SEATTLE (GenomeWeb) – Researchers have discovered a large genomic rearrangement that disrupts the DNA repair pathway gene RAD51D in a family that had been frequently affected by ovarian and breast cancer.
Brittany Burnett, a cancer genetic counselor at Sharp Memorial Hospital in San Diego, California, presented a poster describing this four-generation family at the National Society for Genetic Counselors annual education conference last week. She and her colleagues from Sharp Healthcare and Invitae started from targeted sequencing and copy number data for a 62-year-old woman who had been diagnosed with epithelial ovarian cancer at the age of 61.
Looking at nearly three dozen known or suspected breast or gynecological cancer risk genes evaluated in that woman's genome, the team narrowed in on a large deletion spanning two exons of RAD51D. That prompted more detailed copy number analyses in the DNA of her family members, which unearthed the same deletion in two of her breast or ovarian cancer-affected relatives.
While many of the recurrent alterations identified so far in genes conferring risk for hereditary cancers have involved single base changes or small insertions and deletions, Burnett and her co-authors noted, the new data suggests large germline rearrangements in RAD51D can also ramp up hereditary cancer risk.
A related gene called RAD51C — which codes for a protein that binds the BRCA1 and BRCA2 gene products — has been implicated in breast and ovarian cancer. Myriad Genetics obtained an exclusive license for the gene in 2012 and the firm included RAD51C in the first eight genes assessed by the myRisk Hereditary Cancer panel.
RAD51D is also included in Myriad's myRisk Hereditary Cancer panel, though it is primarily considered an ovarian cancer risk gene. Somewhat less is known about its potential contributions to breast cancer risk, though there are hints from past studies that it may be involved with that condition as well.
A 2011 study in Nature Genetics uncovered several inactivating germline mutations in individuals from families that were inordinately affected by breast or ovarian cancer, while a 2012 paper in the British Journal of Cancer identified coding mutation in RAD51D in a breast and ovarian cancer-prone family from Canada. A Journal of Clinical Oncology paper published in late 2014 detected RAD51C and RAD51D mutations in a subset of individuals with triple-negative breast cancer without BRCA1 or BRCA2 germline mutations.
Alterations in the gene may influence still other types of cancer. Loss of heterozygosity involving RAD51D was recurrently detected in a study of more than 4,000 individuals with a dozen cancer types, published late last year. And this summer, investigators from the Fred Hutchinson Cancer Research Center and elsewhere identified germline mutations in RAD51D and several other genes in men with metastatic prostate cancer.
For the new analysis, Burnett and her team used Invitae's CNVitae algorithm to search for duplications and deletions in targeted next-generation sequence data for a cousin of the ovarian cancer-affected proband who had been diagnosed with ductal carcinoma breast cancer when she was 61 years old and ovarian cancer when she was 68. They also tested samples from a deceased aunt with suspected ovarian cancer and two of the proband's sisters.
The search uncovered the same RAD51D exon 9 and 10 deletion in the proband, cousin, aunt, and a cancer-free sister who had had a hysterectomy and oophorectomy many years earlier, which may have mitigated her cancer risk. Another of the proband's sisters tested negative for the RAD51D deletion and had not been diagnosed with cancer.
"Our findings support the inclusion of RAD51D in the list of genes in which gross deletions/duplications are considered for hereditary cancer risk," Burnett and her co-authors concluded on the poster presented at NSGC.