Gupta Sumati, Greenberg Samantha, Grimmett Jade, Gaston David, Agarwal Neeraj, Lowrance William, Schiffman Joshua, Kohlmann Wendy
Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.
University of Utah School of Medicine, 30 N. 1900 E, Salt Lake City, UT, 84112, USA.
Fam Cancer. 2017 Oct;16(4):545-550. doi: 10.1007/s10689-017-9980-2.
Interpretation of next-generation sequencing (NGS) of tumor tissue in patients with advanced Urinary Tract Cancer (UTC) is performed to guide treatment selection but may reveal pathogenic variants with germline implications. We identified three patients with UTC with unexpected germline DNA repair gene mutations. Specific testing for these was prompted by the detection of these mutations by tumor NGS. All three patients were nonsmokers with a strong family history of cancer. Two patients had upper tract UTC with age at diagnosis in the 40 s. One had a family history suggestive of hereditary breast/ovarian predisposition and a FANCA mutation detected on NGS was confirmed to be germline. The second patient had a family history suggestive of Lynch syndrome but was found to have a germline BRCA2 mutation that was suggested by NGS. The third patient had bladder cancer at an advanced age, a family history of late-onset gastrointestinal malignancies that did not meet criteria for clinical testing for a hereditary cancer predisposition syndrome. NGS identified an MUTYH mutation, and targeted testing confirmed a monoallelic germline MUTYH mutation. Detection of variants with germline implications by tumor NGS may be clinically relevant for patients and their families and warrant genetic counseling and germline genetic testing. The prevalence of germline DNA repair defects in the context of inherited predisposition to UTC merits further study.
对晚期尿路上皮癌（UTC）患者的肿瘤组织进行下一代测序（NGS）解读，旨在指导治疗方案的选择，但可能会揭示具有种系意义的致病变异。我们识别出三名患有UTC且存在意外种系DNA修复基因突变的患者。肿瘤NGS检测到这些突变后，促使我们对其进行了特定检测。所有三名患者均不吸烟，且有很强的癌症家族史。两名患者患有上尿路UTC，诊断时年龄在40多岁。其中一名患者有提示遗传性乳腺癌/卵巢癌易感性的家族史，NGS检测到的FANCA突变经确认是种系突变。第二名患者有提示林奇综合征的家族史，但经发现有NGS提示的种系BRCA2突变。第三名患者高龄时患膀胱癌，有晚发性胃肠道恶性肿瘤家族史，但不符合遗传性癌症易感性综合征的临床检测标准。NGS识别出一个MUTYH突变，靶向检测确认了单等位基因种系MUTYH突变。肿瘤NGS检测到具有种系意义的变异可能对患者及其家族具有临床相关性，需要进行遗传咨询和种系基因检测。在遗传性UTC易感性背景下种系DNA修复缺陷的患病率值得进一步研究。
