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Pancreatic Cancer Analysis Unearths Outcome-Related Pathogenic BRCA Pathway Mutations

NEW YORK (GenomeWeb) – A new study suggests that pathogenic mutations affecting BRCA pathway genes such as BRCA1, BRCA2, and PALB2 may be more common in sporadic forms of pancreatic ductal adenocarcinoma (PDAC) than previously thought.

Researchers from Tokyo Women's Medical University, Tohoku University, and elsewhere used targeted BRCA pathway gene sequencing, BRCA2 expression profiling, and mutation hotspot testing in 50 cancer-related genes to assess samples from more than three dozen individuals with sporadic PDAC and four individuals with familial forms of the disease. Their results, published online today in Scientific Reports, highlighted rare, germline mutations in BRCA pathway genes in nearly 29 percent of the PDAC cases considered — variants that appeared to coincide with better five year survival times.

"Patients harboring potentially deleterious mutations in the BRCA pathway genes showed significantly better prognosis than those with benign mutations or no mutation," senior author Toru Furukawa, an integrated medical science and histopathology researcher affiliated with Tokyo Women's Medical University and Tohoku University, and his co-authors wrote. They noted 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."

While germline mutations in BRCA pathway genes such as BRCA1, BRCA2, and PALB2 have been relatively well documented in familial forms of PDAC, less is known about the proportion of sporadic PDAC cases marked by BRCA pathway mutations — alterations that may help in identifying tumors most apt to respond to platinum-based chemotherapy or PARP inhibitors.

"[W]e aimed to analyze mutations in BRCA pathway genes as well as 50 cancer-associated genes concurrently in apparently sporadic, surgically resected PDAC to evaluate molecular epidemiological and clinicopathological characteristics in BRCA pathway-mutated PDACs," the authors explained.

The researchers used Ion Torrent instruments to do targeted sequencing on BRCA1, BRCA2, and PALB2 coding sequences in matched tumor and normal samples from 42 individuals with surgically resected PDAC. They also profiled mutation hotspots in 50 oncogenes or tumor suppressor genes with the Ion Ampliseq Cancer Hotspot panel.

From these data, the team documented 13 new and known rare, germline variants in BRCA pathway genes, which occurred in 12 of the PDAC cases, or roughly 29 percent. All but two of the germline variants affected BRCA2 mutations, with single variants identified in the BRCA1 and PALB2 genes.

The researchers took a closer look at specific BRCA2 mutations using tumor expression data, uncovering new pathogenic mutations in the germline. By folding in overall survival rates at five years, meanwhile, they saw significantly better outcomes in PDAC cases marked by potentially deleterious BRCA pathway mutations.

PDAC patients with such variants had average five-year survival rates of nearly 69 percent compared with 19 percent survival rates at five years in those with wild-type BRCA pathway genes or benign mutations in this pathway.

"[T]he results suggest that rare germline variations in BRCA pathway genes may be found in patients with PDAC relatively more frequently than previously anticipated," Furukawa and his colleagues wrote. "Hence, testing for mutations in BRCA pathway genes could be warranted not only in familial cases but also in apparently sporadic cases."

Across the broader set of cancer-related genes, the team identified two germline changes to the MLH1 genes. It also narrowed in on 68 somatic alterations in known PDAC contributors such as TP53, KRAS, SMAD4, and CDKN2A, including new variants in some of the genes, but did not detect clear ties between the BRCA pathway variants and the other cancer gene mutations.