Structural Variants at the<i>BRCA1/2</i>Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma

Ewing, Ailith; Meynert, Alison; Churchman, Michael; Grimes, Graeme R.; Hollis, Robert L.; Herrington, C. Simon; Rye, Tzyvia; Bartos, Clare; Croy, Ian; Ferguson, Michelle; Lennie, Mairi; McGoldrick, Trevor; McPhail, Neil; Siddiqui, Nadeem; Dowson, Suzanne; Glasspool, Rosalind; Mackean, Melanie; Nussey, Fiona; McDade, Brian; Ennis, Darren; McMahon, Lynn; Matakidou, Athena; March, Ruth; Barrett, J. Carl; McNeish, Iain A.; Biankin, Andrew V.; Roxburgh, Patricia; Gourley, Charlie; Semple, Colin A.

doi:10.1158/1078-0432.ccr-20-4068

Cited by 31 publications

(34 citation statements)

References 59 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the BriTROC-1 patients were all recruited at relapse (17), necessitating analysis of FFPE material from the time of diagnosis for the comparator late stage cohort. We also did not perform whole exome sequencing or deep WGS, so are unable to comment upon small variants (SNV, indel) beyond our targeted panel nor on larger scale rearrangements that are prevalent in HGSC (9,14). Thus, we cannot confirm all the SV and LOH findings from a previous study that performed deep WGS on 16 early stage HGSC samples (33).…”

Section: Discussionmentioning

confidence: 99%

“…Defective homology-mediated DNA repair mechanisms are believed to be present in approximately 50% of newly-diagnosed HGSC cases (6,11), most commonly driven by germline or somatic mutations in BRCA1 or BRCA2 , which are associated with improved prognosis (12) and response to PARP inhibition (13). Recent data also indicate that structural variants at the BRCA1/2 loci are another common source of homologous repair deficiency in high grade serous ovarian carcinoma (14).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The genomic landscape of early stage ovarian high grade serous carcinoma

Cheng

Mirza

Ennis

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

PurposeHigh grade serous carcinoma (HGSC) is the commonest type of ovarian cancer. Nearly all HGSC cases are diagnosed at late stage and it is not clear whether early stage HGSC has unique characteristics compared to late stage tumours.Experimental DesignWe analysed samples from 45 patients with FIGO stage I - IIA HGSC - 40 from the pathology archives of three large UK cancer centres and 5 from the BriTROC-1 study. We performed shallow whole genome sequencing (sWGS) and targeted next generation sequencing to investigate somatic mutations and copy number alterations. We compared results to 51 stage IIIC/IV HGSC patients from the BriTROC-1 study.ResultsThere was no difference in median age between the early stage (median 61.3 years, range 40-84) and late stage (median 62.3 years, range 34-76) patients at diagnosis. TP53 mutations were near-universal (92% early stage, 100% late stage samples) and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2, or focal copy number alterations between early- and late-stage cohorts. There were also no unique amplifications or deletions in either cohort. However, median ploidy was greater in late stage (median 3.1) than early stage (median 2.0) samples. In addition, there were higher numbers of breakpoints per 10MB and per chromosome arm and higher absolute copy number in late stage than early stage cohorts; early stage samples had longer segment length. Overall copy number signature exposures were significantly different between early and late stage samples with greater signature 3 exposure in early stage and greater signature 4 in late stage. Both simplex plot and unsupervised hierarchical clustering suggested that a subset of late stage samples retain early stage appearances with high signature 3 and co-clustering with the early stage samplesConclusionsThese data suggest that there are no unique mutations or focal copy number alterations in early stage HGSC. However, whole genome duplication is significantly more common in late-stage disease, suggesting evolution during disease progression. However, a subset of late stage HGSC retains early-stage features, which are associated with improved overall survival.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The genomic landscape of early stage ovarian high grade serous carcinoma

Cheng

Mirza

Ennis

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, multimegabase large rearrangements (LRs) at the BRCA1/2 loci have been suggested to lead to HRD, accounting for approximately 16% of patients [ 33 ]. Owing to their different structures, the BRCA1 and BRCA2 proteins exhibit distinct functions in the cell.…”

Section: From Ovarian Cancer Genetics To Homologous Recombination Def...mentioning

confidence: 99%

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations

Quesada

Fabbro

Solassol

2022

Cancers

View full text Add to dashboard Cite

High-grade serous ovarian cancer (HGSOC), the most frequent and lethal form of ovarian cancer, exhibits homologous recombination deficiency (HRD) in 50% of cases. In addition to mutations in BRCA1 and BRCA2, which are the best known thus far, defects can also be caused by diverse alterations to homologous recombination-related genes or epigenetic patterns. HRD leads to genomic instability (genomic scars) and is associated with PARP inhibitor (PARPi) sensitivity. HRD is currently assessed through BRCA1/2 analysis, which produces a genomic instability score (GIS). However, despite substantial clinical achievements, FDA-approved companion diagnostics (CDx) based on GISs have important limitations. Indeed, despite the use of GIS in clinical practice, the relevance of such assays remains controversial. Although international guidelines include companion diagnostics as part of HGSOC frontline management, they also underscore the need for more powerful and alternative approaches for assessing patient eligibility to PARP inhibitors. In these companion reviews, we review and present evidence to date regarding HRD definitions, achievements and limitations in HGSOC. Part 1 is dedicated to technical considerations and proposed perspectives that could lead to a more comprehensive and dynamic assessment of HR, while Part 2 provides a more integrated approach for clinicians.

show abstract

“…At the gene sequence level, identification of mutational disruption in BRCA1 and BRCA2 ( BRCA1 / 2 m) has ultimately paved the way for integration of poly-(ADP-ribose) polymerase (PARP) inhibitor use into routine care for some patients [8-10]. Indeed, there continues to be an intense research effort surrounding mechanisms and implications of homologous recombination DNA repair (HRR) disruption beyond BRCA1 / 2 m [11]; these include mutation of non- BRCA1 / 2 HRR genes [12], large-scale genomic variants disrupting BRCA1 / 2 [13], epigenetic inactivation of HRR players such as BRCA1 and RAD51C [5, 14], and overexpression of the BRCA2 regulator EMSY [15, 16].…”

Section: Introductionmentioning

confidence: 99%

Multiomic characterisation of high grade serous ovarian carcinoma enables high resolution patient stratification

Hollis

Meynert

Michie

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Background: High grade serous ovarian carcinoma (HGSOC) is the most common type of ovarian cancer; most patients experience disease recurrence which accumulates chemoresistance, leading to treatment failure. Previous investigations have characterised HGSOC at the genomic and transcriptomic level, identifying subtypes of patients with differential outcome and treatment response. However, the relationship between molecular events identified at the gene sequence, gene copy number and gene expression levels remains poorly defined. Methods: We perform multi-layer molecular characterisation of a large retrospective HGSOC cohort (n=362) with detailed clinical annotation to interrogate the relationship between patient groups defined by gene mutation, copy number events, gene expression patterns and infiltrating immune cell burden. We construct a high resolution picture of the molecular landscape in HGSOC and identify features of tumours associated with distinct clinical behaviour in patients. Results: BRCA2-mutant (BRCA2m) and EMSY-overexpressing cases demonstrated prolonged survival (multivariable hazard ratio 0.40 and 0.53) and higher chemotherapy response rates at first- and second-line treatment. CCNE1-gained (CCNE1g) cases demonstrated shorter survival (multivariable hazard ratio 1.52, 95% CI 1.10-2.10), under-representation of FIGO stage IV cases (P=0.017) and no significant difference in treatment response. We demonstrate marked overlap between the TCGA- and derived subtypes: the TCGA DIF, IMR, PRO and MES subtypes correlated with the Tothill C4, C2, C5 and C1 subtypes (P<0.001). IMR/C2 cases displayed higher BRCA1/2m frequency (25.5% and 32.5%) and significantly greater infiltration of immune cells (P<0.001), while PRO/C5 cases had the highest CCNE1g rate (23.9% and 22.2%) and were uniformly low in immune cell infiltration. The survival benefit for cases with aberrations in homologous recombination repair (HRR) genes was apparent across all transcriptomic subtypes (hazard ratio range 0.48-0.68). There was significant co-occurrence of RB loss and HRR gene aberrations (P=0.005); RB loss was further associated with favourable survival within cases harbouring HRR aberrations (multivariable hazard ratio 0.50, 95% CI 0.30-0.84). Conclusions: These data paint a high resolution picture of the molecular landscape in HGSOC, better defining patients who may benefit most from specific molecular therapeutics and highlighting those for whom novel treatment strategies are needed to improve outcomes.

show abstract

Structural Variants at theBRCA1/2Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma

Cited by 31 publications

References 59 publications

The genomic landscape of early stage ovarian high grade serous carcinoma

The genomic landscape of early stage ovarian high grade serous carcinoma

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations

Multiomic characterisation of high grade serous ovarian carcinoma enables high resolution patient stratification

Contact Info

Product

Resources

About