Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair

Ceccaldi, Raphaël; Liu, Jessica C.; Amunugama, Ravindra; Hajdú, Ildikó; Primack, Benjamin; Petalcorin, Mark I.R.; O’Connor, Kevin W.; Konstantinopoulos, Panagiotis A.; Elledge, Stephen J.; Boulton, Simon J.; Yusufzai, Timur; D’Andrea, Alan D.

doi:10.1038/nature14184

Cited by 711 publications

(902 citation statements)

References 41 publications

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“…The reduction in proofreading capacity of lagging-strand polymerases (Reijns et al 2015), coupled with increased fork stalling at telomeric locations (Lormand et al 2013) could result in an incompletely replicated template (Chow et al 2012) that is ligated with the leading strand fulllength chromatid to create a nonpalindromic fusion (Stohr et al 2010). The higher incidence of templated insertions we detected at intra-chromosomal junctions also suggests an active contribution of DNA synthesis to repair (Lowden et al 2011), conceivably involving the A-NHEJ-associated DNA polymerase theta (Yousefzadeh et al 2014;Ceccaldi et al 2015;Mateos-Gomez et al 2015) or alpha (Reijns et al 2015) by way of incomplete primer removal. Thus, the more prominent role of LIG1 in intra-chromosomal fusion events provides a mechanistic link to the asymmetric architecture via distinctive chromatid replication.…”

Section: A-and C-nhej Of Dysfunctional Human Telomeresmentioning

confidence: 80%

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

et al. 2016

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Telomeres shorten with each cell division and can ultimately become substrates for nonhomologous end-joining repair, leading to large-scale genomic rearrangements of the kind frequently observed in human cancers. We have characterized more than 1400 telomere fusion events at the single-molecule level, using a combination of high-throughput sequence analysis together with experimentally induced telomeric double-stranded DNA breaks. We show that a single chromosomal dysfunctional telomere can fuse with diverse nontelomeric genomic loci, even in the presence of an otherwise stable genome, and that fusion predominates in coding regions. Fusion frequency was markedly increased in the absence of TP53 checkpoint control and significantly modulated by the cellular capacity for classical, versus alternative, nonhomologous end joining (NHEJ). We observed a striking reduction in inter-chromosomal fusion events in cells lacking DNA ligase 4, in contrast to a remarkably consistent profile of intra-chromosomal fusion in the context of multiple genetic knockouts, including DNA ligase 3 and 4 doubleknockouts. We reveal distinct mutational signatures associated with classical NHEJ-mediated inter-chromosomal, as opposed to alternative NHEJ-mediated intra-chromosomal, telomere fusions and evidence for an unanticipated sufficiency of DNA ligase 1 for these intra-chromosomal events. Our findings have implications for mechanisms driving cancer genome evolution.

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Section: A-and C-nhej Of Dysfunctional Human Telomeresmentioning

confidence: 80%

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

et al. 2016

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“…Progression-free survival was signifi cantly longer in the BRCA mutant subgroup (HR 0·27, 95% CI 0·16-0·44, p<0·0001) and LOH high subgroup (HR 0·62, 0·42-0·90, p=0·011) than in the LOH low subgroup (fi gure 2A). 12 month progressionfree survival was higher in the BRCA mutant subgroup (50%, 95% CI 33-65) and LOH high subgroup (28%, 18-39) than in the LOH low subgroup (10%, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. The proportionality of hazards assumption was not violated (appendix pp [4][5]15).…”

Section: Resultsmentioning

confidence: 99%

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

Swisher

Lin

Oza

et al. 2017

The Lancet Oncology

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SummaryBackground Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination defi ciency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination defi ciency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantifi ed with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor.

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“…Homologous recombination-deficient tumors depend on other error-prone mechanisms for double-stranded break repair, such as the Polθ/PARP1-mediated alternative end-joining pathway. 10,11 The reliance on alternative end-joining repair pathways subsequently renders homologous recombination-deficient tumors more sensitive to chemotherapy as well as to PARPi. 3,4,[12][13][14][15][16][17][18][19] Only one PARPi has been FDA approved for the treatment of ovarian cancer, olaparib, and this is only in the setting of BRCA mutation and at least three prior lines of chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…6 The BRCA1/2 genes have an important role in homologous recombination, and other genes involved in homologous recombination, such as BRIP1, RAD51C, and RAD51D, have also been implicated as less common sources of genetic susceptibility to high-grade serous carcinoma. [6][7][8][9] Homologous recombination-deficient high-grade serous carcinomas (including BRCA1/2 mutations) depend on alternative, error-prone mechanisms for doublestrand break repair, such as the Polθ/PARP1-mediated alternative end-joining pathway for DNA repair, 10,11 and subsequently have been shown to have increased sensitivity to platinum chemotherapy and to poly ADP-ribose polymerase inhibitors (PARPi), and improved overall survival. 3,4,[12][13][14][15][16][17][18][19] Studies from The Cancer Genome Atlas Research Network (TCGA) demonstrated that nearly one-third of ovarian high-grade serous carcinomas had BRCA1-/2 alterations, which included 20% with either germline or somatic mutations in BRCA1/2 and an additional 11% with BRCA1 epigenetic silencing via hypermethylation.…”

mentioning

confidence: 99%

Morphologic correlates of molecular alterations in extrauterine Müllerian carcinomas

et al. 2016

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Extrauterine high-grade serous carcinomas can exhibit various histologic patterns including (1) classic architecture that is papillary, micropapillary and infiltrative and (2) solid, endometrioid, and transitional (ie, SET) patterns. Although the SET pattern has been associated with germline BRCA mutations, potential molecular underpinnings have not been fully investigated. DNA was isolated from 174 carcinomas of the fallopian tube, ovary, or peritoneum. Targeted next-generation sequencing was performed and single-nucleotide and copy number variants were correlated with morphologic subtype. Overall, 79% of tumors were classified as high-grade serous carcinoma (n = 138), and the most common mutations in high-grade serous carcinomas were TP53 (94%), BRCA1 (25%), BRCA2 (11%), and ATM (7%). Among chemotherapy-naive high-grade serous carcinomas, 40 cases exhibited classic morphology and 40 cases had non-classic morphology (SET or ambiguous features). Mutations in homologous recombination pathways were seen across all tumor histotypes. High-grade serous carcinomas with homologous recombination mutations were six times more likely to be associated with nonclassic histology (P = 0.002) and were significantly more likely to be platinum sensitive and have improved progression-free survival (PFS) (P = 0.007 and P = 0.004, respectively). In a multivariate analysis adjusted for age, homologous recombination mutation status and increased copy number variants were independently associated with improved PFS (P = 0.008 and P = 0.005, respectively). These findings underscore the potential significance of variant morphologic patterns and comprehensive genomic analysis in high-grade serous carcinomas with potential implications for pathogenesis, as well as response to targeted therapies. Extrauterine Müllerian carcinomas (ovarian, fallopian tube, and peritoneal) are the eighth most common malignancy in women and the fifth most common cause of death from cancer among women in the United States. 1 The 5-year survival for highgrade serous carcinoma, the most common and most lethal of all pelvic Müllerian carcinomas, is approximately 40%. 2 These tumors are difficult to detect in early stage and thus frequently present with metastatic disease. Although most high-grade serous carcinomas are associated with a poor prognosis, some patients with the disease have significantly better outcomes. [3][4][5] Germline mutations in BRCA1 and BRCA2 account for the majority of inherited cases of high-grade serous carcinomas, and the recognition of these germline mutations has led to the widespread use of prophylactic bilateral salpingo-oophorectomies to

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Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair

Cited by 711 publications

References 41 publications

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

Morphologic correlates of molecular alterations in extrauterine Müllerian carcinomas

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