CDKN2A Germline Mutations in Familial Pancreatic Cancer

Abstract

CDKN2A germline mutations are rare in FPC families. However, these data provide further evidence for a pancreatic cancer-melanoma syndrome associated with CDKN2A germline mutations affecting p16. Thus, all members of families with combined occurrence of pancreatic cancer and melanoma should be counseled and offered screening for p16 mutations to identify high-risk family members who should be enrolled in a clinical screening program.

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

“…3,33,34 This study represents the largest study of this gene in an unselected series of pancreatic cancer patients. As such, there are multiple observations in this descriptive study.…”

“…25 However, one smaller study of 23 families with familial pancreatic cancer revealed two truncating mutations (both in families also affected by melanoma) affecting p16 but none in p14ARF. 3 With regard to the type of mutation in CDKN2A, one previous report suggests that splicing mutations were more common in melanoma families affected with pancreatic cancer than in those without (17 vs 5% of mutations), 29 however, the underlying reason for an individual developing pancreatic cancer rather than melanoma is not yet fully understood.…”

“…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.…”

p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors

“…Furthermore, in families with BRCA2, MMR genes and INK4/ARF locus mutations, there is an increased risk of cutaneous melanoma, acute lymphatic leukemia and blast leukemia in childhood (Magnusson et al, 2008;Daniotti et al, 2009). Similarly, mutations in the INK4/ARF locus gene have been detected in familial atypical mole multiple melanoma syndrome, and in individuals with combined occurrence of pancreatic cancer and melanoma (Bartsch et al, 2002;Ghiorzo et al, 2004;Hruban et al, 2007). Finally, INK4/ARF locus/CDK4 germline mutations associated with BRCA1, BRCA2 and p53 alterations have been described in familial breast carcinoma (Monnerat et al, 2007).…”