Institute of Biomedical Technology/BioMediTech, University of Tampere and Fimlab Laboratories, Tampere, Finland.
PLoS One. 2013 Aug 13;8(8):e71802. doi: 10.1371/journal.pone.0071802. eCollection 2013.
Inherited factors predisposing individuals to breast and ovarian cancer are largely unidentified in a majority of families with hereditary breast and ovarian cancer (HBOC). We aimed to identify germline copy number variations (CNVs) contributing to HBOC susceptibility in the Finnish population.
A cohort of 84 HBOC individuals (negative for BRCA1/2-founder mutations and pre-screened for the most common breast cancer genes) and 36 healthy controls were analysed with a genome-wide SNP array. CNV-affecting genes were further studied by Gene Ontology term enrichment, pathway analyses, and database searches to reveal genes with potential for breast and ovarian cancer predisposition. CNVs that were considered to be important were validated and genotyped in 20 additional HBOC individuals (6 CNVs) and in additional healthy controls (5 CNVs) by qPCR.
An intronic deletion in the EPHA3 receptor tyrosine kinase was enriched in HBOC individuals (12 of 101, 11.9%) compared with controls (27 of 432, 6.3%) (OR = 1.96; P = 0.055). EPHA3 was identified in several enriched molecular functions including receptor activity. Both a novel intronic deletion in the CSMD1 tumor suppressor gene and a homozygous intergenic deletion at 5q15 were identified in 1 of 101 (1.0%) HBOC individuals but were very rare (1 of 436, 0.2% and 1 of 899, 0.1%, respectively) in healthy controls suggesting that these variants confer disease susceptibility.
This study reveals new information regarding the germline CNVs that likely contribute to HBOC susceptibility in Finland. This information may be used to facilitate the genetic counselling of HBOC individuals but the preliminary results warrant additional studies of a larger study group.
在大多数遗传性乳腺癌和卵巢癌（HBOC）家族中，导致个体易患乳腺癌和卵巢癌的遗传因素在很大程度上尚未确定。我们旨在确定导致芬兰人群 HBOC 易感性的种系拷贝数变异（CNV）。
对 84 名 HBOC 个体（BRCA1/2-启动子突变阴性且预先筛选了最常见的乳腺癌基因）和 36 名健康对照者进行了全基因组 SNP 芯片分析。通过基因本体论术语富集、通路分析和数据库搜索进一步研究了影响 CNV 的基因，以揭示具有乳腺癌和卵巢癌易感性的潜在基因。考虑到重要的 CNVs 通过 qPCR 在另外 20 名 HBOC 个体（6 个 CNVs）和额外的健康对照组（5 个 CNVs）中进行了验证和基因分型。
与对照组（432 名中的 27 名，6.3%）相比，EPHA3 受体酪氨酸激酶内含子缺失在 HBOC 个体中更为丰富（101 名中的 12 名，11.9%）（OR=1.96；P=0.055）。EPHA3 被鉴定为几种富含分子功能的基因，包括受体活性。CSMD1 肿瘤抑制基因的一个新内含子缺失和 5q15 上的纯合基因间缺失在 101 名 HBOC 个体中的 1 名（1.0%）中被发现，但在健康对照组中非常罕见（436 名中的 1 名，0.2%和 899 名中的 1 名，0.1%），表明这些变体易患疾病。
本研究揭示了导致芬兰 HBOC 易感性的种系 CNVs 的新信息。这些信息可用于促进 HBOC 个体的遗传咨询，但初步结果需要对更大的研究组进行进一步研究。
