Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes

Aberrant DNA repair processes are a hallmark of human tumours. How these deficiencies variously impact the genomes of ovarian cancer between and within histotypes remains unknown. We studied the whole genome pointmutation and structural variation patterns of 133 tumours (59 high grade serous (HGSC), 35 clear cell (CCOC), 29 endometrioid (ENOC), and 10 adult granulosa cell tumours (GCT)) as a substrate for class discovery in ovarian cancer. Ab-initio clustering of integrated point mutation and structural variation signatures revealed seven novel subgroups, comprising between and within histotype stratification. Prevalence of fold-back inversions (FBI) co-localised with high level amplification events divided HGSC into two prognostically significant subgroups. This finding was recapitulated in two additional independent cohorts (total n=576 cases), and transcended gene based mutation status and gene expression as prognostically relevant features of HGSC. CCOC were divided into one group harbouring a signature reflective of active genome editing via APOBEC enzymes (26%) and a complementary group with an age-relatedmutational signature. ENOC were divided intomicrosatellite instable (MSI) cases (28%) with a distinctmismatch repairmutation signature and an outlying mutation rate, with the remainder of cases distributed amongst the remaining six groups. We suggest the FBI, MSI, and APOBEC groups represent biologic strata that could direct treatment strategies. Taken together, our work establishes the efficacy of the somatic genome as a biomarker to stratify ovarian cancers, simultaneously identifying patients that may benefit from emerging therapeutics and distinct subgroups within classic ovarian cancer histotypes.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

4 Datasets 2 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001003265	For CCOC cohorts, OvCaRe cases were reviewed, including frozen material, by at least two expert gynecopathologists prior to inclusion in the sequencing cohort who provided the confirmation on final selected cohort. Frozen H&E from Tokyo were also used for evaluation along with representative H&E photos and review done at the Jikei School of Medicine. All CCOC tumours are primary tumour samples. Library construction and sequencing Frozen specimens with >50% tumour cellularity (based on initial slide review) were used for cryosectioning and subsequent nucleic acid extraction. Patient tumour and normal blood samples derived from primary, untreated fresh frozen tumour specimens harvested at diagnosis during standard of care debulking surgery. Germline DNA was provided from peripheral blood buffy coat on all specimens except 13 from Tokyo, where non-cancer frozen tissue was used as a germline source. DNA extraction from both matched normal (blood) and tumour samples (frozen tissue) were performed using the QIAamp Blood and Tissue DNA kit (Qiagen) and quantified using a Qbit fluorometer and reagents (high-sensitivity assay). Three lanes of Illumina HiSeq 2500 v4 chemistry for normal samples and five lanes for tumour samples were obtained. The PCR-free protocol was adopted to eliminate the PCR-induced bias and improve coverage across the genome.	Illumina Genome Analyzer II Illumina HiSeq 2000	70
EGAD00001003266	For ENOC cohorts, OvCaRe cases were reviewed, including frozen material, by at least two expert gynecopathologists prior to inclusion in the sequencing cohort who provided the confirmation on final selected cohort. Frozen H&E from Tokyo were also used for evaluation along with representative H&E photos and review done at the Jikei School of Medicine. For ENOC, DAH985 and DG1288 are recurrent and both were treated with chemotherapy after their first surgery. DAH123 is a untreated sample, metastasis from an primary endometrial tumour. All HGSC, GCT, CCOC and the rest ENOC tumours are primary tumour samples. Library construction and sequencing Frozen specimens with >50% tumour cellularity (based on initial slide review) were used for cryosectioning and subsequent nucleic acid extraction. Patient tumour and normal blood samples derived from primary, untreated fresh frozen tumour specimens harvested at diagnosis during standard of care debulking surgery. Germline DNA was provided from peripheral blood buffy coat on all specimens except 13 from Tokyo, where non-cancer frozen tissue was used as a germline source. DNA extraction from both matched normal (blood) and tumour samples (frozen tissue) were performed using the QIAamp Blood and Tissue DNA kit (Qiagen) and quantified using a Qbit fluorometer and reagents (high-sensitivity assay). Three lanes of Illumina HiSeq 2500 v4 chemistry for normal samples and five lanes for tumour samples were obtained. The PCR-free protocol was adopted to eliminate the PCR-induced bias and improve coverage across the genome.	Illumina HiSeq 2000	58
EGAD00001003267	For GCT cohorts, OvCaRe cases were reviewed, including frozen material, by at least two expert gynecopathologists prior to inclusion in the sequencing cohort who provided the confirmation on final selected cohort. Frozen H&E from Tokyo were also used for evaluation along with representative H&E photos and review done at the Jikei School of Medicine. All GCT tumours are primary tumour samples. Library construction and sequencing Frozen specimens with >50% tumour cellularity (based on initial slide review) were used for cryosectioning and subsequent nucleic acid extraction. Patient tumour and normal blood samples derived from primary, untreated fresh frozen tumour specimens harvested at diagnosis during standard of care debulking surgery. Germline DNA was provided from peripheral blood buffy coat on all specimens except 13 from Tokyo, where non-cancer frozen tissue was used as a germline source. DNA extraction from both matched normal (blood) and tumour samples (frozen tissue) were performed using the QIAamp Blood and Tissue DNA kit (Qiagen) and quantified using a Qbit fluorometer and reagents (high-sensitivity assay). Three lanes of Illumina HiSeq 2500 v4 chemistry for normal samples and five lanes for tumour samples were obtained. The PCR-free protocol was adopted to eliminate the PCR-induced bias and improve coverage across the genome.	Illumina HiSeq 2000	20
EGAD00001003268	HGSC cases in the OvCaRe and CRCHUM Tumour Banks were selected according to the following criteria: (i) were administered platinum taxane based therapy; (ii) relapsed within 12 months (365 days) or had at least longer than 4.5 years (1642.5 days) follow-up data; (iii) had at least 50% tumour content by H&E staining and expert pathology review. All cases were re-reviewed by expert pathologists to confirm the diagnosis of HGSC. Germline BRCA1 and BRCA2 was determined for all patients through hereditary cancer screening programs. The design of cases selection as a discovery cohort was engineered to amplify biological differences by selecting cases from the extremes of the outcome distribution. All HGSC tumours are primary tumour samples. Library construction and sequencing Frozen specimens with >50% tumour cellularity (based on initial slide review) were used for cryosectioning and subsequent nucleic acid extraction. Patient tumour and normal blood samples derived from primary, untreated fresh frozen tumour specimens harvested at diagnosis during standard of care debulking surgery. Germline DNA was provided from peripheral blood buffy coat on all specimens except 13 from Tokyo, where non-cancer frozen tissue was used as a germline source. DNA extraction from both matched normal (blood) and tumour samples (frozen tissue) were performed using the QIAamp Blood and Tissue DNA kit (Qiagen) and quantified using a Qbit fluorometer and reagents (high-sensitivity assay). Three lanes of Illumina HiSeq 2500 v4 chemistry for normal samples and five lanes for tumour samples were obtained. The PCR-free protocol was adopted to eliminate the PCR-induced bias and improve coverage across the genome.	Illumina HiSeq 2000	118

Publications	Citations
Single-cell genomic variation induced by mutational processes in cancer. Funnell T, O'Flanagan CH, Williams MJ, McPherson A, McKinney S, Kabeer F, Lee H, Salehi S, Vázquez-García I, Shi H, Leventhal E, Masud T, Eirew P, Yap D, Zhang AW, Lim JLP, Wang B, Brimhall J, Biele J, Ting J, Au V, Van Vliet M, Liu YF, Beatty S, Lai D, Pham J, Grewal D, Abrams D, Havasov E, Leung S, Bojilova V, Moore RA, Rusk N, Uhlitz F, Ceglia N, Weiner AC, Zaikova E, Douglas JM, Zamarin D, Weigelt B, Kim SH, Da Cruz Paula A, Reis-Filho JS, Martin SD, Li Y, Xu H, de Algara TR, Lee SR, Llanos VC, Huntsman DG, McAlpine JN, IMAXT Consortium, Shah SP, Aparicio S. Nature 612: 2022 106-115	77
DiffInvex identifies evolutionary shifts in driver gene repertoires during tumorigenesis and chemotherapy. Khalil A, Supek F. Nat Commun 16: 2025 4209	0

Publications

Citations

Single-cell genomic variation induced by mutational processes in cancer.
Funnell T, O'Flanagan CH, Williams MJ, McPherson A, McKinney S, Kabeer F, Lee H, Salehi S, Vázquez-García I, Shi H, Leventhal E, Masud T, Eirew P, Yap D, Zhang AW, Lim JLP, Wang B, Brimhall J, Biele J, Ting J, Au V, Van Vliet M, Liu YF, Beatty S, Lai D, Pham J, Grewal D, Abrams D, Havasov E, Leung S, Bojilova V, Moore RA, Rusk N, Uhlitz F, Ceglia N, Weiner AC, Zaikova E, Douglas JM, Zamarin D, Weigelt B, Kim SH, Da Cruz Paula A, Reis-Filho JS, Martin SD, Li Y, Xu H, de Algara TR, Lee SR, Llanos VC, Huntsman DG, McAlpine JN, IMAXT Consortium, Shah SP, Aparicio S. Nature 612: 2022 106-115

DiffInvex identifies evolutionary shifts in driver gene repertoires during tumorigenesis and chemotherapy.
Khalil A, Supek F. Nat Commun 16: 2025 4209