Pathogenic Variants in Adult-Onset Cancer Predisposition Genes in Pediatric Cancer: Prevalence and Impact on Tumor Molecular Features and Clinical Management.
Pathogenic Variants in Adult-Onset Cancer Predisposition Genes in Pediatric Cancer: Prevalence and Impact on Tumor Molecular Features and Clinical Management.
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儿童癌症中成人发病的癌症易感基因的致病变异：患病率及其对肿瘤分子特征和临床治疗的影响。
DOI：
10.1158/1078-0432.ccr-22-2482
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Nichols,KimE
中科院分区：
文献类型：
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作者：
McGee,RoseB;Oak,Ninad;Harrison,Lynn;Xu,Ke;Nuccio,Regina;Blake,AliseK;Mostafavi,Roya;Lewis,Sara;Taylor,LeslieM;Kubal,Manish;Ouma,Annastasia;Hines-Dowell,StacyJ;Cheng,Cheng;Furtado,LarissaV;Nichols,KimE
儿童肿瘤的临床基因组测序越来越多地揭示成人发病的癌症易感基因（aoCPG）的致病变异。然而，人们对aoCPG变异是种系起源的频率以及它们是否影响肿瘤分子特征和/或临床护理仍然知之甚少。在本研究中，我们检查了aoCPG变异的患病率、谱和对肿瘤基因组特征和患者管理的影响。实验设计这是一项对1018名患有癌症的儿童进行回顾性研究，这些儿童接受了肿瘤的临床基因组测序。对肿瘤基因组数据进行查询，寻找影响24个预选aocpg的致病变异。对现有肿瘤全基因组测序（WGS）数据进行二次命中突变、杂合性缺失（LOH）、DNA突变特征和同源重组缺陷（HRD）的评估。肿瘤携带一种或多种致病性aoCPG变异的患者，根据遗传性癌症评估和家庭或提供者偏好，进行随后的种系检测。结果33例（3%）患者的肿瘤含有影响一个或多个aocpg的致病变异。在21个具有足够WGS测序数据的肿瘤中，6个肿瘤（29%）具有影响剩余aoCPG等位基因的第二hit或LOH，其中4个肿瘤（67%）也表现出与改变的aoCPG一致的DNA突变特征。另外两个肿瘤表现为HRD，与已鉴定的aoCPG变体的关系不确定。完成种系检测的26例患者中有21例（81%）种系aoCPG变异阳性。所有种系阳性患者都被告知未来的癌症风险、监测和降低风险的措施。没有患者因aoCPG数据而立即改变癌症治疗。结论saocpg变异在小儿肿瘤中罕见；然而，许多起源于生殖系。几乎三分之一的肿瘤aoCPG变异表现出第二次命中和/或赋予异常DNA突变谱，表明其在肿瘤形成中起作用。aoCPG信息有助于癌症风险预测，但不常用于改变儿童癌症的治疗。
PurposeClinical 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.Experimental DesignThis 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.ResultsThirty-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.ConclusionsAoCPG 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.