目的:目前鉴定遗传性结直肠癌(HCRC)的方法在临床实践中非常耗时。这项研究旨在开发一种节省时间的方法来诊断HCRC。
方法:前瞻性纳入了100例疑似HCRC患者(队列1)和116例DNA错配修复缺陷的结直肠癌患者(队列2)。对肿瘤和匹配的白细胞(WBC)或正常组织进行下一代测序(NGS)测试。使用基于WBC/正常组织的NGS数据的常规方法作为参考,在队列1中探索了使用基于仅肿瘤的NGS数据的ColonCore方法在预测种系变异中的表现,并在队列2中进行了验证.
结果:在队列1中,ColonCore方法诊断出17例林奇综合征(LS)和14例家族性腺瘤性息肉病(FAP);并且通过常规方法,分别为16例和10例。ColonCore方法诊断LS(阳性预测值[PPV]94.1%)和FAP(PPV71.4%)的敏感性为100%。此外,不符合HCRC现有临床标准的7例多发性腺瘤/息肉患者中,有2例预测在APC和MUTYH中存在种系变异.此外,ColonCore方法鉴别队列2中LS患者的敏感性达到85.7%,PPV为85.7%.
结论:ColonCore方法可能是预测与HCRC相关的种系变异的可接受工具。我们的工作表明NGS测试对CRC患者进行精确诊断和治疗的重要性。
OBJECTIVE: The current procedure for identifying hereditary colorectal cancer (HCRC) is time consuming in clinical practice. This study aimed to develop a time-saving approach to diagnosing HCRC.
METHODS: A total of 100 suspected HCRC patients were prospectively enrolled (cohort 1) and 116 colorectal cancer patients with DNA mismatch repair-deficient were retrospectively included (cohort 2). Next-generation sequencing (NGS) tests were performed on tumors and matched white blood cells (WBCs) or normal tissues. Using the conventional method upon WBC/normal tissue-based NGS data as a reference, the performance of the ColonCore method using tumor-only-based NGS data in predicting germline variants was explored in cohort 1 and validated in cohort 2.
RESULTS: In cohort 1, the ColonCore method diagnosed 17 Lynch syndrome (LS) and 14 familial adenomatous polyposis (FAP); and by the conventional method, the cases were 16 and 10, respectively. The ColonCore method showed sensitivities of 100% in diagnosing LS (positive predictive value [PPV] 94.1%) and FAP (PPV 71.4%). Moreover, two of seven patients with multiple adenomas/polyps who did not meet existing clinical criteria for HCRC were predicted to harbor germline variants in APC and MUTYH. Additionally, the sensitivity of the ColonCore method in identifying LS patients from cohort 2 reached 85.7% with a PPV of 85.7%.
CONCLUSIONS: The ColonCore method might be an acceptable tool for predicting germline variants associated with HCRC. Our work indicates the essentiality of NGS tests in CRC patients for precision diagnosis and treatment.