Eleven candidate susceptibility genes for common familial colorectal cancer.
Eleven candidate susceptibility genes for common familial colorectal cancer.
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DOI：
10.1371/journal.pgen.1003876
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Aaltonen LA
中科院分区：
文献类型：
--
作者：
Gylfe AE;Katainen R;Kondelin J;Tanskanen T;Cajuso T;Hänninen U;Taipale J;Taipale M;Renkonen-Sinisalo L;Järvinen H;Mecklin JP;Kilpivaara O;Pitkänen E;Vahteristo P;Tuupanen S;Karhu A;Aaltonen LA
据推测，遗传因素在三分之一的结直肠癌（CRC）病例中起作用。然而，在大多数家族性CRC病例中，易感性的遗传基础仍然无法解释。对于受影响人数很少的家庭来说尤其如此。为了确定这种常见表型的易感基因，我们研究了来自1514名芬兰CRC患者的家族性病例。96例家族性CRC患者既往未诊断为遗传性CRC综合征，纳入分析。86例患者有一个受影响的一级亲属，10例患者有两个或更多。外显子组测序被用来搜索携带推定的功能丧失变体的基因，因为这样的改变可能是致病突变的候选者。在两个或三个家族性CRC病例中鉴定出11个具有罕见截短变体的基因：UACA、SFXN4、TWSG1、PSPH、NUDT 7、ZNF 490、PRSS 37、CCDC 18、PRADC 1、MRPL 3和AKR1C4。在所有相应的癌症样本中检查杂合性缺失，并在涉及四个候选基因的七个场合中检测到杂合性缺失。在所有七种情况下，野生型等位基因丢失（P = 0.0078），提供了额外的证据表明，这11个基因可能包括真正的罪魁祸首。 该研究提供了一组候选易感基因，可以解释常见家族性CRC的一个子集。需要在其他人群中进行额外的遗传验证，以提供因果关系的确凿证据，并描述相应表型的自然史。许多有结直肠癌家族史的个体在已知的癌症易感基因中没有可检测到的种系突变。我们的目的是通过对96例独立的家族性结直肠癌病例进行外显子组测序来鉴定这种常见表型的新易感基因。86例患者有一个受影响的一级亲属，10例患者有两个或更多。没有一个病人以前被诊断为遗传性综合征。我们把搜索的重点放在具有罕见变异的基因上，这些基因预计会截短蛋白质产物，因为这些基因可能是疾病易感性的候选基因。使用这种方法，我们确定了11个基因的截断种系变异，存在于两个或三个独立的家族性结直肠癌病例中。我们分析了各自的肿瘤DNA，发现七分之七的情况下野生型等位基因丢失，涉及四个基因。没有肿瘤显示突变等位基因的丢失，这为我们提供了疾病因果关系的额外证据。需要进一步的研究来提供致病性的确凿证据。关于已确认的易感基因的遗传知识最终可以转化为携带易感等位基因的个体的癌症预防和早期诊断的工具。
Hereditary factors are presumed to play a role in one third of colorectal cancer (CRC) cases. However, in the majority of familial CRC cases the genetic basis of predisposition remains unexplained. This is particularly true for families with few affected individuals. To identify susceptibility genes for this common phenotype, we examined familial cases derived from a consecutive series of 1514 Finnish CRC patients. Ninety-six familial CRC patients with no previous diagnosis of a hereditary CRC syndrome were included in the analysis. Eighty-six patients had one affected first-degree relative, and ten patients had two or more. Exome sequencing was utilized to search for genes harboring putative loss-of-function variants, because such alterations are likely candidates for disease-causing mutations. Eleven genes with rare truncating variants in two or three familial CRC cases were identified: UACA, SFXN4, TWSG1, PSPH, NUDT7, ZNF490, PRSS37, CCDC18, PRADC1, MRPL3, and AKR1C4. Loss of heterozygosity was examined in all respective cancer samples, and was detected in seven occasions involving four of the candidate genes. In all seven occasions the wild-type allele was lost (P = 0.0078) providing additional evidence that these eleven genes are likely to include true culprits. The study provides a set of candidate predisposition genes which may explain a subset of common familial CRC. Additional genetic validation in other populations is required to provide firm evidence for causality, as well as to characterize the natural history of the respective phenotypes. Many individuals with a family history of colorectal cancer have no detectable germline mutation in the known cancer predisposing genes. We aimed to identify novel susceptibility genes for this common phenotype by performing exome sequencing on 96 independent cases with familial colorectal cancer. Eighty-six patients had one affected first-degree relative, and ten patients had two or more. None of the patients had a previous diagnosis of a hereditary syndrome. We focused our search on genes with rare variants, predicted to truncate the protein product, since these are likely candidates for disease predisposition. Using this approach we identified truncating germline variants in eleven genes, present in two or three independent familial colorectal cancer cases. We analyzed the respective tumor DNAs and found loss of the wild-type allele in seven out of seven occasions, involving four genes. No tumor showed loss of the mutant allele which provides us with additional evidence for disease causality. Further studies are required to provide firm evidence for pathogenicity. Genetic knowledge on confirmed predisposing genes can ultimately be translated into tools for cancer prevention and early diagnosis in individuals carrying predisposition alleles.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Dunlop MG;Dobbins SE;Farrington SM;Jones AM;Palles C;Whiffin N;Tenesa A;Spain S;Broderick P;Ooi LY;Domingo E;Smillie C;Henrion M;Frampton M;Martin L;Grimes G;Gorman M;Semple C;Ma YP;Barclay E;Prendergast J;Cazier JB;Olver B;Penegar S;Lubbe S;Chander I;Carvajal-Carmona LG;Ballereau S;Lloyd A;Vijayakrishnan J;Zgaga L;Rudan I;Theodoratou E;Colorectal Tumour Gene Identification (CORGI) Consortium;Starr JM;Deary I;Kirac I;Kovacević D;Aaltonen LA;Renkonen-Sinisalo L;Mecklin JP;Matsuda K;Nakamura Y;Okada Y;Gallinger S;Duggan DJ;Conti D;Newcomb P;Hopper J;Jenkins MA;Schumacher F;Casey G;Easton D;Shah M;Pharoah P;Lindblom A;Liu T;Swedish Low-Risk Colorectal Cancer Study Group;Smith CG;West H;Cheadle JP;COIN Collaborative Group;Midgley R;Kerr DJ;Campbell H;Tomlinson IP;Houlston RS
通讯作者：
Houlston RS
影响因子：
254.7
作者：
Parkin, DM;Bray, F;Pisani, P
通讯作者：
Pisani, P
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
5
作者：
Lubbe, Steven J.;Di Bernardo, Maria Chiara;Houlston, Richard S.
通讯作者：
Houlston, Richard S.