Clinical and Functional Genomics Group, ACCamargo Cancer Center, Sao Paulo, São Paulo, Brazil.
Clinical Oncology Department, ACCamargo Cancer Center, Sao Paulo, Brazil.
J Med Genet. 2023 Dec 21;61(1):61-68. doi: 10.1136/jmg-2023-109269.
Sarcomas are a rare and diverse group of cancers occurring mainly in young individuals for which an underlying germline genetic cause remains unclear in most cases.
Germline DNA from 177 children, adolescents and young adults with soft tissue or bone sarcomas was tested using multigene panels with 113 or 126 cancer predisposing genes (CPGs) to describe the prevalence of germline pathogenic/likely pathogenic variants (GPVs). Subsequent testing of a subset of tumours for loss of heterozygosity (LOH) evaluation was performed to investigate the clinical and molecular significance of these variants.
GPVs were detected in 21.5% (38/177) of the patients (15.8% in children and 21.6% in adolescents and young adults), with dominant CPGs being altered in 15.2% overall. These variants were found in genes previously associated with the risk of developing sarcomas (, , , ) but also in genes where that risk is still emerging/limited (, and ) or unknown (, , and others). The detection rates of GPVs varied from 0% to 33% across sarcoma subtypes and GPV carriers were more likely to present more than one primary tumour than non-carriers (21.1%×6.5%; p=0.012). Loss of the wild-type allele was detected in 48% of tumours from GPV carriers, mostly in genes definitively associated with sarcoma risk.
Our findings reveal that a high proportion of young patients with sarcomas presented a GPV in a CPG, underscoring the urgency of establishing appropriate genetic screening strategies for these individuals and their families.
肉瘤是一组罕见且多样化的癌症，主要发生在年轻人中，大多数情况下，其潜在的种系遗传原因尚不清楚。
使用包含 113 或 126 个癌症易感基因（CPG）的多基因panel 对 177 名患有软组织或骨肉瘤的儿童、青少年和年轻成年人的种系 DNA 进行了检测，以描述种系致病性/可能致病性变异（GPV）的发生率。随后对肿瘤的亚组进行杂合性缺失（LOH）评估的检测，以研究这些变异的临床和分子意义。
在 177 名患者中的 21.5%（38/177）检测到 GPV，儿童中的发生率为 15.8%，青少年和年轻成年人中的发生率为 21.6%。总的来说，15.2%的患者改变了显性 CPG。这些变异存在于先前与肉瘤发病风险相关的基因中（、、、），但也存在于风险仍在出现/有限（、和）或未知（、、和其他）的基因中。肉瘤亚型之间 GPV 的检出率从 0%到 33%不等，GPV 携带者比非携带者更有可能出现多个原发性肿瘤（21.1%×6.5%；p=0.012）。GPV 携带者的肿瘤中有 48%失去了野生型等位基因，主要是在与肉瘤风险明确相关的基因中。
我们的研究结果表明，很大一部分患有肉瘤的年轻患者存在 CPG 中的 GPV，这突显了为这些个体及其家属制定适当的遗传筛查策略的紧迫性。
