Homologous Recombination Deficiency in Ovarian, Breast, Colorectal, Pancreatic, Non-Small Cell Lung and Prostate Cancers, and the Mechanisms of Resistance to PARP Inhibitors.
Homologous Recombination Deficiency in Ovarian, Breast, Colorectal, Pancreatic, Non-Small Cell Lung and Prostate Cancers, and the Mechanisms of Resistance to PARP Inhibitors.
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DOI：
10.3389/fonc.2022.880643
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发表时间：
2022
影响因子：
4.7
通讯作者：
Shin, Young Kee
中科院分区：
文献类型：
--
作者：
Mekonnen, Negesse;Yang, Hobin;Shin, Young Kee
关键词：
同源重组（HR）是一种高度保守的DNA修复机制，可保护细胞免受外源性和内源性DNA损伤。乳腺癌1（BRCA 1）和乳腺癌2（BRCA 2）通过与其他DNA修复蛋白如范可尼贫血（FA）蛋白、ATM、RAD 51、PALB 2、MRE 11 A、RAD 50和NBN相互作用，在HR修复途径中发挥重要作用。这些途径在癌症中经常异常，导致DNA损伤的积累和基因组不稳定性，称为同源重组缺陷（HRD）。HRD可由染色体和亚染色体畸变以及肿瘤抑制基因启动子的表观遗传失活引起。一个或多个HR基因的缺陷会增加许多恶性肿瘤的风险。DNA单链断裂（SSB）修复中涉及的另一种保守机制是碱基切除修复，其中聚（ADP-核糖）聚合酶（PARP）酶发挥重要作用。PARP抑制剂（PARPI）将SSB转化为更具细胞毒性的双链断裂，其在HR-熟练细胞中修复，但在HRD中保持未修复。阻断HR和碱基切除修复途径是PARPI治疗的基础。PARPI的使用可以扩展到显示“BRCAness”表型的散发性癌症。尽管PARPI在许多癌症中有效，但其疗效受到耐药性发展的限制。在这篇综述中，我们总结了HRD的患病率由于突变，杂合性丢失，和启动子超甲基化的35个DNA修复基因在卵巢癌，乳腺癌，结直肠癌，胰腺癌，非小细胞肺癌和前列腺癌。本文还讨论了克服PARPI耐药性的机制和策略。
Homologous recombination (HR) is a highly conserved DNA repair mechanism that protects cells from exogenous and endogenous DNA damage. Breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) play an important role in the HR repair pathway by interacting with other DNA repair proteins such as Fanconi anemia (FA) proteins, ATM, RAD51, PALB2, MRE11A, RAD50, and NBN. These pathways are frequently aberrant in cancer, leading to the accumulation of DNA damage and genomic instability known as homologous recombination deficiency (HRD). HRD can be caused by chromosomal and subchromosomal aberrations, as well as by epigenetic inactivation of tumor suppressor gene promoters. Deficiency in one or more HR genes increases the risk of many malignancies. Another conserved mechanism involved in the repair of DNA single-strand breaks (SSBs) is base excision repair, in which poly (ADP-ribose) polymerase (PARP) enzymes play an important role. PARP inhibitors (PARPIs) convert SSBs to more cytotoxic double-strand breaks, which are repaired in HR-proficient cells, but remain unrepaired in HRD. The blockade of both HR and base excision repair pathways is the basis of PARPI therapy. The use of PARPIs can be expanded to sporadic cancers displaying the “BRCAness” phenotype. Although PARPIs are effective in many cancers, their efficacy is limited by the development of resistance. In this review, we summarize the prevalence of HRD due to mutation, loss of heterozygosity, and promoter hypermethylation of 35 DNA repair genes in ovarian, breast, colorectal, pancreatic, non-small cell lung cancer, and prostate cancer. The underlying mechanisms and strategies to overcome PARPI resistance are also discussed.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
2.2
作者：
Bogdanova, Natalia;Togo, Alexandr V.;Doerk, Thilo
通讯作者：
Doerk, Thilo
影响因子：
4.6
作者：
Abida W;Armenia J;Gopalan A;Brennan R;Walsh M;Barron D;Danila D;Rathkopf D;Morris M;Slovin S;McLaughlin B;Curtis K;Hyman DM;Durack JC;Solomon SB;Arcila ME;Zehir A;Syed A;Gao J;Chakravarty D;Vargas HA;Robson ME;Joseph V;Offit K;Donoghue MTA;Abeshouse AA;Kundra R;Heins ZJ;Penson AV;Harris C;Taylor BS;Ladanyi M;Mandelker D;Zhang L;Reuter VE;Kantoff PW;Solit DB;Berger MF;Sawyers CL;Schultz N;Scher HI
通讯作者：
Scher HI
DOI：
10.1158/1055-9965.epi-15-0247
发表时间：
2015-09
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Beebe-Dimmer JL;Hathcock M;Yee C;Okoth LA;Ewing CM;Isaacs WB;Cooney KA;Thibodeau SN
通讯作者：
Thibodeau SN
前列腺癌组织中的甲基化模式分析：使用 MS-MLPA 方法鉴定生物标志物。
影响因子：
7.4
作者：
Gurioli G;Salvi S;Martignano F;Foca F;Gunelli R;Costantini M;Cicchetti G;De Giorgi U;Sbarba PD;Calistri D;Casadio V
通讯作者：
Casadio V