Dunford Andrew, Weinstock David M, Savova Virginia, Schumacher Steven E, Cleary John P, Yoda Akinori, Sullivan Timothy J, Hess Julian M, Gimelbrant Alexander A, Beroukhim Rameen, Lawrence Michael S, Getz Gad, Lane Andrew A
Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Nat Genet. 2017 Jan;49(1):10-16. doi: 10.1038/ng.3726. Epub 2016 Nov 21.
There is a striking and unexplained male predominance across many cancer types. A subset of X-chromosome genes can escape X-inactivation, which would protect females from complete functional loss by a single mutation. To identify putative 'escape from X-inactivation tumor-suppressor' (EXITS) genes, we examined somatic alterations from >4,100 cancers across 21 tumor types for sex bias. Six of 783 non-pseudoautosomal region (PAR) X-chromosome genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) harbored loss-of-function mutations more frequently in males (based on a false discovery rate < 0.1), in comparison to zero of 18,055 autosomal and PAR genes (Fisher's exact P < 0.0001). Male-biased mutations in genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon. We conclude that biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence in females as compared to males across a variety of tumor types.
在许多癌症类型中，存在着显著且无法解释的男性主导现象。X染色体基因的一个子集能够逃避X染色体失活，这会保护女性免受单个突变导致的完全功能丧失。为了鉴定假定的“逃避X染色体失活的肿瘤抑制基因”（EXITS），我们检查了来自21种肿瘤类型的4100多种癌症的体细胞改变，以寻找性别偏差。与18055个常染色体和假常染色体区域（PAR）基因中无一例相比，783个非PAR X染色体基因中的6个（ATRX、CNKSR2、DDX3X、KDM5C、KDM6A和MAGEC3）在男性中更频繁地携带功能丧失突变（基于错误发现率<0.1，Fisher精确检验P<0.0001）。在多种癌症的联合分析以及几种个别肿瘤类型中均观察到逃避X染色体失活的基因存在男性偏向性突变，这表明这是一种普遍现象。我们得出结论，女性中EXITS基因的双等位基因表达解释了与男性相比，多种肿瘤类型中女性癌症发病率降低的部分原因。
