在常规种系诊断性染色体微阵列 (CMA) 检测中，发现了影响癌症易感基因 (CPG) 的 CNVs 作为偶然发现。

CNVs affecting cancer predisposing genes (CPGs) detected as incidental findings in routine germline diagnostic chromosomal microarray (CMA) testing.

机构信息

Manchester Centre for Genomic Medicine, Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.

出版信息

J Med Genet. 2018 Feb;55(2):89-96. doi: 10.1136/jmedgenet-2017-104892. Epub 2017 Sep 16.

DOI:10.1136/jmedgenet-2017-104892

PMID:28918392

Abstract

BACKGROUND

Identification of CNVs through chromosomal microarray (CMA) testing is the first-line investigation in individuals with learning difficulties/congenital abnormalities. Although recognised that CMA testing may identify CNVs encompassing a cancer predisposition gene (CPG), limited information is available on the frequency and nature of such results.

METHODS

We investigated CNV gains and losses affecting 39 CPGs in 3366 pilot index case individuals undergoing CMA testing, and then studied an extended cohort (n=10 454) for CNV losses at 105 CPGs and CNV gains at 9 proto-oncogenes implicated in inherited cancer susceptibility.

RESULTS

In the pilot cohort, 31/3366 (0.92%) individuals had a CNV involving one or more of 16/39 CPGs. 30/31 CNVs involved a tumour suppressor gene (TSG), and 1/30 a proto-oncogene (gain of ). , and were affected in multiple cases. In the second stage analysis, 49/10 454 (0.47%) individuals in the extended cohort had 50 CNVs involving 24/105 CPGs. 43/50 CNVs involved a TSG and 7/50 a proto-oncogene (4 gains, 3 deletions). The most frequently involved genes, (n=10) and (n=7), map to the Smith-Magenis and cri-du-chat regions, respectively.

CONCLUSION

Incidental identification of a CNV involving a CPG is not rare and poses challenges for future cancer risk estimation. Prospective data collection from CPG-CNV cohorts ascertained incidentally and through syndromic presentations is required to determine the risks posed by specific CNVs. In particular, ascertainment and investigation of adults with CPG-CNVs and adults with learning disability and cancer, could provide important information to guide clinical management and surveillance.

摘要

背景

通过染色体微阵列（CMA）测试鉴定 CNV 是学习困难/先天异常个体的一线检查方法。虽然已经认识到 CMA 测试可能会识别包含癌症易感性基因（CPG）的 CNV，但关于此类结果的频率和性质的信息有限。

方法

我们研究了 3366 名进行 CMA 测试的先导指数个体中影响 39 个 CPG 的 CNV 增益和缺失，然后研究了一个扩展队列（n=10454）中 105 个 CPG 的 CNV 缺失和 9 个涉及遗传性癌症易感性的原癌基因的 CNV 增益。

结果

在先导队列中，3366 名个体中有 31 名（0.92%）存在涉及 16/39 个 CPG 之一或多个的 CNV。30/31 的 CNV 涉及肿瘤抑制基因（TSG），而 1/30 涉及原癌基因（增益）。、和在多个病例中受到影响。在第二阶段分析中，扩展队列中的 49/10454 名个体（0.47%）存在涉及 24/105 个 CPG 的 50 个 CNV。43/50 的 CNV 涉及 TSG，而 7/50 的 CNV 涉及原癌基因（4 个增益，3 个缺失）。最常涉及的基因、和（分别为 10 个和 7 个），分别映射到 Smith-Magenis 和 cri-du-chat 区域。