia 2009, 11:720-31

3D SKIN ANALYSIS
In a small series (cases = 11), statistical analysis of 3D skin surface disruptions may help differentiation between melanoma and benign lesions.
Source: Ding Y, Skin Res Technol 2009, 15:262-70

TALABOSTAT TRIAL
In a phase II trial of cisplatin + talabostat (an immunostimulatory dipeptidyl peptidase inhibitor) in stage IV melanoma patients, no advantage was observed over cisplatin alone.
Source: Eager RM, BMC Cancer 2009, 9:263

BMP-7 INHIBITION
Bone morphogenetic protein 7 induces mesenchymal-to-epithelial transition in melanoma cells, leading to inhibition of metastasis.
Source: Na YR, Cancer Sci 2009, Epub ahead of print

14-3-3 PROTEIN ISOFORM SIGMA
Epigenetic silencing of 14-3-3sigma might contribute to melanoma progression via loss of cell cycle control, impaired cell senescence and support to migration.
Source: Schultz J, Mol Cancer 2009, 8:53

PLEXIN-B1 AND BRAF
Plexin B1 is repressed by oncogenic B-Raf signaling and functions as a tumor suppressor in human melanoma cells.
Source: Argast GM, Oncogene 2009, 28:2697-709

NRG1/ERBB3 PATHWAY
Neuregulin (NRG) signaling through the receptor tyrosine kinase ERBB3 may inhibit melanocyte differentiation and promote cell migration and proliferation.
Source: Buac K, Pigment Cell Melanoma Res 2009, Epub ahead of print

SYNDECAN-2 AND MIGRATION
Syndecan-2, a transmembrane heparan-sulfate proteoglycan whose expression is enhanced by fibroblasts growth factor-2 (FGF2), stimulates the migratory potential of melanoma cells.
Source: Lee JH, J Biol Chem 2009, Epub ahead of print

EMD 273063 (hu14.18-IL2)
In a phase I-II trial (n=9), a humanized anti-GD2 monoclonal antibody fused to interleukin-2 increased tumor infiltration by T-cells but did not induced tumor response in stage IV melanoma patients.
Source: Ribas A, J Transl Med 2009, 7:68

S-100B AND PROGNOSIS
In patients with stage III melanoma (n=56), serum S100B correlates with disease free survival at multivariable analysis.
Source: Kruijff S, Ann Surg Oncol 2009, Epub ahead of print

ADH-1 + ISOLATED LIMB PERFUSION (ILP)
Systemic ADH-1 (a cyclic pentapeptide that disrupts N-cadherin adhesion complexes) shows synergistic activity with melphalan ILP in patients with in transit melanoma metastases.
Source: Beasley GM, Cancer 2009, Epub ahead of print

CEACAM1 AND PROGNOSIS
In patients with melanoma (n=64), serum CEACAM1 levels are a negative prognostic factor at multivariable survival analysis.
Source: Markel G, Cancer Immunol Immunother 2009, Epub ahead of print

RANTES + GP100 VACCINE
In a mouse in vivo melanoma model, vaccination with chemokine RANTES and gp100 is more effective than gp100 alone.
Source: Aravindaram K, Gene Ther 2009, Epub ahead of print

TIMP-2, NFKB AND IL-8
Tissue inhibitor of metalloproteinase-2 (TIMP-2) induces nuclear factor kappa B (NFkB) activity which in turn activates interleukin-8 (IL-8) expression.
Source: Sun J, J Mol Signal 2009, 4:4

EM011 PRECLINICAL ACTIVITY
In a syngeneic murine in vivo model, the tubulin-binding agent EM011 shows significant anti-melanoma activity with no toxicity.
Source: Anaja R, Int J Cancer 2009, Epub ahead of print

SRC AND UVEAL MELANOMA
The SRC kinase is associated with ERK1/2 activation in primary uveal melanoma but metastatic cell lines are resistant to SRC inhibition.
Source: Maat W, Br J Cancer 2009, 101:312-9

HUMAN ENDOGENOUS RETROVIRUSES (HERV)
Retrovirus-like particles and the expression of HERV mRNA and proteins have been demonstrated in melanoma tissue and might be implicated in melanomagenesis.
Source: Singh S, Br J Dermatol 2009, Epub ahead of print

MUTATED EGFR INDUCES MELANOMA
In a medaka fish transgenic melanoma model, a mutated EGFR is sufficient to induce malignant melanoma with a 100% penetrance.
Source: Schartl M, J Invest Dermatol 2009, Epub ahead of print

LUNG METASTASECTOMY
In a small series of patients undergoing resection of isolated pulmonary metastases, tumor doubling time, Glut-1 and CD31 expression were significant predictors of survival.
Source: Lee JH, Ann Surg Oncol 2009, Epub ahead of print

VITAMIN D RECEPTOR (VDR) POLYMORPHISMS
In a meta-analysis of 3,769 melanoma cases, the VDR FokI T allele and the BsmI A allele are associated with increased and decreased melanoma risk, respectively.
Source: Randerson-Moor JA, Eur J Cancer 2009, Epub ahead of print

PULSED ELECTRIC FIELD THERAPY
In an in vivo mouse model, pulsed electric field therapy disrupts the melanoma's blood supply and causes complete remission without recurrence.
Source: Nucitelli R, Int J Cancer 2009, 125:438-45

SEASON OF DIAGNOSIS
In a population-based study (n=26,060), season of diagnosis has no impact on survival from malignant melanoma.
Source: Jayasekara H, Int J Cancer 2009, 125:488-90

OXALIPLATIN + DOCETAXEL + GM-CSF
A phase II trial (n=19) demonstrated that combining oxaliplatin + docetaxel + GM-CSF yields no objective tumor response in previously treated advanced melanoma patients.
Source: Locke F, Cancer Chemother Pharmacol 2009, Epub ahead of print

MACROPHAGE MARKERS OF PROGNOSIS
Serum levels of CD163 (n=227) and tumor infiltration by CD68+ macrophages (n=190) independently correlates with survival of TNM stage I-II melanoma patients.
Source: Jensen TO, J Clin Oncol 2009, 27:3330-7

THYROID GENE EXPRESSION
Induction of thyroid gene expression by MAP kinase and PI3K/Akt pathways inhibition sensitizes melanoma cells to radioiodine therapy.
Source: Hou P, PLoS One 2009, 4:e6200

ASA AND MELANOMA RISK
A large Dutch population-based case-control study suggested that continuous use of low-dose acetylsalicylic acid (ASA) may be associated with reduced melanoma risk in women.
Source: Joosse A, J Invest Dermatol 2009, Epub ahead of print

FABP7 EXPRESSION
Immunohistochemistry analysis of 37 paired primary and metastatic melanomas revealed that fatty acid-binding protein-7 (FABP7) is more expressed in primary (73%) than metastatic (27%) samples.
Source: Goto Y, J Invest Dermatol 2009, Epub ahead of print

CXCR1 or CXCR2 KNOCKDOWN
In a human melanoma xenograft model, RNA interference mediated knockdown of CXCR1 or CXCR2 (receptors for chemokine CXCL-8) inhibits tumor growth.
Source: Singh S, Int J Cancer 2009, Epub ahead of print

SKI KNOCKDOWN
In a human melanoma xenograft model, RNA interference mediated knockdown of SKI (an antagonist of TGF-beta signaling) inhibits tumor growth.
Source: Chen D, Pigment Cell Melanoma Res 2009, Epub ahead of print

BRAF AND MC1R MUTATIONS
In 123 Australian patients, BRAF-mutant melanomas were less frequent in people with high levels of lifetime sun exposure, with no association between germline MC1R status and somatic BRAF mutations.
Source: Hacker E, J Invest Dermatol 2009, Epub ahead of print

GALECTIN-3: PROGNOSTIC ROLE
Serum levels of galectin-3 have an independent prognostic value in patients with stage III-IV cutaneous melanoma patients.
Source: Vereecken P, Melanoma Res 2009, Epub ahead of print

GAB2 AMPLIFICATION
Among acral and mucosal melanomas (n=23), GAB2 is amplified in 26% of cases and might be critical for melanomas arising from sun-protected sites.
Source: Chernoff KA, Clin Cancer Res 2009, 15:4288-91

ANTI HMW-MAA ANTIBODY
The melanoma specific 9.2.27PE immunotoxin (which recognizes the high molecular weight melanoma associated antigen, HMW-MAA) efficiently kills melanoma cells in vitro.
Source: Risberg K, Int J Cancer 2009, 125:23-33

ADJUVANT GM-CSF
Granulocyte-macrophage colony stimulating factor (GM-CSF) administered as adjuvant therapy in 98 patients with stage II-IV melanoma yielded a 60% 5-year disease-specific survival rate.
Source: Spitler LE, J Immunother 2009, 32:632-7

INTERFERING WITH DNMT3A
In a mouse model, knockdown of DNA methyltransferase 3a (DNMT3A) by RNA interference inhibits melanoma growth and metastasis.
Source: Deng T, Biochem Biophys Res Commun 2009, 387:611-6

CPK PREDICTS ILI TOXICITY
In 171 patients undergoing isolated limb infusion (ILI) for in transit metastases, creatine phosphokinase (CPK) serum levels correlate with locoregional toxicity.
Source: Santillan AA, Ann Surg Oncol 2009, 16:2570-8

VITAMIN D SERUM LEVELS
In 205 patients with cutaneous melanoma, vitamin D serum levels are higher in stage IV as compared to stage I disease.
Source: Nürnberg B, Anticancer Res 2009, 29:3669-74

VITAMIN D AND PPAR
Vitamin D inhibits melanoma cell proliferation in vitro, the effect being modulated by peroxisome proliferator-activated receptor (PPAR) signaling.
Source: Sertznig P, Anticancer Res 2009, 29:3647-58

GNAQ MUTATIONS AND UVEAL MELANOMA
GNAQ mutations are frequent in uveal melanoma (53%) but are not correlated with disease free survival of 75 patients.
Source: Bauer J, Br J Cancer 2009, 101:813-5

ERYTHROPOIETIN AND MELANOMA
Overexpression of functional erythropoietin receptor (EpoR) expression in melanoma metastasis specimens might be a warning for the treatment of anemia in these patients.
Source: Mirmohammadsadegh A, J Invest Dermatol 2009, Epub ahead of print

BIMODAL MELANOMA PATHWAYS
Epidemiological data support that early-onset melanoma may represent gene-intermittent sun exposure interaction while late-onset melanoma may reflect chronic exposure sun damage.
Source: Anderson WF, Cancer 2009, Epub ahead of print

DELIMOTECAN PRECLINICAL ACTIVITY
In a xenograft model, delimotecan (a camptothecin analog bound to carboxymethyl dextran) is active against a DTIC-resistant human melanoma cell line.
Source: Bigioni M, Int J Cancer 2009, Epub ahead of print

AUTOANTIBODIES AND RESPONSE TO IFNalpha
In two randomized trials of adjuvant interferon-alpha, appearance of autoantibodies was not associated with melanoma patient relapse-free survival.
Source: Bouwhuis MG, J Natl Cancer Inst 2009, 101:869-77

RETINOIC ACID AND MELANOMA
In an in vitro model, retinoic acid receptor gamma (RARg) inhibits melanoma invasiveness by inducing expression of carbohydrate sulfotransferase-10 (CHST10).
Source: Zhao X, Cancer Res 2009, 69:5218-25

C10, A TLR3 INHIBITOR
In a xenograft model, phenylmethimazole (C10) decreases toll like receptor-3 (TLR3) and non-canonical WNT5a signaling, and shows anti-melanoma activity.
Source: Schwartz AL, Clin Cancer Res 2009, 15:4114-22

STROMAL MMP-13 AND INVASIVENESS
In a mouse model, melanoma invasion and metastasis are reduced in matrix metalloproteinase-13 (MMP-13) knockout animals as compared to wild-type littermates.
Source: Zigrino P, J Invest Dermatol 2009, Epub ahead of print

SALIVARY MARKERS OF ADVANCED MELANOMA
In a mouse melanoma model, microarray analysis showed that salivary transcriptomes were significantly different in tumor-bearing mice vs controls.
Source: Gao K, PLoS One 2009, 4:e5875

IDO INHIBITORS DISCOVERY
In a mouse melanoma model, potent competitive inhibitors of IDO (indoleamine 2,3-dioxygenase; a tumor immune escape related enzyme) have been discovered.
Source: Yue EW, J Med Chem 2009, Epub ahead of print

TAXOL + CISPLATIN + DTIC
In a phase I-II trial (n=46), paclitaxel + cisplatin + dacarbazine optimal doses were determined, the overall response rate being 41% (2 CR + 17 PR).
Source: Papadopoulos NE, Am J Clin Oncol 2009, Epub ahead of print

ONCOLYTIC + IL18 GENE THERAPY
In a mouse model, oncolytic adenoviral vector encoding IL-18 showed greater anti-melanoma activity than oncolytic virus or IL-18 gene therapy alone.
Source: Zheng JN, Cancer Gene Ther 2009, Epub ahead of print

CLINICAL TRIAL OF XENOGENEIC VACCINE
A phase I trial showed that a human and mouse gp100 DNA vaccine is safe and can lead to immune response in patients with early stage melanoma.
Source: Yuan J, Cancer Immun 2009, 9:5

UVEAL MELANOMA METASTASIS DETECTION
In a small study (n=27), 18-FDG PET-CT and S-100B serum levels are useful to detect liver metastases from cutaneous but not uveal melanoma.
Source: Strobel K, Eur J Nucl Med Mol Imaging 2009, Epub ahead of print

WFDC1: CANDIDATE MELANOMA SUPPRESSOR
In a human melanoma xenograft model, WFDC1 overexpression resulted in a significant delay of tumor growth, which likely involves upregulation of DKK1 (a WNT pathway inhibitor).
Source: Liu S, Clin Exp Metastasis 2009, Epub ahead of print

CDKN2A NEW MUTATIONS
In an Italian study on familial melanoma, 68/204 (33%) melanoma-prone families showed CDKN2A mutations, three being novel mutations (L94P, A86T, c.407dupG).
Source: Bruno W, J Am Acad Dermatol 2009, Epub ahead of print

IMAGING: DW-MRI VERSUS PET-CT
In a small study (n=35), multi-contrast MRI including a diffusion-weighted (DW) sequence performs better than 18-FDG based PET-CT in the staging of advanced melanoma.
Source: Laurent V, Eur J Radiol 2009, Epub ahead of print

RISK MODIFIER GENES
The screening of 1536 SNP from 152 genes identified risk modifier genes in 19 CDKN2A+ (BCL7A, IL9) and 9 CDKN2A- (BCL2L1) melanoma-prone families.
Source: Yang XR, Int J Cancer 2009, Epub ahead of print

SENTINEL NODE BIOPSY AND LYMPHADENECTOMY
In 70 patients with sentinel node metastasis, no completion lymphadenectomy appears to be necessary when disease burden is minimal.
Source: van der Ploeg IM, Ann Surg 2009, 249:1003-7

ISOLATED LIMB INFUSION (ILI)
In elderly (>=75 years) patients (n=86), ILI yielded tumor response, survival and toxicity rates similar to those observed in younger patients.
Source: Kroon HM, Ann Surg 2009, 249:1008-13

LYMPH NODE RATIO (N-RATIO)
Using the SEER databse, the Authors found that the proportion of positive over examined lymph nodes predicts survival of stage III melanoma patients.
Source: Xing Y, Cancer 2009, 115:2505-13

DIOSMIN AND IFN-alpha
In an in vivo murine model, diosmin (a flavonoid) and interferon-alpha showed synergic anti-melanoma activity.
Source: Alvarez N, Cancer Biother Radiopharm 2009, 24:347-52

DENDRITIC CELL VACCINE
Vaccination with dendritic cells pulsed with autologous melanoma cells yielded an encouraging 5-year survival rate in patients with metastatic disease.
Source: Dillman RO, Cancer Biother Radiopharm 2009, 24:311-9

NDV GENE THERAPY
In an in vivo murine model, oncolytic Newcastle Disease Virus (NDV) encoding IL-2 shows anti-melanoma activity.
Source: Zamarin D, Gene Ther 2009, 16:796-804

RB18A/MED1 AND TUMORIGENIC PHENOTYPE
In vivo knockdown of RB18A/MED1 (TRAP220, DRIP205), a cofactor of transcription, triggers strong tumorigenic phenotype of human melanoma cells.
Source: Ndong Jde L, Int J Cancer 2009, 124:2597-606

RILUZOLE TRIAL
In a phase 0 trial conducted in advanced melanoma patients, riluzole inhibits metabotropic glutamate receptors activity (which is increased in melanoma).
Source: Yip D, Clin Cancer Res 2009, 15:3896-902

MDM2 GERMLINE POLYMORPHISM
Germline analysis of T/G polymorphism at position 309 of the MDM2 promoter showed an increased G allele frequency in patients with melanoma.
Source: Gluck I, Melanoma Res 2009, 19:199-202

DACARBAZINE PLUS THALIDOMIDE
In a phase II trial, addition of thalidomide to DTIC in metastatic melanoma yielded no therapeutic advantage.
Source: Ott PA, Chemotherapy 2009, 55:221-7

UNKNOWN PRIMARY SITE MELANOMA
Patients with stage III and IV melanoma from unknown primary site show a better prognosis than those with melanoma from known primary site.
Source: Lee CC, J Clin Oncol 2009, 27:3489-95

NK4 SYSTEMIC GENE THERAPY
In an in vivo mouse melanoma model, gene therapy enforcing the expression of NK4 (an antagonist of HGF) shows anti-melanoma activity.
Source: Kishi Y, Cancer Sci 2009, 100:1351-8

IBUPROFEN AND MELANOMA MIGRATION
Ibuprofen inhibits TNF-induced human melanoma migration in an in vitro study.
Source: Redpath M, Br J Dermatol 2009, 161:25-33

ErbB1 INHIBITION BY GEFINITIB
In an in vitro study, small molecule inhibitor gefitinib inhibits the proliferation of human melanoma cells.
Source: Djerf EA, Melanoma Res 2009, 19:156-66

MELANOMA FOLLOW-UP
In a German study (n=1969), stage I-II melanoma patients appear to be adequately followed-up with physical examination and lymph node sonography (without chest X-rays, blood work or abdomen sonography).
Source: Leiter U, Melanoma Res 2009, 19:50-7

BIOCHEMOTHERAPY VERSUS IFN-alpha
In a phase III randomized trial, adjuvant biochemotherapy was not better than interferon-alpha 2b in terms of overall or relapse-free survival.
Source: Kim KB, Melanoma Res 2009, 19:42-9

MELANOMA THICKNESS TRENDS
In a German study (n=6475), primary melanoma thickness decreases over time except for melanoma of the feet and nodular or acrolentiginous melanoma.
Source: Baumert J, Melanoma Res 2009, 19:24-30

COX-2 AS PROGNOSTIC FACTOR
In 129 patients with cutaneous melanoma, immunohistochemistry for COX-2 expression correlated with disease specific survival at univariate analysis.
Source: Becker MR, Melanoma Res 2009, 19:8-16

UVEAL MELAN0MA LIVER METASTASIS
In a retrospective study (n = 74), patients undergoing radical liver resection lived longer than those who did not undergo surgery.
Source: Frenkel S, Br J Ophthalmol 2009, 93:1042-6

SUNLIGHT AND MELANOMA
In a pooled analysis (cases = 5700), recreational sun exposure and sunburn are strong predictors of melanoma at all latitudes.
Source: Chang YM, Int J Epidemiol 2009, 38:814-30

PROGRESSION OF NRAS AND BRAF MUTATIONS
In human primary cutaneous melanomas (n=29), frequencies of NRAS and BRAF mutations increase from the radial to the vertical growth phase.
Source: Greene VR, J Invest Dermatol 2009, 129:1483-8

ORAL CAVITY PRIMARY MELANOMA
The Authors present 10 cases of oral melanoma and review 117 cases from the international literature.
Source: Aguas SC, Med Oral Patol Oral Cir Bucal 2009, 14:E265-71

MELANOMA METHYLATION PROFILE
In 16 human melanoma cell lines, aberrant hypermethylation is frequent and independent of BRAF and NRAS mutations.
Source: Tellez CS, Melanoma Res 2009, 19:146-55

PHASE II TRIAL OF PLITIDEPSIN
In 35 patients with metastatic melanoma, plitidepsin (a pro-apoptotic cyclic depsipeptide) yielded 5.7% partial response and 14.3% stable disease rates.
Source: Eisen T, Melanoma Res 2009, 19:185-92

ACTIVITY OF SRC INHIBITORS
In a human in vitro melanoma model, SRC inhibitors dasatinib and bosutinib inhibit malignant cell growth and sinergize with platinum compounds.
Source: Homsi J, Melanoma Res 2009, 19:167-75

ANTI-TELOMERASE ANTISENSE OLIGOS
In a murine in vivo melanoma model, small double-stranded oligodeoxynucleotides targeting telomerase RNA show anti-melanoma activity.
Source: Noreen F, Oligonucleotides 2009, 19:169-78

DOXYCYCLINE INHIBITS MELANOMA MIGRATION
In an in vitro model, doxycycline inhibits adhesion and migration of melanoma cells by inhibiting expression and phosphorylation of focal adhesion kinase (FAK).
Source: Sun T, Cancer Lett 2009, Epub ahead of print

POLH POLYMORPHISMS AND MELANOMA RISK
In a case control study (cases = 1075), the c.1783G p.595V allele of the xeroderma pigmentosum variant gene (POLH) is associated with melanoma risk.
Source: Di Lucca J, Eur J Cancer 2009, Epub ahead of print

IL-10 POLYMORPHISMS AND MELANOMA RISK
In a case control study (cases = 165), distal and proximal interleukin-10 promoter polymorphisms are associated with risk of cutaneous melanoma.
Source: Schoof N, Genes Immun 2009, Epub ahead of print

TREMELIMUMAB AND Th17 CELLS
In patients with metastatic melanoma, CTLA4 blockade by mAb tremelimumab increases CD4+ T-cells producing IL-17, a cytokine promoting autoimmunity.
Source: Von Euw E, J Transl Med 2009, 7:35

MAGE VACCINATION AND IMMUNOSUPPRESSION
The CD4(+) T-cell response of melanoma patients to a MAGE-A3 peptide vaccine involves potential regulatory T cells with immunosuppressive activity.
Source: Francois V, Cancer Res 2009, 69:4335-45

ERLOTINIB PLUS BEVACIZUMAB
In a melanoma xenograft model, erlotinib (anti-EGFR small molecule inhibitor) plus bevacizumab (anti-VEGF antibody) show synergistic anti-melanoma activity.
Source: Schicher N, Clin Cancer Res 2009, 15:3495-502

MODIFIED HEPARINS AND MELANOMA METASTASIS
In a preclinical study, modified heparins inhibit integrin alpha(IIb)beta(3)-mediated adhesion of melanoma cells to platelets in vitro and in vivo.
Source: Zhang C, Int J Cancer 2009, Epub ahead of print

ISOLATED HYPOXIC HEPATIC PERFUSION (IHHP)
In a small study (n=8), IHHP with melphalan obtained 3/8 partial responses in patients with liver metastases from ocular melanoma.
Source: Van Etten B, Eur J Surg Oncol 2009, 35:539-45

LOW DOSE IFN WITH VS WITHOUT HIGH DOSE IFN
In a RCT (n=674), the addition of a high dose interferon alpha (HDI) induction phase to a 2-year low-dose adjuvant IFN treatment schedule did not improve the survival.
Source: Hauschild A, J Clin Oncol 2009, Epub ahead of print

JASPINE-B ANTI-MELANOMA EFFECT
In an in vitro model, Jaspine-B (a derivative of a marine sponge) inhibits sphingomyelin synthase (SMS, which converts ceramide into sphingomyelin) and induces melanoma cell apoptosis.
Source: Salma Y, Biochem Pharmacol 2009, Epub ahead of print

EB1 REGULATES MELANOMA MIGRATION
In an in vitro model, inhibition of microtubule end binding protein EB1 decreases melanoma migration by interfering with the balance between lamellipodial and filopodial protrusion.
Source: Schober JM, Cancer Lett 2009, Epub ahead of print

HN1 EXPRESSION AND MELANOMA DIFFERENTIATION
In murine melanoma cells, inhibition of HN1 expression a differentiated phenotype that includes increased melanogenesis and cell cycle arrest.
Source: Laughlin KM, Differentiation 2009, Epub ahead of print

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