Other factors which predicted the presence of a BRCA2 mutation included a case of breast cancer diagnosed at age 35 or below (P = 0.01) and a family history of pancreatic cancer (P = 0.03).
To investigate whether the BRCA2 gene plays a role in carcinogenesis of hepatocellular carcinomas or pancreatic cancers in view of frequent losses of heterozygosity on chromosome 13q12-13 in those tumors, we screened the entire coding region of this gene for mutations in 60 hepatocellular carcinomas and 36 pancreatic cancers.
Germline mutations of BRCA2 are predicted to account for approximately 35% of families with multiple case, early onset female breast cancer, and they are also associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer.
Germline mutations of BRCA1 are also associated with ovarian cancer and mutations of BRCA2 are associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer.
Germline mutations in BRCA2 have been shown to predispose to both breast and pancreatic cancer, germline mutations in p16 to melanoma and pancreatic cancer (the FAMMM syndrome), and genetic mutations in STK11/LKB1 to pancreatic cancer in patients with the Peutz-Jeghers Syndrome (PJS).
In patients from group A, >80% of the coding sequence of BRCA2 was analysed; in patients from group B, the regions in which germline BRCA2 mutations have been described to be associated with pancreatic cancer were screened.
These findings confirm the increased risk of pancreatic cancer in individuals with BRCA2 mutations and identify germ-line BRCA2 mutations as the most common inherited genetic alteration yet identified in familial pancreatic cancer.
Germline mutations in the BRCA2, CDKN2A/p16, hMSH2, hMLH1, hPMS1, hPMS2, LKB1/STK1, and PRSS1 genes have been associated with increased risk for pancreatic cancer.
Some studies have shown that families with germline mutations in the breast cancer susceptibility gene BRCA2 have an increased risk of breast and ovarian cancers, as well as a modestly increased risk of pancreatic cancer.
BRCA2 is an FA gene and additionally conveys an inherited risk for breast, ovarian, and pancreatic cancer for individuals carrying a single mutated allele [N. G. Howlett et al., Science (Wash. DC), 297: 606-609, 2002].
Proportion of ovarian cancer was increased in the 5' portion of BRCA1, and presence of prostate or pancreatic cancer in a family was correlated with presence of ovarian cancer in BRCA2.
Since carriers of germline BRCA2 gene mutations have an increased risk of developing pancreatic cancer, the FA pathway has been investigated as a tumor suppressor pathway in pancreatic cancer.Recently van der Heijden et al. identified FANCC and FANCG gene mutations in patients with young-onset pancreatic cancer.
Individuals with a high-risk genetic background require counseling, genetic testing if appropriate (BRCA2 mutation or p16INK4A inactivity) and secondary screening for pancreatic cancer in specialist centers.
In particular, the relative risk to male BRCA2 mutation carriers is high before age 65 years, largely attributable to breast, prostate, and pancreatic cancers.