目的：对乳腺癌患者进行种系突变BRCA1/2检测指导临床管理是一种标准方法。新一代基因测序（NGS）方法使得检测到乳腺癌其他易感基因突变成为可能。通过用NGS进行种系突变频率的检测在那些乳腺癌或者三阴乳腺癌中推荐BRCA1/2检测已有报道。我们对25种包括BRCA1/2癌症易感基因的突变频率和预测因素进行了评估，同时在一研究机构中通过序列分析的乳腺癌患者以了解在这类群体基因检测的意义。
方法：入组患者包括2010～2012年期间在一个癌症中心已确认为Ⅰ～Ⅲ期并同意加入DNA库研究共488例乳腺癌患者。获得其个人及肿瘤家族史和种系DNA，应用NGS方法对突变进行确认。
结果：确认了10.7%女性患者携带有害基因突变：6.1%的BRCA1/2突变（非犹太人患者占5.1%）和4.6%其他乳腺/卵巢癌包括CHEK2（n=10）、ATM（n=4）、BRIP1（n=4）以及PALB2、PTEN、NBN、RAD51C、RAD51D、MSH6和PMS2之一的易感基因突变。然而，除了年轻患者（P＜0.01），犹太人种（P＜0.01），三阴性乳腺癌（P=0.01）及有乳腺癌/卵巢癌家族史（P=0.01）对BRCA1/2突变有预测价值外，在其他乳腺癌肿瘤易感基因中未发现有预测因子。
结论：在乳腺癌患者基因序列分析中，用一组25个易感基因检测发现有10.7%的患者有存在一个使女性有患乳腺癌或卵巢癌的倾向的种系突变基因。但当这些基因仅作为一个单一组进行分析时，其预测BRCA1/2突变的预测因素并不能预测其他乳腺/卵巢癌易感基因突变的情况。额外的检测将有助于明确那些除了BRCA1/2突变的高危携带突变基因个体。
J Clin Oncol. 2016 Mar 14. [Epub ahead of print]
Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer.
Tung N, Lin NU, Kidd J, Allen BA, Singh N, Wenstrup RJ, Hartman AR, Winer EP, Garber JE.
Beth Israel Deaconess Medical Center; Dana-Farber Cancer Institute; Harvard Medical School, Boston, MA; Myriad Genetic Laboratories, Inc., Salt Lake City, UT.
PURPOSE: Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population.
METHODS: Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations.
RESULTS: Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes.
CONCLUSION: Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define individuals at higher risk of carrying mutations in genes other than BRCA1/2.
PMID: 26976419
PII: JCO650747
DOI: 10.1200/JCO.2015.65.0747
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