Multiple primary tumors (MPTs) are a harbinger of hereditary cancer syndromes. Affected individuals often fit genetic testing criteria for a number of hereditary cancer genes and undergo multigene panel testing. Other genomic testing options, such as whole exome (WES) and whole genome sequencing (WGS) are available, but the utility of these genomic approaches as a second-tier test for those with uninformative multigene panel testing has not been explored. Here, we report our germline sequencing results from WGS in 9 patients with MPTs who had non-informative multigene panel testing. Following germline WGS, sequence (agnostic or 735 selected genes) and copy number variant (CNV) analysis was performed according to the American College of Medical Genetics (ACMG) standards and guidelines for interpreting sequence variants and reporting CNVs. In this cohort, WGS, as a second-tier test, did not identify additional pathogenic or likely pathogenic variants in cancer predisposition genes. Although we identified a CHEK2 likely pathogenic variant and a MUTYH pathogenic variant, both were previously identified in the multigene panels and were not explanatory for the presented type of tumors. CNV analysis also failed to identify any pathogenic or likely pathogenic variants in cancer predisposition genes. In summary, after multigene panel testing, WGS did not reveal any additional pathogenic variants in patients with MPTs. Our study, based on a small cohort of patients with MPT, suggests that germline gene panel testing may be sufficient to investigate these cases. Future studies with larger sample sizes may further elucidate the additional utility of WGS in MPTs.

多原发性肿瘤（MPT）是遗传性癌症综合征的先兆。受影响的个体通常符合许多遗传性癌症基因的基因检测标准，并接受多基因小组检测。还可以使用其他基因组测试选项，例如全外显子组 (WES) 和全基因组测序 (WGS)，但尚未探索这些基因组方法作为针对那些信息不丰富的多基因组测试的第二层测试的实用性。在这里，我们报告了 9 名 MPT 患者的全基因组测序结果，这些患者进行了非信息性多基因面板测试。种系全基因组测序后，根据美国医学遗传学学会 (ACMG) 标准和指南进行序列（不可知或 735 个选定基因）和拷贝数变异 (CNV) 分析，以解释序列变异和报告 CNV。在该队列中，WGS 作为二级测试，没有发现癌症易感基因中的其他致病或可能致病变异。尽管我们鉴定了一个 CHEK2 可能的致病性变异和一个MUTYH 致病性变异，但这两种变异之前都在多基因组中鉴定过，并且不能解释所呈现的肿瘤类型。CNV 分析也未能识别出癌症易感基因中的任何致病性或可能的致病性变异。总之，经过多基因组测试后，WGS 并未发现 MPT 患者存在任何其他致病性变异。我们的研究基于一小群 MPT 患者，表明种系基因组测试可能足以调查这些病例。未来更大样本量的研究可能会进一步阐明 WGS 在 MPT 中的额外效用。