Kontham Vinaykumar, von Holst Susanna, Lindblom Annika
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
PLoS One. 2013 Dec 11;8(12):e83936. doi: 10.1371/journal.pone.0083936. eCollection 2013.
Family history is a major risk factor for colorectal cancer and many families segregate the disease as a seemingly monogenic trait. A minority of familial colorectal cancer could be explained by known monogenic genes and genetic loci. Familial polyposis and Lynch syndrome are two syndromes where the predisposing genes are known but numerous families have been tested without finding the predisposing gene. We performed a genome wide linkage analysis in 121 colorectal families with an increased risk of colorectal cancer. The families were ascertained from the department of clinical genetics at the Karolinska University Hospital in Stockholm, Sweden and were considered negative for Familial Polyposis and Lynch syndrome. In total 600 subjects were genotyped using single nucleotide polymorphism array chips. Parametric- and non-parametric linkage analyses were computed using MERLIN in all and subsets of families. No statistically significant result was seen, however, there were suggestive positive HLODs above two in parametric linkage analysis. This was observed in a recessive model for high-risk families, at locus 9q31.1 (HLOD=2.2, rs1338121) and for moderate-risk families, at locus Xp22.33 (LOD=2.2 and HLOD=2.5, rs2306737). Using families with early-onset, recessive analysis suggested one locus on 4p16.3 (LOD=2.2, rs920683) and one on 17p13.2 (LOD/HLOD=2.0, rs884250). No NPL score above two was seen for any of the families. Our linkage study provided additional support for the previously suggested region on chromosome 9 and suggested additional loci to be involved in colorectal cancer risk. Sequencing of genes in the regions will be done in future studies.
家族史是结直肠癌的主要危险因素,许多家族将该疾病作为一种看似单基因性状进行遗传。少数家族性结直肠癌可由已知的单基因和基因位点来解释。家族性息肉病和林奇综合征是两种已知易感基因的综合征,但许多家族经过检测并未发现易感基因。我们对121个患结直肠癌风险增加的结直肠癌家族进行了全基因组连锁分析。这些家族来自瑞典斯德哥尔摩卡罗林斯卡大学医院临床遗传学系,被认为不存在家族性息肉病和林奇综合征。总共600名受试者使用单核苷酸多态性阵列芯片进行基因分型。使用MERLIN对所有家族及其子集进行参数和非参数连锁分析。未观察到具有统计学意义的结果,然而,在参数连锁分析中,有一些提示性的阳性全基因组优势对数(HLOD)高于2。在高危家族的隐性模型中,在9q31.1位点观察到这种情况(HLOD = 2.2,rs1338121);在中度风险家族中,在Xp22.33位点观察到(LOD = 2.2且HLOD = 2.5,rs2306737)。对早发性家族进行隐性分析表明,在4p16.3有一个位点(LOD = 2.2,rs920683),在17p13.2有一个位点(LOD/HLOD = 2.0,rs884250)。没有一个家族的非参数连锁(NPL)得分高于2。我们的连锁研究为先前提出的9号染色体区域提供了额外支持,并提示其他位点可能与结直肠癌风险有关。未来的研究将对这些区域的基因进行测序。