Engelmark Malin T, Ivansson Emma L, Magnusson Jessica J, Gustavsson Inger M, Beskow Anna H, Magnusson Patrik K E, Gyllensten Ulf B
Department of Genetics and Pathology, Section of Medical Genetics, Rudbeck Laboratory, University of Uppsala, Sweden.
Hum Mol Genet. 2006 Nov 15;15(22):3351-60. doi: 10.1093/hmg/ddl411. Epub 2006 Oct 11.
Cervical cancer is caused by a combination of environmental and genetic risk factors. Infection by oncogenic types of human papillomavirus is recognized as the major environmental risk factor and epidemiological studies indicate that host genetic factors predispose to disease development. A number of genetic susceptibility factors have been proposed, but with exception of the human leukocyte antigen CHLA, class II, have not shown consistent results among studies. We have performed the first genomewide linkage scan using 278 affected sib-pairs to identify loci involved in susceptibility to cervical cancer. A two-step qualitative non-parametric linkage analysis using 387 microsatellites with an average spacing of 10.5 cM revealed excess allelic sharing at nine regions on eight chromosomes. These regions were further analysed with 125 markers to increase the map density to 1.28 cM. Nominal significant linkage was found for three of the nine loci [9q32 (maximum lod-score, MLS) =1.95, P<0.002), 12q24 (MLS=1.25, P<0.015) and 16q24 (MLS=1.35, P<0.012)]. These three regions have previously been connected to human cancers that share characteristics with cervical carcinoma, such as esophageal cancer and Hodgkin's lymphoma. A number of candidate genes involved in defence against viral infections, immune response and tumour suppression are found in these regions. One such gene is the thymic stromal co-transporter (TSCOT). Analyses of TSCOT single nucleotide polymorphisms further strengthen the linkage to this region (MLS=2.40, P<0.001). We propose that the 9q32 region contains susceptibility locus for cervical cancer and that TSCOT is a candidate gene potentially involved in the genetic predisposition to this disease.
宫颈癌是由环境和遗传风险因素共同作用引起的。致癌型人乳头瘤病毒感染被认为是主要的环境风险因素，流行病学研究表明宿主遗传因素易导致疾病发展。已经提出了许多遗传易感因素，但除了人类白细胞抗原Ⅱ类（HLA）外，各研究结果并不一致。我们首次使用278对患病同胞对进行全基因组连锁扫描，以确定与宫颈癌易感性相关的基因座。使用平均间距为10.5厘摩（cM）的387个微卫星进行两步定性非参数连锁分析，结果显示在8条染色体上的9个区域存在等位基因过度共享。使用125个标记对这些区域进行进一步分析，将图谱密度提高到1.28厘摩。在9个基因座中的3个发现了名义上显著的连锁关系[9q32（最大对数优势得分，MLS）=1.95，P<0.002]、12q24（MLS=1.25，P<0.015）和16q24（MLS=1.35，P<0.012）。此前已发现这三个区域与具有宫颈癌共同特征的人类癌症有关，如食管癌和霍奇金淋巴瘤。在这些区域发现了许多参与抗病毒感染、免疫反应和肿瘤抑制的候选基因。其中一个这样的基因是胸腺基质共转运蛋白（TSCOT）。对TSCOT单核苷酸多态性的分析进一步加强了与该区域的连锁关系（MLS=2.40，P<0.001）。我们认为9q32区域包含宫颈癌的易感基因座，TSCOT是一个可能参与该疾病遗传易感性的候选基因。
