Investigators Identify Patterns of Rare Germline Variants in 12 Cancer Types

A new study is taking a look at the inherited components of 12 cancer types. The study was published in the December 22, 2015 issue of Nature Communications and systematically analyzed 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. The investigators found that the frequency of rare germline truncations in 114 cancer susceptibility-associated genes varies widely.

The analysis suggests that rare germline truncations occurred in 4% of acute myeloid leukemia (AML), in 19% of ovarian cancer, and in a surprisingly high frequency in 11% of stomach cancer cases.

“In general, we have known that ovarian and breast cancers have a significant inherited component, and others, such as acute myeloid leukemia and lung cancer, have a much smaller inherited genetic contribution,” said senior author Li Ding, PhD, associate professor of medicine and assistant director of the McDonnell Genome Institute at Washington University, in a press release. “But this is the first time on a large scale that we’ve been able to pinpoint gene culprits or even the actual mutations responsible for cancer susceptibility.”

Dr. Ding and colleagues identified 13 cancer genes with significant enrichment of rare truncations. Some rare truncations associated with specific cancers included RAD51C in AML, PALB2 in stomach cancer and MSH6 in endometrial cancers. They also discovered there was significant tumor-specific loss of heterozygosity that occured in 9 genes (ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2 and RAD51C/D).

The new information has implications for improving the accuracy of existing genetic tests for cancer risk and eventually expanding the available tests to include a wider variety of tumors. By examining germline mutations in tumors they found that it was not enough for the mutations simply to be present. The mutations needed to be enriched in the tumor. In 114 genes known to be associated with cancer, they found rare germline mutations in all 12 cancer types, but in varying frequencies depending on the type.

“We also found a significant number of germline truncations in the BRCA1 and BRCA2 genes present in tumor types other than breast cancer, including stomach and prostate cancers,” said Ding. “This suggests we should pay attention to the potential involvement of these two genes in other cancer types.”

Dr. Ding said among the patients with BRCA1 truncations in the germline, 90% had BRCA1 truncation enriched in the tumor, regardless of cancer type. However, Ding said more research is warranted to confirm these results before they can be used to advise patients making healthcare decisions.