仅仅通过癌症家族史确定遗传性乳腺癌和卵巢癌基因突变携带者并非理想的首选方法，而大多数人群基因检测研究仅仅局限于高风险人群始祖突变。
2018年9月26日，美国医学遗传学与基因组学会官方期刊、英国《自然》旗下《医学遗传学》在线发表澳大利亚彼得马卡伦癌症中心、皇家墨尔本医院、墨尔本大学、加文医学研究所、英国伦敦大学圣乔治医院的研究报告，针对健康女性人群，对确定可防治突变的临床效果进行了调查。
该研究利用11基因组定制测序对参与LifePool项目的5908位澳大利亚健康女性亚组进行种系DNA筛查。筛查检测结果临床可防治的女性被邀请到家族癌症诊所进行检测后遗传咨询和确诊检测。结局衡量指标包括致病突变发生率、遗传咨询率、减少风险手术率、其他家庭成员检测率。
结果发现，携带临床可防治致病突变女性38例，占0.64%。其中，42%的致病突变携带者并无一级亲属有乳腺癌或卵巢癌，89%随后转诊至家族性癌症诊所。13例符合指征女性其中6例（46%）接受了减少风险手术，此外每例携带者平均有3.3位其他家庭成员接受了基因检测。
因此，该研究结果表明，对于该队列女性，遗传性乳腺癌和卵巢癌基因检测被广泛接受，并且确定的大多数高风险基因携带者并无家族史，并不符合根据现有家族史进行基因检测的指南标准。
Genet Med. 2018 Sep 26. [Epub ahead of print]
Population-based genetic testing of asymptomatic women for breast and ovarian cancer susceptibility.
Simone M. Rowley, Lyon Mascarenhas, Lisa Devereux, Na Li, Kaushalya C. Amarasinghe, Magnus Zethoven, Jue Er Amanda Lee, Alexandra Lewis, James A. Morgan, Sharne Limb, Mary-Anne Young, Paul A. James, Alison H. Trainer, Ian G. Campbell.
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Royal Melbourne Hospital, Melbourne, Victoria, Australia; University of Melbourne, Melbourne, Victoria, Australia; Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Georges University Hospital NHS Foundation Trust, London, United Kingdom.
PURPOSE: The identification of carriers of hereditary breast and ovarian cancer (HBOC) gene variants through family cancer history alone is suboptimal, and most population-based genetic testing studies have been limited to founder mutations in high-risk populations. Here, we determine the clinical utility of identifying actionable variants in a healthy cohort of women.
METHODS: Germline DNA from a subset of healthy Australian women participating in the lifepool project was screened using an 11-gene custom sequencing panel. Women with clinically actionable results were invited to attend a familial cancer clinic (FCC) for post-test genetic counseling and confirmatory testing. Outcomes measured included the prevalence of pathogenic variants, and the uptake rate of genetic counseling, risk reduction surgery, and cascade testing.
RESULTS: Thirty-eight of 5908 women (0.64%) carried a clinically actionable pathogenic variant. Forty-two percent of pathogenic variant carriers did not have a first-degree relative with breast or ovarian cancer and 89% pursued referral to an FCC. Forty-six percent (6/13) of eligible women pursued risk reduction surgery, and the uptake rate of cascade testing averaged 3.3 family members per index case.
CONCLUSION: Within our cohort, HBOC genetic testing was well accepted, and the majority of high-risk gene carriers identified would not meet eligibility criteria for genetic testing based on their existing family history.
DOI: 10.1038/s41436-018-0277-0
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