Melanoma: Tucker MA

Fraser MC, Goldstein AM, Tucker MA, Anonymous00128. · Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, USA. · J Drugs Dermatol. · Pubmed #14964756 No free full text.

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Goldstein AM, Tucker MA. · No affiliation provided · J Natl Cancer Inst. · Pubmed #16234555 links to  free full text

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Gerstenblith MR, Goldstein AM, Tucker MA, Fraser MC. · Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland 20852-7236, USA. · Cancer Nurs. · Pubmed #18025917 No free full text.

Abstract: A complex interaction of genetic, host, and environmental factors results in cutaneous malignant melanoma, the fifth most common cancer among men and the sixth among women in the United States. Mortality rates for cutaneous malignant melanoma depend on stage at diagnosis; thus, efforts are aimed at early detection and identification of risk factors for melanoma to distinguish those individuals requiring close surveillance. Melanoma susceptibility genes CDKN2A and CDK4 play a role in the development of melanoma, especially among some familial melanoma kindreds. The functions of CDKN2A and CDK4 in melanoma development, however, are currently incompletely understood. Therefore, at this time, predictive genetic testing for CDKN2A mutations outside of defined research protocols is not recommended because of the low likelihood of detecting mutations even in high-risk groups, the present inadequacy of interpreting a test result due to variations in penetrance and unclear associations with other cancers, and the minimal influence knowledge of mutation status currently has on medical management. Oncology nurses have an important role in identifying individuals at high risk for melanoma regardless of CDKN2A mutation status, encouraging enrollment in skin surveillance programs, and providing patient education regarding sun protection, prevention and early detection of melanoma.

Tucker MA, Goldstein AM. · Genetic Epidemiology Branch, DCEG, NCI, Executive Plaza South 7122, 6120 Executive Blvd, Rockville, MD 20892-7236, USA. · Oncogene. · Pubmed #12789279 No free full text.

Abstract: Melanoma incidence rates are rising rapidly, particularly in older men. Older men are also more likely to have thick melanomas, which confer high mortality and morbidity. The reasons for the rate of increase are not known; increasing sun and UV exposure, however, is the major hypothesized explanation. In the past several years, two major susceptibility genes for melanoma, CDKN2A and CDK4, have been identified, but the two genes together account for a minority of familial melanoma. Other high-risk susceptibility genes are being sought actively. Genetic epidemiologic studies suggest that penetrance of each of the two identified genes is altered by other factors, either genetic or environmental. Epidemiologic studies have also identified other major host factors important in the development of melanoma. In European, North American, and Australian populations, the presence of clinically identified dysplastic nevi confers greatly increased risk of melanoma. A new measure of sun exposure, based on individual residential history, confers substantially increased risk of melanoma. Recent surveys of sun behavior in the US reveal extensive sunburning and use of tanning beds in adolescents and adults. Sun protective behaviors are not as prevalent as in Australia, where population rates of melanoma are stabilizing.

Goldstein AM, Tucker MA. · Genetic Epidemiology Branch/National Cancer Institute, Executive Plaza South, Room 7004, 6120 Executive Blvd, MSC 7236, Bethesda, MD 20892-7236. · Arch Dermatol. · Pubmed #11708953 No free full text.

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Kefford RF, Newton Bishop JA, Bergman W, Tucker MA. · Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital, New South Wales, Australia. · J Clin Oncol. · Pubmed #10506626 No free full text.

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Solomon DA, Kim JS, Yang XR, Tucker MA, Goldstein AM, Samuels Y, Waldman T. · Department of Oncology, Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC, USA. · Pigment Cell Melanoma Res. · Pubmed #19500277 No free full text.

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Tucker MA. · Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Room 7122, Bethesda, MD 20892-7236, USA. · Hematol Oncol Clin North Am. · Pubmed #19464592 No free full text.

Abstract: Melanoma is a complex, heterogeneous cancer that continues to increase in incidence. Multiple studies have consistently identified major host and environmental risk factors for melanoma. Nevi, particularly dysplastic nevi, confer much higher risks than most pigmentary characteristics. Ultraviolet radiation exposure is the predominant environmental risk factor for melanoma. Recently, both rare high risk susceptibility genes and common polymorphic genes contributing to melanoma risk have been identified.

Bradford PT, Goldstein AM, McMaster ML, Tucker MA. · Genetic Epidemiology Branch, DCEG, NCI, NIH, 6120 Executive Blvd, Room 7005, Rockville, MD 20852-7236, USA. · Arch Dermatol. · Pubmed #19380664 No free full text.

Abstract: OBJECTIVE: To examine incidence and survival patterns of acral lentiginous melanoma (ALM) in the United States. DESIGN: Population-based registry study. We used the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute to evaluate data from 17 population-based cancer registries from 1986 to 2005. PARTICIPANTS: A total 1413 subjects with histologically confirmed cases of ALM. Main Outcome Measure Incidence and survival patterns of patients with ALM. RESULTS: The age-adjusted incidence rate of ALM overall was 1.8 per million person-years. The proportion of ALM among all melanoma subtypes was greatest in blacks (36%). Acral lentiginous melanoma had 5- and 10-year melanoma-specific survival rates of 80.3% and 67.5%, respectively, which were less than those for all cutaneous malignant melanomas overall (91.3% and 87.5%, respectively; P < .001). The ALM 5- and 10-year melanoma-specific survival rates were highest in non-Hispanic whites (82.6% and 69.4%), intermediate in blacks (77.2% and 71.5%), and lowest in Hispanic whites (72.8% and 57.3%) and Asian/Pacific Islanders (70.2% and 54.1%). Acral lentiginous melanoma thickness and stage correlated with survival according to sex and in the different racial groups. CONCLUSIONS: Population-based data showed that ALM is a rare melanoma subtype, although its proportion among all melanomas is higher in people of color. It is associated with a worse prognosis than cutaneous malignant melanoma overall. Hispanic whites and Asian/Pacific Islanders have worse survival rates than other groups, and factors such as increased tumor thickness and more advanced stage at presentation are the most likely explanations.

Ng D, Yang XR, Tucker MA, Goldstein AM. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA. · BMC Res Notes. · Pubmed #18803848 links to  free full text

Abstract: ABSTRACT: BACKGROUND: A subset of cutaneous malignant melanoma and dysplastic nevi (CMM/DN) families is linked to 1p36. To date, no CMM/DN susceptibility gene has been identified at this locus. Data from mouse studies identified chromodomain helicase DNA binding protein 5 (CHD5) as a tumor suppressor affecting cellular proliferation and apoptosis via the CDKN2A/p53 pathway. Based on these findings, we felt it was important to screen CHD5 as a familial CMM/DN susceptibility gene. METHODS: Eight unrelated CMM/DN families showing prior evidence of linkage to the 1p36 locus were identified for CHD5 mutation screening. One CMM/DN affected and one unaffected individual from each family were selected for sequencing of the CHD5 coding exons and their respective intron-exon boundaries. CHD5 variants that were identified solely among affecteds in the screening panel were further assessed by sequencing additional affected and unaffected members of these families to determine if the variant co-segregated with the CMM/DN phenotype. RESULTS: Single nucleotide polymorphisms in the CHD5 intronic and coding regions were identified among affecteds in the screening panel. None of these variants completely co-segregated with CMM/DN affection status among these eight families. CONCLUSION: There is no evidence to support CHD5 as a major melanoma susceptibility gene among the eight CMM/DN families screened.

Gudbjartsson DF, Sulem P, Stacey SN, Goldstein AM, Rafnar T, Sigurgeirsson B, Benediktsdottir KR, Thorisdottir K, Ragnarsson R, Sveinsdottir SG, Magnusson V, Lindblom A, Kostulas K, Botella-Estrada R, Soriano V, Juberías P, Grasa M, Saez B, Andres R, Scherer D, Rudnai P, Gurzau E, Koppova K, Kiemeney LA, Jakobsdottir M, Steinberg S, Helgason A, Gretarsdottir S, Tucker MA, Mayordomo JI, Nagore E, Kumar R, Hansson J, Olafsson JH, Gulcher J, Kong A, Thorsteinsdottir U, Stefansson K. · deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland. · Nat Genet. · Pubmed #18488027 No free full text.

Abstract: Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 x 10(-9)) and BCC (OR = 1.33, P = 1.2 x 10(-6)). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 x 10(-7)) and BCC (OR = 1.14, P = 6.1 x 10(-4)). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 x 10(-4)). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.

Harland M, Goldstein AM, Kukalizch K, Taylor C, Hogg D, Puig S, Badenas C, Gruis N, ter Huurne J, Bergman W, Hayward NK, Stark M, Tsao H, Tucker MA, Landi MT, Scarra GB, Ghiorzo P, Kanetsky PA, Elder D, Mann GJ, Holland EA, Bishop DT, Bishop JN, Anonymous00007. · Division of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Cancer Research UK Cancer Centre at Leeds, St James's University Hospital, Leeds, UK. · Eur J Cancer. · Pubmed #18394881 links to  free full text

Abstract: CDKN2A is the major melanoma susceptibility gene so far identified, but only 40% of three or more case families have identified mutations. A comparison of mutation detection rates was carried out by "blind" exchange of samples across GenoMEL, the Melanoma Genetics Consortium, to establish the false negative detection rates. Denaturing high performance liquid chromatography (DHPLC) screening results from 451 samples were compared to screening data from nine research groups in which the initial mutation screen had been done predominantly by sequencing. Three samples with mutations identified at the local centres were not detected by the DHPLC screen. No additional mutations were detected by DHPLC. Mutation detection across groups within GenoMEL is carried out to a consistently high standard. The relatively low rate of CDKN2A mutation detection is not due to failure to detect mutations and implies the existence of other high penetrance melanoma susceptibility genes.

Tucker MA. · Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Room 7122, Bethesda, MD 20892-7236, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #18319329 links to  free full text

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Goldstein AM, Stacey SN, Olafsson JH, Jonsson GF, Helgason A, Sulem P, Sigurgeirsson B, Benediktsdottir KR, Thorisdottir K, Ragnarsson R, Kjartansson J, Kostic J, Masson G, Kristjansson K, Gulcher JR, Kong A, Thorsteinsdottir U, Rafnar T, Tucker MA, Stefansson K. · Genetic Epidemiology Branch, Division of Cancer Epidemiologyand Genetics/NCI/NIH/DHHS, Executive Plaza South, Room 7004, 6120 Executive Blvd MSC 7236, Bethesda, MD 20892-7236, USA. · J Med Genet. · Pubmed #18178632 No free full text.

Abstract: BACKGROUND: Germline CDKN2A mutations have been observed in 20-40% of high risk, melanoma prone families; however, little is known about their prevalence in population based series of melanoma cases and controls. METHODS: We resequenced the CDKN2A gene, including the p14ARF variant and promoter regions, in approximately 703 registry ascertained melanoma cases and 691 population based controls from Iceland, a country in which the incidence of melanoma has increased rapidly. RESULTS: We identified a novel germline variant, G89D, that was strongly associated with increased melanoma risk and appeared to be an Icelandic founder mutation. The G89D variant was present in about 2% of Icelandic invasive cutaneous malignant melanoma cases. Relatives of affected G89D carriers were at significantly increased risk of melanoma, head and neck cancers, and pancreatic carcinoma compared to relatives of other melanoma patients. Nineteen other germline variants were identified, but none conferred an unequivocal risk of melanoma. CONCLUSIONS: This population based study of Icelandic melanoma cases and controls showed a frequency of disease related CDKN2A mutant alleles ranging from 0.7% to 1.0%, thus expanding our knowledge about the frequency of CDKN2A mutations in different populations. In contrast to North America and Australia where a broad spectrum of mutations was observed at a similar frequency, in Iceland, functional CDKN2A mutations consist of only one or two different variants. Additional genetic and/or environmental factors are likely critical for explaining the high incidence rates for melanoma in Iceland. This study adds to the geographic regions for which population based estimates of CDKN2A mutation frequencies are available.

Goldstein AM, Chaudru V, Ghiorzo P, Badenas C, Malvehy J, Pastorino L, Laud K, Hulley B, Avril MF, Puig-Butille JA, Miniere A, Marti R, Chompret A, Cuellar F, Kolm I, Mila M, Tucker MA, Demenais F, Bianchi-Scarra G, Puig S, de-Paillerets BB. · Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD 20892, USA. · Int J Cancer. · Pubmed #17397031 No free full text.

Abstract: The G101W founder mutation is the most common CDKN2A mutation in Italy, Spain, and France. As the background of modifying genes, environmental exposures, and sun behavior vary across countries, studying G101W carriers from distinct countries offers a unique opportunity to evaluate possible modifying factors in melanoma development. We evaluated 76 G101W cases and 59 carrier controls from France, Italy, Spain, and the United States. Hair color and dysplastic nevi distributions differed significantly in cases and controls across the 4 study groups. Cases also varied significantly for eye color, freckling, and nevi. The distribution of MC1R variants in cases differed significantly across study groups because 12% of Italian melanoma patients had > or =2 MC1R variants vs. >50% for the other case groups. Several MC1R covariates showed significant associations with melanoma risk in all groups combined and in the American, French, and Spanish samples; no significant findings were observed in the Italian sample. In multiple-case families, the number and type of MC1R variants varied significantly between multiple-primary-melanoma and single-primary-melanoma patients from the 4 groups; there was also a significant decrease in median age at melanoma diagnosis as the number or type of MC1R variants increased. The variation in the effects of the cutaneous phenotypic and MC1R factors across the study sample suggests that these factors differentially contribute to development of melanoma even on a common genetic background of a germline CDKN2A mutation. Differences in melanoma risk across geographic regions justify the need for individual studies in each country before counseling should be considered.

Lea CS, Holly EA, Hartge P, Lee JS, Guerry D, Elder DE, Halpern A, Sagebiel RW, Tucker MA. · Statistics and Epidemiology Program, Research Triangle Institute International, Research Triangle Park, NC, USA. · Am J Epidemiol. · Pubmed #17158470 links to  free full text

Abstract: Reproductive hormonal factors may have a potential role in cutaneous melanoma. This study estimated the risk of melanoma in women related to self-reported changes in nevi during pregnancy, while using oral contraceptives and/or hormone replacement therapy. Trained interviewers administered a questionnaire obtaining information about oral contraceptive use, hormone replacement therapy, reproductive history, sun exposure, occupation, and medical history from 318 Caucasian women newly diagnosed between 1991 and 1992 from two pigmented lesion clinics in San Francisco, California, and Philadelphia, Pennsylvania. A total of 395 frequency-matched control participants were recruited from hospital-affiliated outpatient clinics. Clinicians conducted skin examinations to assess the number and type of nevi, extent of freckling, solar damage, and skin type. For women aged less than 55 years, there was an association between a livebirth 5 years before diagnosis (odds ratio = 2.6, 95% confidence interval: 1.3, 5.3) and between number of births and melanoma risk (for > or = 3 births: odds ratio = 3.3, 95% confidence interval: 1.7, 6.5; ptrend < 0.001). Changes in nevi during recent pregnancies were a risk factor for melanoma, based upon small numbers (odds ratio = 2.9, 95% confidence interval: 1.1, 8.1). Oral contraceptive use and hormone replacement therapy were not associated with melanoma risk.

Goldstein AM, Chan M, Harland M, Gillanders EM, Hayward NK, Avril MF, Azizi E, Bianchi-Scarra G, Bishop DT, Bressac-de Paillerets B, Bruno W, Calista D, Cannon Albright LA, Demenais F, Elder DE, Ghiorzo P, Gruis NA, Hansson J, Hogg D, Holland EA, Kanetsky PA, Kefford RF, Landi MT, Lang J, Leachman SA, Mackie RM, Magnusson V, Mann GJ, Niendorf K, Newton Bishop J, Palmer JM, Puig S, Puig-Butille JA, de Snoo FA, Stark M, Tsao H, Tucker MA, Whitaker L, Yakobson E, Anonymous00122. · Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892-7236, USA. · Cancer Res. · Pubmed #17047042 links to  free full text

Abstract: GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available.

Goldstein AM, Chan M, Harland M, Hayward NK, Demenais F, Bishop DT, Azizi E, Bergman W, Bianchi-Scarra G, Bruno W, Calista D, Albright LA, Chaudru V, Chompret A, Cuellar F, Elder DE, Ghiorzo P, Gillanders EM, Gruis NA, Hansson J, Hogg D, Holland EA, Kanetsky PA, Kefford RF, Landi MT, Lang J, Leachman SA, MacKie RM, Magnusson V, Mann GJ, Bishop JN, Palmer JM, Puig S, Puig-Butille JA, Stark M, Tsao H, Tucker MA, Whitaker L, Yakobson E, Anonymous00094, Anonymous00095. · Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland 20892-7236, USA. · J Med Genet. · Pubmed #16905682 No free full text.

Abstract: BACKGROUND: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. METHODS: These four features were examined in 385 families with > or =3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. RESULTS: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, > or =2 patients with MPM, median age at melanoma diagnosis < or =40 years and > or =6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only > or =1 patient with MPM and age at diagnosis < or =40 years simultaneously predicted the mutation risk. CONCLUSIONS: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer-CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.

Fears TR, Guerry D, Pfeiffer RM, Sagebiel RW, Elder DE, Halpern A, Holly EA, Hartge P, Tucker MA. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. · J Clin Oncol. · Pubmed #16728488 No free full text.

Abstract: PURPOSE: We developed a model to estimate the 5-year absolute risk of melanoma to efficiently identify individuals at increased risk of melanoma for potential interventions. PATIENTS AND METHODS: We used data from a case-control study with 718 non-Hispanic white patients with invasive cutaneous melanoma from melanoma clinics in Philadelphia, PA and San Francisco, CA; matched controls were 945 patients from outpatient clinics with similar catchment areas. All participants underwent extensive interviews and skin examinations. We selected easily obtained clinical characteristics and responses to simple questions for study in order to develop sex-specific relative risk models. These models were combined with incidence and mortality rates by United States geographic areas to develop estimates of the absolute risk of developing melanoma within 5 years. RESULTS: Relative risk models yielded an attributable risk of 86% for men and 89% for women, using at most seven variables. Attributable risks did not vary by age, ultraviolet B flux or hours outdoors. The absolute individual risks varied widely, depending on age, other host characteristics, and geographic area. Individual absolute risk can be estimated using a program available online. CONCLUSION: Our procedures allow for estimating the absolute risk of developing melanoma to assist in the identification of patients at high risk. Such high-risk individuals could undergo interventions including a complete skin examination, counseling to avoid sun exposures, regular self and professional surveillance, or participation in prevention trials. It is important to emphasize that these projections are not intended to identify current melanoma cases.

Buckel TB, Goldstein AM, Fraser MC, Rogers B, Tucker MA. · Division of Cancer Prevention and Genetic Epidemiology Branch, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. · Arch Dermatol. · Pubmed #16618869 links to  free full text

Abstract: BACKGROUND: Individuals at increased risk of melanoma should use sun-protective measures to decrease their risk of developing melanoma. OBSERVATION: We report a case of a 39-year-old patient with a CDKN2A mutation who developed 3 primary melanomas within a few years of initiating tanning bed use. CONCLUSION: Intense UV exposure as an adult likely contributed to the development of additional primary melanomas in this individual.

Goldstein AM, Landi MT, Tsang S, Fraser MC, Munroe DJ, Tucker MA. · Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892-7236, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #16172233 links to  free full text

Abstract: Major risk factors for melanoma include many nevi, especially dysplastic nevi, fair pigmentation, freckling, poor tanning ability, and germ line mutations in the CDKN2A, CDK4, or MC1R genes. We evaluated the relationship between MC1R and melanoma risk in CDKN2A melanoma-prone families with extensive clinical and epidemiologic data. We studied 395 subjects from 16 American CDKN2A families. Major melanoma risk factors were assessed by clinical examination or questionnaire; MC1R was sequenced. Odds ratios were estimated by unconditional and conditional logistic regression models. We examined the distribution of MC1R variants and median ages at melanoma diagnosis in multiple primary melanoma (MPM) and single primary melanoma (SPM) patients. Presence of multiple MC1R variants was significantly associated with melanoma, even after adjustment for major melanoma risk factors. All 40 MPM patients had at least one MC1R variant; 65% of MPM patients versus only 17% of SPM patients had at least two MC1R variants (P < 0.0001). For all 69 melanoma patients combined, as well as the 40 MPM patients, there was a statistically significant decrease in median age at diagnosis as numbers of MC1R variants increased (P = 0.010 and P = 0.008, respectively). In contrast, no significant reduction in age at melanoma diagnosis was observed for SPM patients (P = 0.91). The current study suggests that the presence of multiple MC1R variants is associated with the development of multiple melanoma tumors in patients with CDKN2A mutations. Additional studies are needed to confirm these findings and to explore the mechanisms that may contribute to this relationship.

Strouse JJ, Fears TR, Tucker MA, Wayne AS. · Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · J Clin Oncol. · Pubmed #16034049 No free full text.

Abstract: PURPOSE: To evaluate risk factors for the development of and factors influencing survival in pediatric melanoma. PATIENTS AND METHODS: We evaluated 1,255 children (age < 20 years) and 2,673 young adults (age 20 to 24 years) with melanoma in the 2001 National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER) database. We estimated exposure to UV radiation based on Environmental Protection Agency (EPA) measurements. RESULTS: The incidence of pediatric melanoma increased 46% (95% CI, 40 to 52) per year of age and 2.9% (95% CI, 2.1 to 3.6) per year from 1973 to 2001. Incidence rates were lower in black patients (-95%; 95% CI, -98 to -90) compared with white patients and in male patients (-39%; 95% CI -46 to -31) compared with females. Increased ambient UV radiation was associated with elevated risk (19% per kJ; 95% CI, 9 to 30). Children with melanoma had a 5-year melanoma-specific survival of 93.6% (95% CI, 91.9 to 94.9), which improved from 1973 to 2001. The hazard ratio of death from melanoma increased with male sex; older age; advanced disease; location of the primary other than extremities or torso; earlier year of diagnosis; and previous cancer. CONCLUSION: The incidence of melanoma in the United States is increasing rapidly in children. Risk factors for pediatric melanoma include being white, being female, increasing age, and environmental UV radiation. Survival is decreased for children and adolescents with unfavorable prognostic factors (male sex, unfavorable site, and/or second primary or regional or distant metastasis). More effective therapeutic strategies are needed for these groups.

Laud K, Marian C, Avril MF, Barrois M, Chompret A, Goldstein AM, Tucker MA, Clark PA, Peters G, Chaudru V, Demenais F, Spatz A, Smith MW, Lenoir GM, Bressac-de Paillerets B, Anonymous00032. · Service de Génétique, Institut Gustave Roussy, 94800 Villejuif, France. · J Med Genet. · Pubmed #15937071 links to  free full text

Abstract: OBJECTIVE: Comprehensive analysis of the 9p21 locus including the CDKN2A, ARF, and CDKN2B genes in 53 individuals from melanoma index cases considered to be at heightened risk of melanoma. METHODS AND RESULTS: Using a combination of DNA sequencing, gene copy number by real time quantitative PCR, linkage analysis, and transcript analysis in haploid somatic cell hybrids, we found no evidence for germline alteration in either coding or non-coding domains of CDKN2A and CDKN2B. However, we identified a p14ARF exon 1beta missense germline mutation (G16D) in a melanoma-neural system tumour syndrome (CMM+NST) family and a 8474 bp germline deletion from 196 bp upstream of p14ARF exon 1beta initiation codon to 11233 bp upstream of exon 1alpha of p16(INK4A) in a family with five melanoma cases. For three out of 10 families with at least three melanoma cases, the disease gene was unlinked to the 9p21 region, while linkage analysis was not fully conclusive for seven families. CONCLUSIONS: These data reinforce the hypothesis that ARF is a melanoma susceptibility gene and suggest that germline deletions specifically affecting p14ARF may not be solely responsible for NST susceptibility. Predisposition to CMM+NST could either be due to complete disruption of the CDKN2A locus or be the result of more complex genetic inheritance. In addition, the absence of any genetic alteration in 50 melanoma prone families or patients suggests the presence of additional tumour suppressor genes possibly in the 9p21 region, and on other chromosomes.

Harland M, Taylor CF, Chambers PA, Kukalizch K, Randerson-Moor JA, Gruis NA, de Snoo FA, ter Huurne JA, Goldstein AM, Tucker MA, Bishop DT, Bishop JA. · Genetic Epidemiology Division, Cancer Research UK Clinical Centre, St James's University Hospital, Beckett Street, Leeds LS9 7TF, England. · Oncogene. · Pubmed #15856016 No free full text.

Abstract: Germline mutations of CDKN2A that affect the p16INK4a transcript have been identified in numerous melanoma pedigrees worldwide. In the UK, over 50% of pedigrees with three or more cases of melanoma have been found to carry mutations of CDKN2A. Mutations that affect p14ARF exon 1beta exclusively are very rare. This has led to the suggestion that it is p16INK4a and not p14ARF that plays the critical role in melanoma predisposition. We report the identification of a cluster of five different germline mutations at the p14ARF exon 1beta splice donor site in melanoma pedigrees. All the five splice site variants showed evidence of being causal mutations. Three of the variants were demonstrated to result in aberrant splicing of the p14ARF mRNA, confirming their role in melanoma predisposition. No other point mutations were identified in the coding region of p14ARF. The p14ARF transcript of CDKN2A is clearly important in disease predisposition in a subset of melanoma pedigrees. Curiously, the only mutations so far reported to affect p14ARF exon 1beta exclusively have been knockout mutations. Further investigation into the spectrum of mutations observed in this gene may help clarify the exact role of p14ARF in melanoma predisposition.

Kleinerman RA, Tucker MA, Tarone RE, Abramson DH, Seddon JM, Stovall M, Li FP, Fraumeni JF. · Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD 20852-7362, USA. · J Clin Oncol. · Pubmed #15800318 No free full text.

Abstract: PURPOSE: Many children diagnosed with retinoblastoma (Rb) survive into adulthood and are prone to subsequent cancers, particularly hereditary patients, who have germline Rb-1 mutations. We have extended the follow-up of a large cohort of Rb patients for 7 more years to provide new information on the risk of additional cancers after radiotherapy in long-term survivors. PATIENTS AND METHODS: We analyzed the risk of new cancers through 2000 in 1,601 Rb survivors, diagnosed from 1914 to 1984, at two US medical centers. The standardized incidence ratio (SIR) was calculated as the ratio of the observed number of cancers after hereditary and nonhereditary Rb to the expected number from the Connecticut Tumor Registry. The cumulative incidence of a new cancer after hereditary and nonhereditary Rb and radiotherapy was calculated with adjustment for competing risk of death. RESULTS: Subsequent cancer risk in 963 hereditary patients (SIR, 19; 95% CI, 16 to 21) exceeded the risk in 638 nonhereditary Rb patients (SIR, 1.2; 95% CI, 0.7 to 2.0). Radiation further increased the risk of another cancer in hereditary patients by 3.1-fold (95% CI, 2.0 to 5.3). Hereditary patients continued to be at significantly increased risk for sarcomas, melanoma, and cancers of the brain and nasal cavities. The cumulative incidence for developing a new cancer at 50 years after diagnosis of Rb was 36% (95% CI, 31% to 41%) for hereditary and 5.7% (95% CI, 2.4% to 11%) for nonhereditary patients. CONCLUSION: Hereditary Rb predisposes to a variety of new cancers over time, with radiotherapy further enhancing the risk of tumors arising in the radiation field.