Phenotypic and Histopathological Tumor Characteristics According to CDKN2A Mutation Status among Affected Members of Melanoma Families

Taylor, Nicholas; Handorf, Elizabeth A.; Mitra, Nandita; Avril, Marie Françoise; Azizi, Esther; Bergman, Wilma; Bianchi‐Scarrǎ, Giovanna; Bishop, D. Timothy; Paillerets, Brigitte Bressac-de; Calista, Donato; Cannon‐Albright, Lisa A.; Cuéllar, Francisco; Cust, Anne E.; Demenais, Florence; Elder, David E.; Friedman, Eitan; Gerdes, Anne; Ghiorzo, Paola; Goldstein, Alisa M.; Grazziotin, Thaís Corsetti; Hansson, Johan; Hayward, Nicholas K.; Hočevar, Marko; Höiom, Veronica; Holland, Elizabeth A.; Ingvar, Christian; Landi, Maria Teresa; Landman, Gilles; Larre-Borges, Alejandra; Leachman, Sancy A.; Mann, Graham J.; Nagore, Eduardo; Olsson, Håkan; Palmer, Jane M.; Perić, Barbara; Pjanova, Dace; Puig, Susana; Schmid, Helen; Stoep, Nienke van der; Tucker, Margaret A.; Wadt, Karin; Whitaker, Linda; Yang, Xiaohong R.; Newton-Bishop, Julia; Gruis, Nelleke A.; Kanetsky, Peter A.

doi:10.1016/j.jid.2016.01.009

Cited by 14 publications

(17 citation statements)

References 15 publications

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“…Our results for US melanoma-prone families are consistent with two prior studies that reported the phenotypic characteristics for CDKN2A (n ¼ 670 individuals; Taylor et al, 2016) and CDK4 (n ¼ 140 individuals; Puntervoll et al, 2013) carriers from North America, Europe, and Global P-value adjusting for age at diagnosis, gender, and superficial spreading melanoma subtype.…”

Section: Discussionsupporting

confidence: 91%

“…CDKN2A and CDK4 carriers in melanoma-prone families also demonstrated a high frequency of superficial spreading melanomas, which is consistent with prior studies (Sargen et al, 2015;Taylor et al, 2016). This association suggests that alterations of the CDKN2A(p16)/CDK4 pathway are important in the development of tumors with this histologic subtype.…”

Section: Discussionsupporting

confidence: 89%

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Variation in Cutaneous Patterns of Melanomagenesis According to Germline CDKN2A/CDK4 Status in Melanoma-Prone Families

Sargen

Pfeiffer

Yang

et al. 2020

Journal of Investigative Dermatology

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CDKN2A and CDK4 are well-established melanoma susceptibility genes, but their effect on tumor location and distribution is unknown. We used a caseecase study design to assess for differences in tumor location between mutation carriers (CDKN2A ¼ 141 patients, 348 melanomas; CDK4 ¼ 15 patients, 54 melanomas) and noncarriers (104 patients, 157 melanomas) in US melanoma-prone families. Associations between groups were assessed with chi-square tests. Odds ratios (ORs) for tumor location were adjusted for diagnosis age, gender, and superficial spreading subtype. Models included random effects to account for within individual and family correlations. Compared with having a truncal melanoma, CDK4 (vs. noncarriers: lower extremities OR ¼ 14.5, 95% confidence interval [CI] ¼ 5.02e42.0, P < 0.001; upper extremities OR ¼ 6.88, 95% CI ¼ 2.37e19.9, P < 0.001; head and neck OR ¼ 18.6, 95% CI ¼ 4.04e85.2, P < 0.001) and CDKN2A (vs. noncarriers: lower extremities OR ¼ 3.01, 95% CI ¼ 1.56e5.82, P < 0.05; upper extremities OR ¼ 1.91, 95% CI ¼ 1.03e3.52, P < 0.05; head and neck OR ¼ 5.40, 95% CI ¼ 2.10e13.9, P < 0.001) carriers had higher odds of developing melanoma at all other sites. Similar findings were observed for analyses stratified by gender, age, and first versus subsequent melanoma diagnoses. Further studies are needed to understand the biology underlying these genotype-associated patterns of tumor development, which could provide new insights into melanoma treatment and prevention.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

Variation in Cutaneous Patterns of Melanomagenesis According to Germline CDKN2A/CDK4 Status in Melanoma-Prone Families

Sargen

Pfeiffer

Yang

et al. 2020

Journal of Investigative Dermatology

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“…published) impact on the biological function of CDKN2A or bioinformatically inferred deleterious impact on CDKN2A function, and evidence of cosegregation within melanoma families. Variants not meeting any of these criteria were classified as benign (Taylor et al , 2016). Individual participants were classified based on presence of a pathogenic mutation; benign variant carriers and wildtype individuals were combined for analyses and classified as having “no known pathogenic” mutations at CDKN2A .…”

Section: Methodsmentioning

confidence: 99%

Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families

Taylor

Mitra

Goldstein

et al. 2017

Journal of Investigative Dermatology

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Germline mutations in the cyclin-dependent kinase inhibitor 2A gene (CDKN2A) are frequently identified among melanoma kindreds, and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2 mm, 5 mm, and atypical nevus counts among blood-related members of melanoma families. Compared to individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (OR=1.64; 95% CI: 1.18, 2.28) nevi, but not 2 mm nevi (OR=1.06; 95% CI: 0.92, 1.21) or 5 mm nevi (OR=1.26; 95% CI: 0.94, 1.70). Stratification by case status revealed more pronounced positive associations among non-case family members, who were nearly three times (OR=2.91; 95% CI: 1.75, 4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results are supportive of the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis.

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“…GenoMEL used a common protocol to obtain research data as previously described. [10] Written informed consent was obtained from each participant, and individual GenoMEL centers received study approval from their respective institutional review boards. Consenting participants completed a self-administered questionnaire that solicited information on phenotypic characteristics, and personal and family history of melanoma and other cancers.…”

Section: Study Populationmentioning

confidence: 99%

“…Consenting participants completed a self-administered questionnaire that solicited information on phenotypic characteristics, and personal and family history of melanoma and other cancers. [10,11]…”

Section: Study Populationmentioning

confidence: 99%

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT

Taylor

Mitra

Lü

et al. 2019

Journal of the American Academy of Dermatology

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Phenotypic and Histopathological Tumor Characteristics According to CDKN2A Mutation Status among Affected Members of Melanoma Families

Cited by 14 publications

References 15 publications

Variation in Cutaneous Patterns of Melanomagenesis According to Germline CDKN2A/CDK4 Status in Melanoma-Prone Families

Variation in Cutaneous Patterns of Melanomagenesis According to Germline CDKN2A/CDK4 Status in Melanoma-Prone Families

Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT

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