FEATURED , Research , Risk Assessment , Genetic Testing

Peter D. Beitsch, MD/

Do we now start testing patients who have familial BC but not BRCA 1 or 2?

Four Additional Genes Added to the List of Associated Breast Cancer Risk

As we do more and more genetic testing with ever expanding panels, we discover more genes related to breast cancer. 

Familial aggregation of breast cancerIn this paper (abstract below) from a large French cohort of Hereditary Breast and Ovarian Cancer families, 4 genes not previously associated with breast cancer were added to the list!  And even more interesting (and not really surprising) that pathogenic variants in the same gene carry different risks of developing breast cancer - in this case ATM.  The more we test, the more we learn and push the field forward.

Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost‐effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of this study was to assess the contribution of rare, deleterious‐predicted variants in DNA repair genes in familial breast cancer (BC) in a well‐characterized and homogeneous population. We analysed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC (N=1,207), and general population controls (N=1,199). Sequencing data were filtered for rare loss‐of‐function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2, ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI, MAST1, POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (ORLoF=17.4 vs. ORMV=1.6; PHet=0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious‐predicted variants in PALB2, ATM and CHEK2 and to add MAST1, POLH, RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates. 

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