Original article
Increased prevalence of lung, breast, and pancreatic cancers in addition to melanoma risk in families bearing the cyclin-dependent kinase inhibitor 2A mutation: Implications for genetic counseling

Presented in part as an oral communication at the European Organization for Research and Treatment of Cancer melanoma group meeting in Majorca, Spain, on September 13-14, 2013.
https://doi.org/10.1016/j.jaad.2014.06.036Get rights and content

Background

Cyclin-dependent kinase inhibitor 2A (CDKN2A) is the major high-risk susceptibility gene for melanoma.

Objective

We sought to evaluate the effect of CDKN2A mutations in Spanish patients with a high risk of developing melanoma and the association with clinical and family history features.

Methods

A cross-sectional study design was used to analyze the CDKN2A impact in 702 Spanish patients with a high risk of developing melanoma.

Results

The CDKN2A mutation prevalence was 8.5% in patients with sporadic multiple primary melanoma and 14.1% in familial melanoma. Number of cases in the family, number of primary melanomas, and age of onset were associated with the presence of CDKN2A mutation. Having a CDKN2A mutation in the family increased the prevalence of other cancers (prevalence ratio [PR] 2.99, P = .012) and prevalence of pancreatic (PR 2.97, P = .006), lung (PR 3.04, P < .001), and breast (PR 2.19, P = .018) cancers but not nephrourologic or colon cancer.

Limitations

Smoking status was not assessed in the individuals with lung cancer.

Conclusions

Melanoma-prone families with mutations in CDKN2A have an increased prevalence of a broad spectrum of cancers including lung, pancreatic, and breast cancer. This information should be included in genetic counseling and cancer prevention programs for CDKN2A mutation carriers.

Section snippets

Patients

A cross-sectional study design was used to analyze the CDKN2A impact in patients with a high risk of developing melanoma. Overall, 702 patients with melanoma were included in the study: 236 patients with sporadic multiple primary melanoma (SMP), and 466 patients with familial melanoma belonging to 330 high-risk melanoma-prone families with at least 2 melanoma cases (269 families with 2 melanoma cases, 47 families with 3 melanoma cases, 11 families with 4 melanoma cases, and 3 families with 5

Results

CDKN2A and CDK4 were tested in 702 patients with melanoma: 236 patients with SMP and 466 with familial melanoma belonging to 330 high-risk melanoma-prone families with at least 2 melanoma cases. Overall, 32 germline CDKN2A mutations were identified: 18 previously described mutations,13, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 9 mutations previously observed at the somatic level,32, 33 and 5 novel unreported mutations (data available on request). CDK4 mutations were not observed.

Several

Discussion

In this study we have explored the effect of germline mutations in CDKN2A, which is the major high-risk melanoma susceptibility gene, in the largest Spanish cohort to our knowledge of patients at high risk (SMP and familial melanoma cases). Overall, we found a slightly increased prevalence of CDKN2A mutations in melanoma-prone families than in SMP, consistent with that reported in similar studies from other Mediterranean areas.34, 35, 36

Previous studies have found an association between the

References (41)

  • A.M. Goldstein et al.

    High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL

    Cancer Res

    (2006)
  • H.F. Vasen et al.

    Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden)

    Int J Cancer

    (2000)
  • B. Mukherjee et al.

    Risk of non-melanoma cancers in first-degree relatives of CDKN2A mutation carriers

    J Natl Cancer Inst

    (2012)
  • P. Ghiorzo et al.

    Characterization of ligurian melanoma families and risk of occurrence of other neoplasia

    Int J Cancer

    (1999)
  • A. Borg et al.

    High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families

    J Natl Cancer Inst

    (2000)
  • S. Puig et al.

    Inherited susceptibility to several cancers but absence of linkage between dysplastic nevus syndrome and CDKN2A in a melanoma family with a mutation in the CDKN2A (P16INK4A) gene

    Hum Genet

    (1997)
  • C. Badenas et al.

    Genetic counseling in melanoma

    Dermatol Ther

    (2012)
  • S.A. Leachman et al.

    Selection criteria for genetic assessment of patients with familial melanoma

    J Am Acad Dermatol

    (2009)
  • Ribes J, Esteban L, Cleries R, Galceran J, Marcos-Gragera R, Gispert R, et al. Cancer incidence and mortality...
  • S.A. Miller et al.

    A simple salting out procedure for extracting DNA from human nucleated cells

    Nucleic Acids Res

    (1988)
  • Cited by (51)

    • Associations of genetic susceptibility to 16 cancers with risk of breast cancer overall and by intrinsic subtypes

      2022, Human Genetics and Genomics Advances
      Citation Excerpt :

      There is some biological evidence to support the association of breast cancer risk with these newly identified genetic variants. For example, several studies suggested that cyclin-dependent kinase inhibitor 2A (CDKN2A gene, encoding for tumor suppressor proteins, MIM: 600160), well known as a susceptibility gene for melanoma and pancreatic cancer, may also be involved in breast tumorigenesis.43–45 Activation of mitogen-activated protein kinases (MAPK) in breast cancer leads to increased proliferation, invasion, and metastasis of breast cancer.46–48

    • Palbociclib in advanced acral melanoma with genetic aberrations in the cyclin-dependent kinase 4 pathway

      2021, European Journal of Cancer
      Citation Excerpt :

      Thus, there is an urgent unmet need to search for treatment alternatives for patients with advanced AM. Aberrations in the p16-cyclin D1-cyclin-dependent kinase (CDK)4/6-Rb pathway have been implicated in 22–78% of melanomas [5–7]. Oncogenic alterations that disrupt function of this pathway are linked to melanoma genesis and may be critical early oncogenic events that drive tumour progression [8].

    • Hereditary melanoma: A five-year study of brazilian patients in a cancer referral center-phenotypic characteristics of probands and pathological features of primary tumors

      2018, Anais Brasileiros de Dermatologia
      Citation Excerpt :

      Studies have shown an increased risk of developing pancreatic carcinoma in European and North American families with CDKN2A mutations.12 Additionally, FMS may be associated with other cancers, such as central nervous system tumors, uveal melanoma, lung and breast carcinomas.12-15 We have been monitoring families at high risk for cutaneous melanoma since June 2010.

    View all citing articles on Scopus

    The research at the Melanoma Unit in Barcelona is partially funded by Spanish Fondo de Investigaciones Sanitarias grants 09/01393 and 12/00840; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) of the Instituto de Salud Carlos III, Spain; Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) grant 2009 SGR 1337 of the Catalan Government, Spain; European Commission under the Sixth Framework Program, contract no. LSHC-CT-2006-018702 (GenoMEL); and National Cancer Institute of the US National Institutes of Health (CA83115). Ms Potrony had a personal grant from the CIBERER of the Instituto de Salud Carlos III, Spain. The work was carried out at the Esther Koplowitz Center, Barcelona.

    Ms Potrony and Dr Puig-Butillé contributed equally to this work.

    Conflicts of interest: None declared.

    View full text