Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers.
Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers.
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DOI：
10.1186/bcr3670
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发表时间：
2014-06-03
期刊：
影响因子：
--
通讯作者：
Tutt AN
中科院分区：
文献类型：
--
作者：
Watkins JA;Irshad S;Grigoriadis A;Tutt AN
已发现聚（ADP-核糖）聚合酶（PARP）抑制剂和铂类化疗药物对BRCA 1或BRCA 2基因中含有有害生殖系或体细胞突变的肿瘤特别有效，其产物有助于DNA双链断裂的保守同源重组修复。尽管如此，临床试验环境中的一些挫折突出了围绕PARP抑制剂研究的一些问题，特别是确定从此类药物中受益的患者。一种发现这种患者亚群的潜在方法是检查肿瘤DNA中同源重组缺陷的证据。然而，尽管许多乳腺癌和卵巢癌的基因组充满了畸变，但能够塑造基因组景观的许多因素的存在意味着只有一些观察到的DNA异常是癌细胞无法忠实修复DNA双链断裂的结果。因此，最近开发的用于全面捕获同源重组缺陷可能在BRCA 1/2突变之外出现的不同方式的方法已经使用DNA微阵列和测序数据来解释基因组中潜在的混淆特征。捕获端粒等位基因不平衡、杂合性丢失（洛）和大规模转换评分的评分以及编码突变的总数是总结某些形式的基因组异常的总负担的量度。相比之下，其他研究已经全面编目了不同类型的突变模式及其对给定肿瘤样本的相对贡献。尽管至少有一项研究正在进行中，以探索洛缺失疤痕在卵巢癌中PARP抑制剂的前瞻性临床试验中的应用，但仍存在导致这些生物标志物阳性预测值相对较低的局限性。其基因组经历了一个或多个恢复高保真同源重组的事件的肿瘤可能被错误分类为双链断裂修复缺陷，从而对PARP抑制剂和DNA损伤化疗敏感，这是由于先前的修复缺陷及其基因组瘢痕形成。因此，我们提出，在高基因组瘢痕形成负荷背景下，基因组瘢痕生物标志物与耐药标志物的整合可以改善PARP抑制剂的任何伴随诊断的性能。
Poly (ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapies have been found to be particularly effective in tumors that harbor deleterious germline or somatic mutations in the BRCA1 or BRCA2 genes, the products of which contribute to the conservative homologous recombination repair of DNA double-strand breaks. Nonetheless, several setbacks in clinical trial settings have highlighted some of the issues surrounding the investigation of PARP inhibitors, especially the identification of patients who stand to benefit from such drugs. One potential approach to finding this patient subpopulation is to examine the tumor DNA for evidence of a homologous recombination defect. However, although the genomes of many breast and ovarian cancers are replete with aberrations, the presence of numerous factors able to shape the genomic landscape means that only some of the observed DNA abnormalities are the outcome of a cancer cell’s inability to faithfully repair DNA double-strand breaks. Consequently, recently developed methods for comprehensively capturing the diverse ways in which homologous recombination deficiencies may arise beyond BRCA1/2 mutation have used DNA microarray and sequencing data to account for potentially confounding features in the genome. Scores capturing telomeric allelic imbalance, loss of heterozygosity (LOH) and large scale transition score, as well as the total number of coding mutations are measures that summarize the total burden of certain forms of genomic abnormality. By contrast, other studies have comprehensively catalogued different types of mutational pattern and their relative contributions to a given tumor sample. Although at least one study to explore the use of the LOH scar in a prospective clinical trial of a PARP inhibitor in ovarian cancer is under way, limitations that result in a relatively low positive predictive value for these biomarkers remain. Tumors whose genome has undergone one or more events that restore high-fidelity homologous recombination are likely to be misclassified as double-strand break repair-deficient and thereby sensitive to PARP inhibitors and DNA damaging chemotherapies as a result of prior repair deficiency and its genomic scarring. Therefore, we propose that integration of a genomic scar-based biomarker with a marker of resistance in a high genomic scarring burden context may improve the performance of any companion diagnostic for PARP inhibitors.
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BRCA1和BRCA2突变载体中乳腺癌和卵巢癌的病理学：BRCA1/2修饰符研究者联盟的结果（CIMBA）。
DOI：
10.1158/1055-9965.epi-11-0775
发表时间：
2012-01
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：
Mavaddat N;Barrowdale D;Andrulis IL;Domchek SM;Eccles D;Nevanlinna H;Ramus SJ;Spurdle A;Robson M;Sherman M;Mulligan AM;Couch FJ;Engel C;McGuffog L;Healey S;Sinilnikova OM;Southey MC;Terry MB;Goldgar D;O'Malley F;John EM;Janavicius R;Tihomirova L;Hansen TV;Nielsen FC;Osorio A;Stavropoulou A;Benítez J;Manoukian S;Peissel B;Barile M;Volorio S;Pasini B;Dolcetti R;Putignano AL;Ottini L;Radice P;Hamann U;Rashid MU;Hogervorst FB;Kriege M;van der Luijt RB;HEBON;Peock S;Frost D;Evans DG;Brewer C;Walker L;Rogers MT;Side LE;Houghton C;EMBRACE;Weaver J;Godwin AK;Schmutzler RK;Wappenschmidt B;Meindl A;Kast K;Arnold N;Niederacher D;Sutter C;Deissler H;Gadzicki D;Preisler-Adams S;Varon-Mateeva R;Schönbuchner I;Gevensleben H;Stoppa-Lyonnet D;Belotti M;Barjhoux L;GEMO Study Collaborators;Isaacs C;Peshkin BN;Caldes T;de la Hoya M;Cañadas C;Heikkinen T;Heikkilä P;Aittomäki K;Blanco I;Lazaro C;Brunet J;Agnarsson BA;Arason A;Barkardottir RB;Dumont M;Simard J;Montagna M;Agata S;D'Andrea E;Yan M;Fox S;kConFab Investigators;Rebbeck TR;Rubinstein W;Tung N;Garber JE;Wang X;Fredericksen Z;Pankratz VS;Lindor NM;Szabo C;Offit K;Sakr R;Gaudet MM;Singer CF;Tea MK;Rappaport C;Mai PL;Greene MH;Sokolenko A;Imyanitov E;Toland AE;Senter L;Sweet K;Thomassen M;Gerdes AM;Kruse T;Caligo M;Aretini P;Rantala J;von Wachenfeld A;Henriksson K;SWE-BRCA Collaborators;Steele L;Neuhausen SL;Nussbaum R;Beattie M;Odunsi K;Sucheston L;Gayther SA;Nathanson K;Gross J;Walsh C;Karlan B;Chenevix-Trench G;Easton DF;Antoniou AC;Consortium of Investigators of Modifiers of BRCA1/2
通讯作者：
Consortium of Investigators of Modifiers of BRCA1/2
影响因子：
28.2
作者：
Birkbak NJ;Wang ZC;Kim JY;Eklund AC;Li Q;Tian R;Bowman-Colin C;Li Y;Greene-Colozzi A;Iglehart JD;Tung N;Ryan PD;Garber JE;Silver DP;Szallasi Z;Richardson AL
通讯作者：
Richardson AL
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
DOI：
10.1073/pnas.98.1.130
发表时间：
2001-01-02
影响因子：
11.1
作者：
Beger, C;Pierce, LN;Wong-Staal, F
通讯作者：
Wong-Staal, F
影响因子：
10.3
作者：
Esteller, M;Silva, JM;Herman, JG
通讯作者：
Herman, JG