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研究揭示种系致病性在肿瘤发生中的特定背景作用
2021-11-12 17:00

美国纪念斯隆-凯特琳癌症中心Michael F. Berger团队揭示种系致病性在肿瘤发生中的特定背景作用。2021年11月5日出版的《自然—遗传学》发表了这项成果。

通过研究17152名前瞻性测序的癌症患者,研究人员确定了癌症易感基因的致病种系变异,并评估了它们的合子型和伴随肿瘤的体细胞改变的共同发生。肿瘤发生的两个主要途径是明显的。在高致病性基因的致病性种系变体携带者中(总比例为5.1%),双亲失活的谱系依赖性模式导致肿瘤表现出机制特定的体细胞表型和较少的额外体细胞致癌驱动。

然而,这些患者中有27%的癌症,以及在低倾向性基因中具有致病性种系变异患者中的大多数肿瘤,缺乏与种系等位基因相关肿瘤发生的特殊特征。肿瘤对致病性种系变体的依赖性是可变的,而且往往由渗透率和血统决定,这一发现对临床管理有影响。

据了解,人类癌症产生于环境、遗传和体细胞因素,但这些机制在肿瘤发生中是如何相互作用的,人们对此了解甚少。

附:英文原文

Title: The context-specific role of germline pathogenicity in tumorigenesis

Author: Srinivasan, Preethi, Bandlamudi, Chaitanya, Jonsson, Philip, Kemel, Yelena, Chavan, Shweta S., Richards, Allison L., Penson, Alexander V., Bielski, Craig M., Fong, Christopher, Syed, Aijazuddin, Jayakumaran, Gowtham, Prasad, Meera, Hwee, Jason, Sumer, Selcuk Onur, de Bruijn, Ino, Li, Xiang, Gao, JianJiong, Schultz, Nikolaus, Cambria, Roy, Galle, Jesse, Mukherjee, Semanti, Vijai, Joseph, Cadoo, Karen A., Carlo, Maria I., Walsh, Michael F., Mandelker, Diana, Ceyhan-Birsoy, Ozge, Shia, Jinru, Zehir, Ahmet, Ladanyi, Marc, Hyman, David M., Zhang, Liying, Offit, Kenneth, Robson, Mark E., Solit, David B., Stadler, Zsofia K., Berger, Michael F., Taylor, Barry S.

Issue&Volume: 2021-11-05

Abstract: Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we identified pathogenic germline variants in cancer predisposition genes, and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high-penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower-penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management. A study of 17,152 patients with cancer identified pathogenic germline variants in cancer predisposition genes. Although tumors showed biallelic inactivation for high-penetrance genes, this was not the case in most patients with pathogenic variants in low-penetrance genes, suggesting alternative routes to tumorigenesis.

DOI: 10.1038/s41588-021-00949-1

Source: https://www.nature.com/articles/s41588-021-00949-1

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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