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研究揭示癌症中范可尼贫血症DNA修复途径缺失的基因组特征
2022-12-03 18:46

美国洛克菲勒大学Agata Smogorzewska课题组揭示癌症中范可尼贫血症DNA修复途径缺失的基因组特征。相关论文于2022年11月30日在线发表在《自然》杂志上。

研究人员表示,范可尼贫血症(FA)是一种基因组不稳定的模型综合征,是由DNA链间交联修复缺陷导致染色体断裂引起的。FA修复途径可保护其免受内源性和外源性致癌醛类物质的影响。带有FA的人患头颈部(HNSCC)、食道和肛门鳞状细胞癌(SCC)的可能性要高出几百至几千倍。对来自FA患者的SCC(FA SCC)的分子研究是有限的,目前还不清楚FA SCC与主要由烟草和酒精暴露或人乳头瘤病毒(HPV)感染引起的散发性HNSCC的关系。

通过对FA SCC的基因组和外显子进行测序,研究人员证明FA修复缺陷的主要基因组特征是存在大量的结构变异。结构性变异富含小的缺失、不平衡的易位和折返倒置,并且经常连接,从而形成复杂的重排。它们出现在TP53缺失的情况下,而不是在HPV感染的情况下,并导致HNSCC驱动基因的体细胞拷贝数的改变。

分析结果进一步表明,FA途径的缺失可能导致上皮向间质的转化和角质细胞内在炎症信号的增强,这将有助于FA SCC的侵略性。研究人员提出,散发性HPV阴性HNSCC的基因组不稳定性可能是由于FA修复途径,被酒精和烟草衍生的醛类引起的DNA链间交联损伤所淹没,这使得FA SCC成为研究DNA交联损伤导致的肿瘤发生的有力模型。

附:英文原文

Title: Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer

Author: Webster, Andrew L. H., Sanders, Mathijs A., Patel, Krupa, Dietrich, Ralf, Noonan, Raymond J., Lach, Francis P., White, Ryan R., Goldfarb, Audrey, Hadi, Kevin, Edwards, Matthew M., Donovan, Frank X., Hoogenboezem, Remco M., Jung, Moonjung, Sridhar, Sunandini, Wiley, Tom F., Fedrigo, Olivier, Tian, Huasong, Rosiene, Joel, Heineman, Thomas, Kennedy, Jennifer A., Bean, Lorenzo, Rosti, Rasim O., Tryon, Rebecca, Gonzalez, Ashlyn-Maree, Rosenberg, Allana, Luo, Ji-Dung, Carroll, Thomas S., Shroff, Sanjana, Beaumont, Michael, Velleuer, Eunike, Rastatter, Jeff C., Wells, Susanne I., Surralls, Jordi, Bagby, Grover, MacMillan, Margaret L., Wagner, John E., Cancio, Maria, Boulad, Farid, Scognamiglio, Theresa, Vaughan, Roger, Beaumont, Kristin G., Koren, Amnon, Imielinski, Marcin, Chandrasekharappa, Settara C., Auerbach, Arleen D., Singh, Bhuvanesh, Kutler, David I., Campbell, Peter J., Smogorzewska, Agata

Issue&Volume: 2022-11-30

Abstract: Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage1,2,3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes4,5,6,7. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas8 (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus9 (HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.

DOI: 10.1038/s41586-022-05253-4

Source: https://www.nature.com/articles/s41586-022-05253-4

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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