Mutations in BRCA1, BRCA2, and PALB2, and a panel of 50 cancer-associated genes in pancreatic ductal adenocarcinoma

Abstract

Mutations in genes of the breast cancer susceptibility gene (BRCA) pathway, namely, BRCA1, BRCA2, and PALB2, can provide useful information for the efficacy of platinum-based or poly ADP-ribose polymerase inhibitors chemotherapeutic regimens. Pancreatic ductal adenocarcinoma (PDAC) is an important target for such precision chemotherapies because of its dismal prognosis. We analyzed mutations in the entire coding regions of the BRCA pathway genes, expression of breast cancer 2 (BRCA2), and mutations in hotspots of 50 cancer-associated genes in 42 surgically resected PDACs, and evaluated their associations with clinicopathological features. We identified 13 rare germline mutations in the BRCA pathway genes; 68 somatic mutations in KRAS, TP53, SMAD4, CDKN2A, GNAS, SMARCB1, and RB1; and 2 germline variations in MLH1. Among them, BRCA2S2148fs was known to be pathogenic. BRCA2R18H and BRCA2G2044V were enriched in tumor tissues. BRCA2K799R and BRCA2R2964T were novel germline variations. Patients harboring potentially deleterious mutations in the BRCA pathway genes showed significantly better prognosis than those with benign mutations or no mutation. These results indicate that rare germline variations in BRCA pathway genes could be found more frequently than previously anticipated and, more importantly, potentially deleterious mutations of them could be a favorable prognostic factor in patients with resectable PDACs.

Hereditary Pancreatic Cancer: A Retrospective Single-Center Study of 5143 Italian Families with History of BRCA-Related Malignancies

“…These results may be justified by the presence of germ-line mutations that predispose these families to hereditary pancreatic, breast, and ovarian tumors. Interestingly, in line with previous literature [37,39], these findings are also confirmed in the BRCA families. Particularly, the age for pancreatic cancer diagnosis in BRCA1 families is significantly lower than in BRCA2 families and general populations, whereas short-term prognosis for patients in BRCA2 families is significantly better than for other groups of patients.…”

Homologous recombination DNA repair defects in PALB2-associated breast cancers

“…1 Bi-allelic PALB2 germline mutations (i.e., affecting both parental alleles of PALB2 ) cause Fanconi anemia, 2 whereas mono-allelic PALB2 germline mutations result in increased risk of breast, pancreatic and ovarian cancer. 3–5 The frequency of PALB2 germline mutations in familial breast cancer ranges from 0.6% to 2.7%, 4 and the average cumulative breast cancer risk in PALB2 germline mutation carriers by the age of 70 years is ~35%, 4 similar to that conferred by BRCA2 germline mutations. 6 Akin to sporadic and BRCA2 breast cancers, PALB2 -associated breast cancers are heterogeneous in terms of their clinicopathologic features, being predominantly estrogen receptor (ER)-positive.…”

Molecular characteristics of BRCA1/2 and PALB2 mutations in pancreatic ductal adenocarcinoma

“…3 8 Similarly, germline mutations in PALB2 have been associated with an increased risk of PDAC development. 9 PALB2 encodes a protein essential for double strand break repair and homologous recombination by serving as a bridging molecule, which connects the BRCA complex and stimulates the strand invasion of RAD51. 10 Targeting BRCA1/2 and PALB2 is considered an attractive therapeutic concept in various cancers, since resistance to genotoxic therapies has been associated with increased DDR signalling and many cancers harbour defects in components of this system.…”