Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee.
Clin Cancer Res. 2023 Apr 3;29(7):1243-1251. doi: 10.1158/1078-0432.CCR-22-2482.
Clinical genomic sequencing of pediatric tumors is increasingly uncovering pathogenic variants in adult-onset cancer predisposition genes (aoCPG). Nevertheless, it remains poorly understood how often aoCPG variants are of germline origin and whether they influence tumor molecular profiles and/or clinical care. In this study, we examined the prevalence, spectrum, and impacts of aoCPG variants on tumor genomic features and patient management at our institution.
This is a retrospective study of 1,018 children with cancer who underwent clinical genomic sequencing of their tumors. Tumor genomic data were queried for pathogenic variants affecting 24 preselected aoCPGs. Available tumor whole-genome sequencing (WGS) data were evaluated for second hit mutations, loss of heterozygosity (LOH), DNA mutational signatures, and homologous recombination deficiency (HRD). Patients whose tumors harbored one or more pathogenic aoCPG variants underwent subsequent germline testing based on hereditary cancer evaluation and family or provider preference.
Thirty-three patients (3%) had tumors harboring pathogenic variants affecting one or more aoCPGs. Among 21 tumors with sufficient WGS sequencing data, six (29%) harbored a second hit or LOH affecting the remaining aoCPG allele with four of these six tumors (67%) also exhibiting a DNA mutational signature consistent with the altered aoCPG. Two additional tumors demonstrated HRD, of uncertain relation to the identified aoCPG variant. Twenty-one of 26 patients (81%) completing germline testing were positive for the aoCPG variant in the germline. All germline-positive patients were counseled regarding future cancer risks, surveillance, and risk-reducing measures. No patients had immediate cancer therapy changed due to aoCPG data.
AoCPG variants are rare in pediatric tumors; however, many originate in the germline. Almost one third of tumor aoCPG variants examined exhibited a second hit and/or conferred an abnormal DNA mutational profile suggesting a role in tumor formation. aoCPG information aids in cancer risk prediction but is not commonly used to alter the treatment of pediatric cancers.
对儿科肿瘤进行临床基因组测序，越来越多地揭示出成人发病癌症易感性基因（aoCPG）中的致病性变异。然而，人们对这些变异是种系来源的频率以及它们是否影响肿瘤分子谱和/或临床治疗知之甚少。在本研究中，我们在本机构检查了 aoCPG 变异对肿瘤基因组特征和患者管理的患病率、谱和影响。
这是一项对 1018 名患有癌症的儿童进行肿瘤临床基因组测序的回顾性研究。对影响 24 个预选 aoCPG 的致病性变异进行了肿瘤基因组数据查询。对可用的肿瘤全基因组测序（WGS）数据进行了二次打击突变、杂合性丢失（LOH）、DNA 突变特征和同源重组缺陷（HRD）的评估。根据遗传性癌症评估和家族或提供者偏好，对其肿瘤携带一个或多个致病性 aoCPG 变异的患者进行了随后的种系检测。
33 名患者（3%）的肿瘤携带影响一个或多个 aoCPG 的致病性变异。在具有足够 WGS 测序数据的 21 个肿瘤中，有 6 个（29%）携带影响剩余 aoCPG 等位基因的二次打击或 LOH，其中 6 个肿瘤中的 4 个（67%）还表现出与改变的 aoCPG 一致的 DNA 突变特征。另外两个肿瘤表现出 HRD，与所鉴定的 aoCPG 变异不确定相关。完成种系检测的 26 名患者中的 21 名（81%）种系检测呈阳性。所有种系阳性患者均接受了有关未来癌症风险、监测和降低风险措施的咨询。由于 aoCPG 数据，没有患者的癌症治疗立即发生改变。
aoCPG 变异在儿科肿瘤中罕见；然而，许多变异起源于种系。研究中检查的肿瘤 aoCPG 变异中有近三分之一表现出二次打击和/或表现出异常的 DNA 突变谱，提示其在肿瘤形成中的作用。aoCPG 信息有助于癌症风险预测，但通常不用于改变儿科癌症的治疗。
