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Breast Cancer Risk Genes Unearthed in Exome Sequence Meta-Analysis

NEW YORK – An international team has uncovered new genes contributing to breast cancer risk in women of European ancestry through an analysis that included protein-coding sequences for more than 244,000 cases and controls.

"[W]e knew already of around 10 genes involved in breast cancer susceptibility with BRCA1, BRCA2, PALB2, ATM and CHEK2 being the most important," co-senior and co-corresponding author Douglas Easton, a researcher at the University of Cambridge's Centre for Cancer Genetic Epidemiology, said in an email. "This study showed that by conducting exome-wide sequencing on a very large scale it is possible to identify more genes."

For a paper published in Nature Genetics on Thursday, Easton and his colleagues brought together exome sequencing profiles for hundreds of thousands of women of European ancestry from the UK Biobank project, the "Breast cancer risk after diagnostic gene sequencing" (BRIDGES) study, and the "Personalized risk assessment for prevention and early detection of breast cancer: integration and implementation" (PERSPECTIVE) research effort, which included 26,268 individuals diagnosed with breast cancer and nearly 217,700 unaffected control individuals.

Using a meta-analysis approach, the team searched for rare missense variants or protein-truncating variants (PTVs) associated with breast cancer risk, performing mutation burden tests and other analyses bolstered by breast cancer family history data.

The researchers uncovered 30 apparent risk genes in a meta-analysis focused on breast cancer-associated PTVs. Half a dozen of those genes reached exome-wide significant associations, they reported, including the proposed tumor suppressor gene MAP3K1 and five well-known breast cancer contributor genes (BRCA1/2, CHEK2, PALB2, and ATM). Other potential tumor suppressor-coding genes such as ATRIP showed more modest ties to breast cancer risk in the PTV analysis, as did the LZTR1, CDH1, RAD51D, and BARD1 genes.

A broader set of 40 genes, including MGAT5, coincided with breast cancer cases occurring before the age of 50. On the other hand, individuals with PTVs in ATRIP tended to develop breast cancer after 50 years old.

As reported in prior studies, the team found that PTVs in BRCA1 were overrepresented in individuals who developed triple-negative breast cancer, whereas alterations affecting CHEK2 turned up more often in individuals with estrogen receptor-positive breast cancer. The presence of rare missense germline mutations in EXOC4 tracked with HER2-positive tumor development, and PTVs or missense variants in still other genes provided tumor pathology clues.

The researchers highlighted 18 genes that appeared to contribute to breast cancer susceptibility in their rare missense mutation-focused meta-analysis. Just one gene — CHEK2 — reached exome-wide significance in the missense variant analyses.

Their combined analyses of PTVs and predicted deleterious missense variants led to exome-wide significant associations involving BRCA1/2, PALB2, CHEK2, and ATM. Depending on the rare missense variant classification and analysis strategy used, the combined mutation analysis also pointed to significant ties between breast cancer risk and alterations involving CDKN2A.

Along with gene and pathway analyses that highlighted DNA double-strand break repair, hormone biosynthesis, and other pathways, the investigators brought in additional whole-genome sequencing data from the UK Biobank project to estimate the proportion of still uncharacterized heritability that might be explained by large rearrangements and/or non-coding sequence changes.

"Overall, we estimate that all new genes would contribute about 2 percent to the familial risk of breast cancer — suggesting that most of what is left to find is in the non-coding genome," Easton noted.

Based on results so far, the authors suggested that germline changes in some 90 genes may contribute to breast cancer susceptibility, though still larger studies are needed to explore that possibility further and to validate the current findings.

Within the set of new risk gene suspects found in the current study, Easton noted that rare germline alterations in the MAP3K1 had the most pronounced ties to breast cancer, conferring risk that was on par with that previously linked to PALB2 alterations. Meanwhile, changes in other candidate risk genes appeared to coincide with moderate breast cancer risk similar to that reported for ATM or CHEK2 risk variants.

"From a clinical viewpoint, it would be relatively straightforward to add new genes to genetic testing panels that are already widely used," Easton said. "This would identify more women at increased risk who could be offered enhanced screening or other preventative options."

"Some further validation will be needed to confirm the levels of risk," he added, "but implementation could then happen quite rapidly."