Molecular Analysis of Clinically Defined Subsets of High-Grade Serous Ovarian Cancer

Lee, Sanghoon; Zhao, Li; Rojas, Christine; Bateman, Nicholas W.; Yao, Hui; Lara, Olivia D.; Celestino, Joseph; Morgan, Margaret; Nguyen, Tri; Conrads, Kelly A.; Rangel, Kelly; Dood, Robert; Hajek, Richard A.; Fawcett, Gloria L.; Chu, Randy A.; Wilson, Kerry; Loffredo, Jeremy; Viollet, Coralie; Jazaeri, Amir A.; Dalgard, Clifton L.; Mao, Xizeng; Song, Xingzhi; Zhou, Ming; Hood, Brian L.; Banskota, Nirad; Wilkerson, Matthew D.; Te, Jerez A.; Soltis, Anthony R.; Roman, Kristin; Dunn, Andrew; Cordover, David; Eterovic, Agda Karina; Liu, Jinsong; Burks, Jared K.; Baggerly, Keith A.; Fleming, Nicole D.; Lu, Karen H.; Westin, Shannon N.; Coleman, Robert L.; Mills, Gordon B.; Casablanca, Yovanni; Zhang, Jianhua; Conrads, Thomas P.; Maxwell, G. Larry; Futreal, P. Andrew; Sood, Anil K.

doi:10.1016/j.celrep.2020.03.066

Cited by 77 publications

(79 citation statements)

References 94 publications

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“…Several recent reports have shown intra-tumour heterogeneity within the same individual between the metastatic and primary tissues as well as within the same tissue 48 – 50 . While no significant genomic variations seem depicted between primary tumours and metastases 51 , the patterns of T-cell infiltration and the composition of the TME can vary between and within patients. Hence, further investigations of immune phenotypes in extended non-serous histology and metastatic cohorts of ovarian cancer are warranted.…”

Section: Discussionmentioning

confidence: 96%

Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer

Desbois¹,

Udyavar²,

Ryner³

et al. 2020

Nat Commun

118

130

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Close proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what controls the spatial distribution of T cells in the tumour microenvironment is not well understood. Here we couple digital pathology and transcriptome analysis on a large ovarian tumour cohort and develop a machine learning approach to molecularly classify and characterize tumour-immune phenotypes. Our study identifies two important hallmarks characterizing T cell excluded tumours: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFβ and activated stroma. Furthermore, we identify TGFβ as an important mediator of T cell exclusion. TGFβ reduces MHC-I expression in ovarian cancer cells in vitro. TGFβ also activates fibroblasts and induces extracellular matrix production as a potential physical barrier to hinder T cell infiltration. Our findings indicate that targeting TGFβ might be a promising strategy to overcome T cell exclusion and improve clinical benefits of cancer immunotherapy.

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Section: Discussionmentioning

confidence: 96%

Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer

Desbois¹,

Udyavar²,

Ryner³

et al. 2020

Nat Commun

118

130

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“…In our previous study of the same cohort of patients, a higher level of strong-binding neoantigens was found in the R0 group than in the NACT group ( Lee et al., 2020 ). In addition, positive correlations were found between the level of strong-binding neoantigens and mutation load and copy number variation load.…”

Section: Resultsmentioning

confidence: 72%

“…The study design and patient cohort was reported previously ( Lee et al., 2020 ). In brief, a total of 30 patients in three groups was included: 10 patients who had no visible residual disease after primary surgery (R0), 10 who had an excellent response to NACT (NACT-ER), and 10 who had a poor response to NACT (NACT-PR).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we evaluated clinically well-annotated primary tumor and metastasis samples that had been obtained prior to definitive surgery or chemotherapy and discovered significant distinct molecular abnormalities (e.g., greater NF1 loss and less chromothripsis-like patterns) and cellular changes (e.g., increased numbers of neoantigens and infiltrated T-cells) in patients who underwent R0 surgery compared with in those who were triaged to NACT ( Lee et al., 2020 ). However, further characterization and understanding is needed with regard to T cell repertoires, including the diversity and clinical relevance of T cells.…”

Section: Introductionmentioning

confidence: 99%

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Distinct T cell receptor repertoire diversity of clinically defined high-grade serous ovarian cancer treatment subgroups

et al. 2021

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Summary In patients with high-grade serous ovarian cancer (HGSC), it is unclear which genomic features are related to complete gross resection (R0), which is typically associated with better clinical outcomes, or response to neoadjuvant chemotherapy (NACT). In this study, we evaluated T cell receptor (TCR) repertoire diversity in primary and metastatic tumor samples (n = 90) from clinically well-annotated patients with HGSC who achieved R0 or received NACT with excellent or poor response based on a laparoscopic triage algorithm. TCR sequencing followed by an integrative analysis with comprehensive multi-omics data identified higher TCR diversity (e.g., higher number of unique productive sequences and less clonal relatedness) in the R0 than NACT groups. We found enrichment of specific TCRβ genes usage, distinct mutual exclusiveness and co-occurrence pattern of TCRβ genes among the groups. We also found significantly positive correlations between clonal relatedness and neoantigens, copy number variations, and mutation load in the groups.

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“…High-grade serous ovarian cancer (HGSOC) is the most common histological subtype (about 70%) of epithelial ovarian cancer (EOC) [1,2] and is a genetically heterogeneous disease that exhibit highly individual evolution and genomic diversity [3][4][5]. Approximately 50% of HGSOCs harbour genetic and epigenetic alterations in gene members of the homologous recombination (HR) DNA repair pathway, most commonly in BRCA1 and BRCA2 [6].…”

Section: Introductionmentioning

confidence: 99%

Somatic Mutations in BRCA2 BRC Repeat Associated with Outcome in Patients with High Grade Serous Ovarian Cancer

Zhang¹,

Zhang²,

Zhu³

et al. 2020

Preprint

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BackgroundThe interaction between BRCA2 BRC repeats and RAD51 is one of the great important factors affecting the homologous recombination in DNA damage repair of tumor cells. We investigated the effect of BRCA2 BRC repeat mutations on outcome in patients with high grade serous ovarian cancer (HGSOC) who received platinum-based chemotherapy.MethodsWe identified the type and location of BRCA2 BRC repeat mutations by PCR and DNA sequencing in tumor and peripheral blood leukocytes (PBL) samples of 113 patients with stage IIIC/IV high grade serous ovarian cancer (HGSOC), and assessed chemotherapy-free interval (CFI), progression-free survival (PFS) and overall survival (OS).Results24 (21.23%) cases with somatic mutation were identified in 113 HGSOC patients. Among them, 8 (7.1%) cases with nonsense mutation resulting in BRCA2 truncation significantly prolonged median CFI (37 vs 8 months,P=0.000), PFS (43 vs 14 months, p=0.000) and OS (56 vs 31 months, P=0.002); Interestingly, 16 (14.13%) cases with missense mutation also prolonged median CFI (15 vs 8 months, P=0.044), PFS (21 vs 14 months, P=0.049) and OS ( 38 vs 31 months, P=0.037). ConclusionsSomatic mutations in BRCA2 BRC5-8 repeat motifs are associated with platinum-based chemotherapy sensitivity and a better outcome in patients with HGSOC.

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Molecular Analysis of Clinically Defined Subsets of High-Grade Serous Ovarian Cancer

Cited by 77 publications

References 94 publications

Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer

Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer

Distinct T cell receptor repertoire diversity of clinically defined high-grade serous ovarian cancer treatment subgroups

Somatic Mutations in BRCA2 BRC Repeat Associated with Outcome in Patients with High Grade Serous Ovarian Cancer

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