Are Homologous Recombination Deficiency Mutations Relevant in Colorectal Cancer?
Are Homologous Recombination Deficiency Mutations Relevant in Colorectal Cancer?
复制标题
同源重组缺陷突变与结直肠癌相关吗？
DOI：
10.1093/jnci/djab170
复制
发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Kopetz,Scott
中科院分区：
文献类型：
--
作者：
Lee,MichaelS;Kopetz,Scott
功能性DNA损伤反应(DDR)通路的丧失增加了基因组的变异性和不稳定性，是癌症发生和侵袭的关键启动特征(1)。异常DDR的原型是BRCA1或BRCA2的胚系缺失，BRCA1或BRCA2是高保真同源重组修复复制应激引起的DNA双链断裂(DSB)所必需的关键肿瘤抑制因子。在致癌过程中野生型BRCA1/2等位基因的丢失会导致同源重组缺陷(HRD)，增加了对铂类化疗药物等疗法的脆弱性，这些疗法将DNA交联并导致DSB，从而压倒DNA损伤修复能力(3)。此外，HRD细胞依赖于更容易出错的替代DDR途径，如非同源末端连接，以充分修复DNA断裂，以避免有丝分裂灾难和细胞死亡，增加突变和基因组不稳定性。这导致HRD对聚腺苷二磷酸核糖聚合酶(PARP)抑制剂具有合成致死性，这损害了需要功能性PARP的替代DDR途径，并在单链断裂时捕获PARP1，阻碍复制分叉，并导致DSB和遗传毒性(4)。PARP抑制剂疗法是美国食品和药物管理局批准用于生殖系BRCA1/2突变患者的多种转移性癌症，包括卵巢癌、乳腺癌、前列腺癌和胰腺癌。针对其他DDR途径成分的新疗法，如ATM、ATR、DNA-PK、CHK1/2和WEE1，正在进行HRD癌症的临床研究(5)。因此，识别更多的癌症类型和HRD的生物标记物可能会扩大可以受益于DDR抑制剂的患者数量。事实上，许多超出种系BRCA1/2突变的基因组异常可导致HRD表型。通过同源重组修复DSB是一个多步骤的过程，除了BRCA1和BRCA2(6)外，还需要多种蛋白质，其中任何一种编码蛋白质的基因突变或丢失都可能损害DSB修复并导致HRD。例如，肿瘤基因组测序检测到15个HRD基因(BRCA1，
The loss of functional DNA damage response (DDR) pathways increases genome mutability and instability and is a critical enabling characteristic underlying cancer development and invasion (1). The archetype of aberrant DDR is germline loss of BRCA1 or BRCA2, key tumor suppressors required for highfidelity homologous recombination to repair DNA doublestrand breaks (DSBs) arising because of replication stress (2). Loss of the wild-type BRCA1/2 allele in the course of carcinogenesis consequently causes homologous recombination deficiency (HRD), increasing vulnerability to therapies like platinum chemotherapeutics that crosslink DNA and cause DSBs, which overwhelms DNA damage repair capabilities (3). Additionally, HRD cells rely on more error-prone alternative DDR pathways, such as nonhomologous end joining, to repair DNA breaks sufficiently to avoid mitotic catastrophe and cell death, increasing mutagenesis and genomic instability. This causes HRD to have synthetic lethality with poly-ADP ribose polymerase (PARP) inhibitors, which impairs alternative DDR pathways requiring functional PARP and traps PARP1 at single-strand breaks, stalling replication forks and causing DSBs and genotoxicity (4). PARP inhibitor therapy is US Food and Drug Administration approved for multiple types of metastatic cancer in patients with germline BRCA1/2 mutations, including ovarian cancer, breast cancer, prostate cancer, and pancreatic cancer. Novel therapies targeting other DDR pathway components, such as ATM, ATR, DNA-PK, CHK1/2, and WEE1, are in clinical investigation for HRD cancers (5). Thus, identifying additional cancer types and biomarkers of HRD may expand the number of patients who could benefit from DDR inhibitors. Indeed, many genomic aberrations beyond germline BRCA1/2 mutations can cause a HRD phenotype. Repair of DSBs via homologous recombination is a multistep process requiring multiple proteins besides BRCA1 and BRCA2 (6), and mutation or loss of a gene encoding any of these proteins could impair DSB repair and cause HRD. For example, tumor genomic sequencing detecting a mutation in at least 1 of 15 HRD genes (BRCA1,