腫瘤譜系影響BRCA基因介導的表型
作者：
小柯機器人發布時間：2019/7/30 10:22:47
美國紀念斯隆-凱特琳癌症中心Barry S. Taylor等研究人員的最新研究，揭示了腫瘤譜系對BRCA基因介導的表型的影響。相關論文於2019年7月25日發表於國際頂尖學術期刊《自然》雜誌上。
該課題組表明，在晚期癌症患者中，2.7%的患者群體攜帶生殖系BRCA1/2基因突變，1.8%的患者群體BRCA1/2基因存在功能缺失性改變，這兩類BRCA1/2基因異常的群體中，諸如雙等位基因失活，接合性依賴性表型外顯率和對聚腺苷二磷酸核糖聚合酶抑制的敏感性的選擇性壓力僅存在於那些與BRCA1/2攜帶者（BRCA相關癌症類型）中可遺傳的癌症風險增加相關的腫瘤類型中。相反,在BRCA非相關腫瘤患者中，儘管攜帶有BRCA1/2基因突變，但是他們的腫瘤發生機制與這類突變沒有直接聯繫。總之,儘管在某些腫瘤中，BRCA基因突變是不可或缺的驅動因素,但在相當比例的其他癌症類型中,這類突變似乎是受腫瘤譜系影響的中性生物學差異，從而對疾病發病機制研究，癌症篩查，臨床試驗設計和治療決策有提示意義。
據了解，BRCA1和BRCA2基因突變使個體易患某些癌症，通過疾病特異性篩查和預防策略已經降低了受影響患者的癌症死亡率。這些經典的腫瘤抑制基因與體細胞雙等位基因失活相關，從而表現出致瘤作用，儘管單倍體不足也可能促進腫瘤的形成和發展。此外,BRCA1/2基因突變的腫瘤類型往往缺乏基於同源重組修復DNA雙鏈斷裂的能力,因此提升了對鉑類藥物化療和聚腺苷二磷酸核糖聚合酶抑制劑的敏感性。然而,在大多數癌症類型中，BRCA1或BRCA2基因突變的表型和治療相關性的研究仍然缺乏。
附：英文原文
Title: Tumour lineage shapes BRCA-mediated phenotypes
Author: Philip Jonsson, Chaitanya Bandlamudi, Michael L. Cheng, Preethi Srinivasan, Shweta S. Chavan, Noah D. Friedman, Ezra Y. Rosen, Allison L. Richards, Nancy Bouvier, S. Duygu Selcuklu, Craig M. Bielski, Wassim Abida, Diana Mandelker, Ozge Birsoy, Liying Zhang, Ahmet Zehir, Mark T. A. Donoghue, Jos Baselga, Kenneth Offit, Howard I. Scher, Eileen M. OReilly, Zsofia K. Stadler, Nikolaus Schultz, Nicholas D. Socci, Agnes Viale, Marc Ladanyi, Mark E. Robson, David M. Hyman, Michael F. Berger, David B. Solit, Barry S. Taylor
Issue&Volume: Volume 571 Issue 7766
Abstract: Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers, and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients. These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours. Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination, and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)-polymerase (PARP). However, the phenotypic and therapeutic relevance of mutations in BRCA1 or BRCA2 remains poorly defined in most cancer types. Here we show that in the 2.7% and 1.8% of patients with advanced-stage cancer and germline pathogenic or somatic loss-of-function alterations in BRCA1/2, respectively, selective pressure for biallelic inactivation, zygosity-dependent phenotype penetrance, and sensitivity to PARP inhibition were observed only in tumour types associated with increased heritable cancer risk in BRCA1/2 carriers (BRCA-associated cancer types). Conversely, among patients with non-BRCA-associated cancer types, most carriers of these BRCA1/2 mutation types had evidence for tumour pathogenesis that was independent of mutant BRCA1/2. Overall, mutant BRCA is an indispensable founding event for some tumours, but in a considerable proportion of other cancers, it appears to be biologically neutrala difference predominantly conditioned by tumour lineagewith implications for disease pathogenesis, screening, design of clinical trials and therapeutic decision-making.
DOI: 10.1038/s41586-019-1382-1
Source: https://www.nature.com/articles/s41586-019-1382-1