Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma–pancreatic carcinoma–prone families

Abstract

BACKGROUND Hereditary pancreatic carcinoma shows extant phenotypic and genotypic heterogeneity as evidenced by its integral association with a variety of hereditary cancer syndromes inclusive of the familial atypical multiple mole melanoma (FAMMM) syndrome in concert with CDKN2A (p16) germline mutations. METHODS Creighton University's familial pancreatic carcinoma resource comprises 159 families of which 19 (12%) show the FAMMM cutaneous phenotypes. The authors describe eight families with the FAMMM–pancreatic carcinoma (FAMMM‐PC) association in concert with a CDKN2A germline mutation. Each family was thoroughly educated about all facets of the study, including the molecular genetics, reduced penetrance of CDKN2A mutations, and their variable expressivity. Genetic counseling was provided to each patient. RESULTS Diversity in cancer presentation within and among the families was noteworthy, wherein melanoma predominated in certain of the families whereas pancreatic carcinoma predominated in others. Early‐onset pancreatic carcinoma (at ages 35, 45, 46, and 49 years) appeared in some of the families whereas markedly later‐onset pancreatic carcinoma occurred in others. There were four incidences of melanoma and pancreatic carcinoma as double primaries in the same individuals. One patient with melanoma and pancreatic carcinoma had a third primary of breast carcinoma. Another patient had sarcoma, esophageal carcinoma, and two melanoma primaries, whereas his daughter had sarcoma and was a carrier of a CDKN2A mutation. CONCLUSIONS The authors suggest that these tumors may collectively, in concert with CDKN2A mutations, constitute a “new” putative hereditary carcinoma syndrome referred to as FAMMM‐PC. More clinical and molecular genetic research on additional families with pancreatic carcinoma in concert with the FAMMM will be required. Cancer 2002;94:84–96. © 2002 American Cancer Society.

Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling

“…2 Mutations in CDKN2A have subsequently been described in familial pancreatic cancer kindreds, some without melanoma. 3,4 Somatic mutations of CDKN2A are present in up to 95% of pancreatic tumors. 5 These findings provide further support for the premise that CDKN2A mutations have an important role in the development of pancreatic cancer.…”

“…In genetic analyses of these families, 20-40% of inherited increased melanoma susceptibility can be linked to mutations of the CDKN2A gene (p16/Ink4) located on chromosome 9p21. [2][3][4][5] As a result of the increased incidence of pancreatic cancer in melanoma families with CDKN2A mutations, it was hypothesized that mutations likely also predispose to pancreatic cancer development. 2 Mutations in CDKN2A have subsequently been described in familial pancreatic cancer kindreds, some without melanoma.…”

Family History of Pancreatic Cancer in a High‐Risk Cancer Clinic: Implications for Risk Assessment

“…Whether or not an individual who meets both HBOS and FPC criteria has a risk of PC above the increased risk imparted by a BRCA1/2 mutation is unknown. Families highly enriched in PC have been described in several cancer syndromes (Lynch et al 2001(Lynch et al , 2002. At the same time, this finding emphasizes the importance of recognizing the heterogeneity of disease presentation in a given cancer syndrome and the possible clinical implications of that variability (e.g.…”

Increased risk of malignancies in a population-based study of 818 soft-tissue sarcoma patients

“…Although no specific tumour type other than STS occurred at significantly increased risk in the present study, malignant melanoma developed in 12 patients and pancreatic cancer in four. Development of STS has been described in association with the CDKN2A mutation associated with the familial atypical multiplemole melanoma syndrome (Lynch et al, 2002(Lynch et al, , 2003. Also, endometrial cancer occurred in 11 women and colorectal cancer in 21 individuals, and some of these cases could signify Lynch syndrome, since STS has been described herein (Sijmons et al, 2000;Medina Arana et al, 2002;Hirata et al, 2006).…”

“…Among these, the most well-known are neurofibromatosis due to mutations in the NF1 gene with an increased risk for neurofibrosarcomas and the Li -Fraumeni syndrome caused by germline mutations in TP53 with increased risks for STS, leukaemia, brain tumours, and breast cancer (Lynch et al, 2003). However, STS have been associated also with premature ageing within the Werner syndrome and Rothmund -Thomson syndrome due to mutations in the genes WRN and RECQ4 (Yu et al, 1996;Lindor et al, 2000) and has been described to develop in melanoma syndrome kindreds with CDKN2A mutations and in Lynch syndrome families with mutations in mismatch-repair genes (Sijmons et al, 2000;Lynch et al, 2002Lynch et al, , 2003Medina Arana et al, 2002;Hirata et al, 2006). In addition, STS occur in familial forms with yet unidentified modes of inheritance and underlying genetic causes.…”