人工智能指导下的 TP53 p.R337H 携带者儿童肾上腺皮质肿瘤风险变异识别:一项遗传关联研究

IF 7 Q1 HEALTH CARE SCIENCES & SERVICES Lancet Regional Health-Americas Pub Date : 2024-08-23 DOI:10.1016/j.lana.2024.100863
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引用次数: 0

摘要

背景儿童肾上腺皮质肿瘤(ACT)是Li-Fraumeni癌症谱的一部分,经常与种系TP53致病变体有关。TP53 p.R337H在巴西南部和东南部的发病率很高,易导致低渗透性肾上腺皮质肿瘤。因此,我们旨在研究是否存在与 TP53 p.R337H 携带者儿童 ACT 患病风险增加相关的遗传变异。方法:我们对巴西南部 TP53 p.R337H 携带者(14 名女孩,7 名男孩)中患有(18 人)或未患有(3 人)ACT 的三组儿童及其父母(其中一人也携带该致病变异体)(发现队列)进行了遗传关联研究。我们分析了三人血液 DNA 全外显子测序的基因组数据。利用深度学习算法,根据受影响儿童从非携带者父母处继承变体以增加患 ACT 风险的模型,我们发现在参与肾上腺皮质肿瘤发生的环磷酸腺苷(cAMP)通路的基因中,非编码变体的代表性显著增强。其中一个变异(SCARB1 基因中的 rs2278986)被证实在患有 ACT 的 TP53 p.R337H 携带者的验证队列中比没有 ACT 的携带者明显富集(OR 1.858; 95% CI 1.146, 3.042, p = 0.01)。解释对变异体rs2278986的分析是未来确认的候选对象,并有可能用作对TP53 p.R337H携带者进行ACT风险分层的工具。
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AI-guided identification of risk variants for adrenocortical tumours in TP53 p.R337H carrier children: a genetic association study

Background

Adrenocortical tumours (ACT) in children are part of the Li-Fraumeni cancer spectrum and are frequently associated with a germline TP53 pathogenic variant. TP53 p.R337H is highly prevalent in the south and southeast of Brazil and predisposes to ACT with low penetrance. Thus, we aimed to investigate whether genetic variants exist which are associated with an increased risk of developing ACT in TP53 p.R337H carrier children.

Methods

A genetic association study was conducted in trios of children (14 girls, 7 boys) from southern Brazil carriers of TP53 p.R337H with (n = 18) or without (n = 3) ACT and their parents, one of whom also carries this pathogenic variant (discovery cohort). Results were confirmed in a validation cohort of TP53 p.R337H carriers with (n = 90; 68 girls, 22 boys) or without ACT (n = 302; 165 women, 137 men).

Findings

We analysed genomic data from whole exome sequencing of blood DNA from the trios. Using deep learning algorithms, according to a model where the affected child inherits from the non-carrier parent variant(s) increasing the risk of developing ACT, we found a significantly enriched representation of non-coding variants in genes involved in the cyclic AMP (cAMP) pathway known to be involved in adrenocortical tumorigenesis. One among those variants (rs2278986 in the SCARB1 gene) was confirmed to be significantly enriched in the validation cohort of TP53 p.R337H carriers with ACT compared to carriers without ACT (OR 1.858; 95% CI 1.146, 3.042, p = 0.01).

Interpretation

Profiling of the variant rs2278986 is a candidate for future confirmation and possible use as a tool for ACT risk stratification in TP53 p.R337H carriers.

Funding

Centre National de la Recherche Scientifique (CNRS), Behring Foundation, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

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期刊介绍: The Lancet Regional Health – Americas, an open-access journal, contributes to The Lancet's global initiative by focusing on health-care quality and access in the Americas. It aims to advance clinical practice and health policy in the region, promoting better health outcomes. The journal publishes high-quality original research advocating change or shedding light on clinical practice and health policy. It welcomes submissions on various regional health topics, including infectious diseases, non-communicable diseases, child and adolescent health, maternal and reproductive health, emergency care, health policy, and health equity.
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