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Early-Onset Form of Ovarian Cancer Risk May Be Paternally Inherited

NEW YORK (GenomeWeb) – New research suggests women may inherit ovarian cancer risk locus on the copy of the X chromosome passed down from their fathers.  

A Roswell Park Cancer Institute team focused in on families with suspected X-linked ovarian cancer inheritance, following a prior observation that sisters sometimes share ovarian cancer risks higher than their mother's risk. Tapping into data for thousands of grandmother-granddaughter pairs from the Familial Ovarian Cancer Registry, the group found that ovarian cancer-affected grandmother-granddaughter pairs were more common when disease occurred in the paternal grandmother.

These cases were typically diagnosed in younger women — up to six years earlier than the average at ovarian cancer diagnosis — regardless of the women's BRCA1/2 mutation status, the researchers reported. When they did germline X-chromosome exome sequencing on 159 BRCA1/2 mutation-negative women from these pairs, they identified a missense variant in the X-chromosome gene MAGEC3 that showed chromosome-wide significant ties to early-onset ovarian cancer.

"The X-linked pattern implies novel ways to prioritize families for screening without additional testing — sisters must both be carriers or neither; fathers of women with potentially inherited ovarian cancer may receive new attention," first and corresponding author Kevin Eng, an oncology, biostatistics, and bioinformatics researcher at Roswell Park Cancer Institute, and his colleagues wrote today in PLOS Genetics.

"This finding has sparked a lot of discussion within our group about how to find these X-linked families," Eng said in a statement.

But fathers and sons in these families were not off the hook when it came to cancer risk either: the team's preliminary pedigree results suggest these men may be at enhanced risk of other cancer types such as prostate cancer. 

"Reinforcing our observation that men in X-linked families may be at increased risk of prostate cancer," the authors explained, "the cytoband housing MAGEC3 (Xq27.2) has been previously linked to these hereditary cancers, raising the possibility that there is a common hereditary X-linked locus responsible for reproductive tract-specific cancers."

For their analysis, the researchers first identified 3,499 grandmother-granddaughter pairs from a familial ovarian cancer registry that encompassed information on more than 50,000 individuals from 2,600 families collected over several decades. They whittled this set down to the 892 pairs, providing clues to ovarian cancer risk transmission, which included 157 granddaughters with ovarian cancer.

The team found that overlapping ovarian cancer diagnoses were more common in the paternal grandmother-granddaughter pairs (where the cancer rate was more than 28 percent) than in the pairs involving maternal grandmothers and their granddaughters. The latter pairs had an ovarian cancer rate just shy of 14 percent. And the presence of ovarian cancer in a paternal grandmother, but not a maternal grandmother, coincided with earlier age of onset in affected granddaughters.

In an effort to tease out the basis of this X-linked inheritance, the researchers did exome sequencing on 159 BRCA1/2 mutation-negative women from the registry, focusing on germline X chromosome and BRCA1 coding sequences. The group included 49 ovarian cancer-affected women with affected mothers, 46 cases who had an affected sister and unaffected mother, and seven ovarian cancer-affected women with an affected sister and mother.

Using this approach, they tracked down a missense mutation in MAGEC3, a gene previously put forward as a potential X-linked tumor suppressor. The variant was in linkage disequilibrium with other nearby variants, suggesting there might be an alternative causal variant or a related haploblock in the X chromosome region identified.

"[W]e cannot rule out the possibility that our reported variant is in linkage with the true variant," the authors wrote. "However, the segregation analysis and age of onset analyses do suggest that it is likely to lie on the X chromosome."