目的:遗传性乳腺癌和卵巢癌(HBOC)和Lynch综合征(LS)的常染色体显性癌症易感性疾病是遗传条件,早期识别和干预对个人和公众健康有积极影响。这项研究的目的是确定使用外显子组测序的种系遗传筛选是否可以用于有效地鉴定HBOC和LS的携带者。
方法:参与者来自美国三个地理和种族不同的地点(罗切斯特,MN;凤凰城,AZ;杰克逊维尔,FL).参与者接受了外显子组+测序(HelixInc,圣马特奥,CA)和特定遗传发现的结果返回:HBOC(BRCA1和BRCA1)和LS(MLH1,MSH2,MSH6,PMS2和EPCAM)。进行图表审查以收集人口统计信息以及个人和家族癌症史。
结果:迄今为止,44,306名参与者已注册Tapestry。HBOC和LS基因中所有变体的注释和解释导致550个携带者的鉴定(患病率,1.24%),其中包括387例HBOC(27.2%BRCA1,42.8%BRCA2)和163例LS(12.3%MSH6,8.8%PMS2,4.5%MLH1,3.8%MSH2和0.2%EPCAM)。这些参与者中有一半以上(52.1%)是新诊断的HBOC和LS携带者。总之,39.2%的HBOC/LS携带者不满足国家综合癌症网络(NCCN)的遗传评估标准。与自我报告的白人种族相比,在代表性不足的少数民族人群中,NCCN标准较不常见(51.5%v37.5%,P=.028)。
结论:我们的研究结果强调需要更广泛地利用种系基因测序来增强LS和HBOC癌症易感性综合征个体的筛查和检测。
OBJECTIVE: The autosomal dominant cancer predisposition disorders hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) are genetic conditions for which early identification and intervention have a positive effect on the individual and public health. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC and LS.
METHODS: Participants were recruited from three geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; Jacksonville, FL). Participants underwent Exome+ sequencing (Helix Inc, San Mateo, CA) and return of results for specific genetic findings: HBOC (BRCA1 and BRCA1) and LS (MLH1, MSH2, MSH6, PMS2, and EPCAM). Chart review was performed to collect demographics and personal and family cancer history.
RESULTS: To date, 44,306 participants have enrolled in Tapestry. Annotation and interpretation of all variants in genes for HBOC and LS resulted in the identification of 550 carriers (prevalence, 1.24%), which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM). More than half of these participants (52.1%) were newly diagnosed carriers with HBOC and LS. In all, 39.2% of HBOC/LS carriers did not satisfy National Comprehensive Cancer Network (NCCN) criteria for genetic evaluation. NCCN criteria were less commonly met in underrepresented minority populations versus self-reported White race (51.5% v 37.5%, P = .028).
CONCLUSIONS: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have LS and HBOC cancer predisposition syndromes.