Association of rare variants with familial breast cancer
Résumé
Germline mutations in the mismatch repair genes , , , and predispose to Lynch syndrome (also known as hereditary non-polyposis colorectal cancer). Recently, we have shown that the 1100delC mutation also is associated with Lynch syndrome/Lynch syndrome-associated families albeit in a polygenic setting. Two of the ten 1100delC positive Lynch syndrome families additionally carried a pathogenic or mutation suggesting that mutations in mismatch repair genes may be involved in 1100delC-associated cancer phenotypes. A phenotype of importance is hereditary breast and colorectal cancer (HBCC), with the 1100delC mutation present in almost one-fifth of the families—again in a polygenic setting. In order to evaluate the involvement of in polygenic CHEK2 cancer susceptibility, we, here, have analyzed the entire coding sequence for genetic alterations in 68 HBCC breast cancer families. Rare variants, with population frequencies below 1%, were identified in 11.8% of HBCC breast cancer families, whereas the same variants were identified in only 1.5% of population controls, suggesting that rare variants are associated with HBCC breast cancer ( ≤ 0.00001). However, screening of the entire coding sequence in 68 non-HBCC breast cancer families showed a similar association (8.8 vs. ~1.4% in controls, ≤ 0.001), suggesting that rare variants are not confined to HBCC breast cancer. Together, our data suggest that rare variants may predispose to familial breast cancer. However, none of the rare variants are obviously pathogenic, suggesting that a more subtle disease mechanism may operate in breast carcinogenesis.
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