Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk — NEJM

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 Advances in sequencing technology have made multigene testing, or “panel testing,” a practical option when looking for genetic variants that may be associated with a risk of breast cancer. In June 2013, the U.S. Supreme Court1 invalidated specific claims made by Myriad Genetics with respect to the patenting of the genomic DNA sequence of BRCA1 and BRCA2. Other companies immediately began to offer panel tests for breast cancer genes that included BRCA1 and BRCA2. The subsequent flourishing of gene-panel testing services (Table 1Table 1Examples of Multigene Testing Panels for Breast Cancer., and Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org) has generated much interest both within the clinical genetics community and in the popular press.2 These panels cover a total of more than 100 genes, and breast cancer is specifically mentioned as an indication for 21 of these genes. However, the fact that the technology is available does not necessarily mean that such tests are appropriate or desirable........

.... Mutations in three other DNA repair genes, RAD51C, RAD51D, and BRIP1, have shown clear evidence of an association with ovarian cancer.49-53 However, in each case, the evidence for association with breast cancer is limited. Recent exome studies and targeted sequencing studies have suggested that breast cancer is associated with deleterious variants in FANCC^,54 FANCM,55 and XRCC2.56 In none of these instances, however, does the evidence reach the threshold level (P<0.0001) that we propose for DNA-repair genes. The recent findings of deleterious mutations in RECQL in women with a strong family history of breast cancer, however, suggests that this gene confers susceptibility to breast cancer.57,58.....

Other Genes

The panels currently marketed for the prediction of risk of cancer contain many other genes, most of which have been included by virtue of their relevance to rare mendelian cancer syndromes. Variants in some of these genes may also be associated with breast cancer. Mutations in DNA mismatch-repair genes (MLH1, MSH2, MSH6, and PMS2) may be associated with breast cancer, but in a recent review, Win et al.59 concluded that the evidence was equivocal. It has also been suggested that MUTYH variants that confer a predisposition to polyposis colorectal cancer may confer a predisposition to breast cancer, but a recent case–control study reported no association.60 Another recent study suggested that carriers of MEN1 mutations may be at increased risk for breast cancer.61 A recent case–control study has reported an association between rare variants in PPM1D and breast cancer.62 However, this association does not reach our proposed significance threshold, and, in addition, the sequence variants are observed as mosaics in lymphocytes and are not inherited. There is currently no clear evidence of an association between breast cancer and any other gene.........