bims-ovdlit 2021-09-12 papers

Issue of 2021–09–12
eight papers selected by
Lara Paracchini, Humanitas Research

Cancers (Basel). 2021 Aug 31. pii: 4394. [Epub ahead of print]13(17):

TCR Clonality and Genomic Instability Signatures as Prognostic Biomarkers in High Grade Serous Ovarian Cancer.

Julie Lecuelle, Romain Boidot, Hugo Mananet, Valentin Derangère, Juliette Albuisson, Vincent Goussot, Laurent Arnould, Zoé Tharin, Isabelle Ray Coquard, François Ghiringhelli, Caroline Truntzer, Jean-David Fumet.

PURPOSE: Immune infiltration is a prognostic factor in high-grade serous ovarian carcinoma (HGSC) but immunotherapy efficacy is disappointing. Genomic instability is now used to guide the therapeutic value of PARP inhibitors. We aimed to investigate exome-derived parameters to assess the tumor microenvironment according to genomic instability profile.
METHODS: We used the HGSC TCGA (the cancer genome atlas) dataset with genomic characteristics, including homologous recombination deficiency (HRD), copy number variant (CNV) signatures, TCR (T cell receptor) clonality and abundance of tissue-infiltrating immune and stromal cell populations. We then investigated the relationship with survival data.
RESULTS: In 578 HGSC patients, HRD status, CNV signature 7 and TCR clonality were associated with longer survival. The combination of high CNV signature 7 expression and HRD status or high CNV signature 3 expression and high TCR clonality was associated with a trend towards longer survival compared to each variable alone. Combining T cell infiltrate and TCR clonality improved the prognostic value compared to T cells infiltration alone. Prognostic value of TCR clonality was confirmed in an independent cohort.
CONCLUSIONS: TCR clonality is an emerging prognostic biomarker that improves T cell infiltrate information. Analysis of TCR clonality combined with genomic instability could be an interesting prognostic biomarker.

Keywords: HGSC; HRD; TCR clonality; biomarkers; prognostic

DOI: https://doi.org/10.3390/cancers13174394

Eur J Cancer. 2021 Sep 03. pii: S0959-8049(21)00533-5. [Epub ahead of print]157 59-62

Secondary haematologic malignancies in women with ovarian cancer receiving poly-ADP ribose polymerase inhibitor therapy.

Koji Matsuo, Maximilian Klar, Ann F Mohrbacher, Lynda D Roman, Jason D Wright.

Keywords: Acute myeloid leukaemia; Haematologic malignancy; Myelodysplastic syndrome; Outcome; Ovarian cancer; PARP inhibitor; Poly-ADP ribose Polymerase inhibitors

DOI: https://doi.org/10.1016/j.ejca.2021.08.016

J Transl Med. 2021 Sep 08. 19(1): 382

Establishment of a novel glycolysis-related prognostic gene signature for ovarian cancer and its relationships with immune infiltration of the tumor microenvironment.

Jianlei Bi, Fangfang Bi, Xue Pan, Qing Yang.

BACKGROUND: Glycolysis affects tumor growth, invasion, chemotherapy resistance, and the tumor microenvironment. In this study, we aimed to construct a glycolysis-related prognostic model for ovarian cancer and analyze its relationship with the tumor microenvironment's immune cell infiltration.
METHODS: We obtained six glycolysis-related gene sets for gene set enrichment analysis (GSEA). Ovarian cancer data from The Cancer Genome Atlas (TCGA) database and two Gene Expression Omnibus (GEO) datasets were divided into two groups after removing batch effects. We compared the tumor environments' immune components in high-risk and low-risk groups and analyzed the correlation between glycolysis- and immune-related genes. Then, we generated and validated a predictive model for the prognosis of ovarian cancer using the glycolysis-related genes.
RESULTS: Overall, 27/329 glycolytic genes were associated with survival in ovarian cancer, 8 of which showed predictive value. The tumor cell components in the tumor microenvironment did not differ between the high-risk and low-risk groups; however, the immune score differed significantly between groups. In total, 13/24 immune cell types differed between groups, including 10 T cell types and three other immune cell types. Eight glycolysis-related prognostic genes were related to the expression of multiple immune-related genes at varying degrees, suggesting a relationship between glycolysis and immune response.
CONCLUSIONS: We identified eight glycolysis-related prognostic genes that effectively predicted survival in ovarian cancer. To a certain extent, the newly identified gene signature was related to the tumor microenvironment, especially immune cell infiltration and immune-related gene expression. These findings provide potential biomarkers and therapeutic targets for ovarian cancer.

Keywords: Glycolysis; Immune alterations; Ovarian cancer; Prognostic signature; Tumor microenvironment

DOI: https://doi.org/10.1186/s12967-021-03057-0

Ann Oncol. 2021 Sep 06. pii: S0923-7534(21)04458-6. [Epub ahead of print]

Analysis of mutation status and homologous recombination deficiency in tumors of patients with germline BRCA1 or BRCA2 mutations and metastatic breast cancer: OlympiAD.

D Hodgson, Z Lai, S Dearden, J C Barrett, E A Harrington, K Timms, J Lanchbury, W Wu, A Allen, E Senkus, S M Domchek, M Robson.

BACKGROUND: Presence of a germline BRCA1 and/or BRCA2 mutation (gBRCAm) may sensitize tumors to poly(ADP-ribose) polymerase (PARP) inhibition via inactivation of the second allele, resulting in gene-specific loss of heterozygosity (gsLOH) and homologous recombination deficiency (HRD). Here we explore whether tissue sample testing provides an additional route to germline testing to inform treatment selection for PARP inhibition.
PATIENTS AND METHODS: In this prespecified exploratory analysis, BRCA1 and/or BRCA2 mutations in blood samples (gBRCAm) and tumor tissue (tBRCAm) were analyzed from patients with human epidermal growth factor 2 (HER2)-negative metastatic breast cancer and known gBRCAm, enrolled in the phase III OlympiAD trial. The frequency and nature of tBRCAm, HRD score status (HRD-positive [score ≥42] versus HRD-negative [score <42] using the Myriad myChoice® CDx test) and rates of gsLOH were determined, and their impact on clinical efficacy (objective response rate and progression-free survival) was explored.
RESULTS: Tissue samples from 161/302 patients yielded tBRCAm, HRD and gsLOH data for 143 (47%), 129 (43%) and 125 (41%) patients, respectively. Concordance between gBRCAm and tBRCAm was 99%. gsLOH was observed in 118/125 (94%) patients (BRCA1m, 73/76 [96%]; BRCA2m, 45/49 [92%]). A second mutation event was recorded for two of the three BRCA1m patients without gsLOH. The incidence of HRD-negative was 16% (21/129) and was more common for BRCA2m (versus BRCA1m) and/or for hormone-receptor-positive (versus triple-negative) disease. Olaparib antitumor activity was observed irrespective of HRD score.
CONCLUSIONS: gBRCAm identified in patients with HER2-negative metastatic breast cancer by germline testing in blood was also identified by tumor tissue testing. gsLOH was common, indicating a high rate of biallelic inactivation in metastatic breast cancer. Olaparib activity was seen regardless of gsLOH status or HRD score. Thus, additional tumor testing to inform PARP inhibitor treatment selection may not be supported for these patients.

Keywords: PARP inhibitor; Tumor tissue testing; gBRCAm

DOI: https://doi.org/10.1016/j.annonc.2021.08.2154

Lancet Oncol. 2021 Sep 06. pii: S1470-2045(21)00520-9. [Epub ahead of print]

Understanding the new therapeutic options for mesothelioma.

Hedy Lee Kindler.

DOI: https://doi.org/10.1016/S1470-2045(21)00520-9

Nature. 2021 Sep 08.

Using DNA sequencing data to quantify T cell fraction and therapy response.

TRACERx Consortium

The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy1,2. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations. Here we develop T cell exome TREC tool (T cell ExTRECT), a method for estimation of T cell fraction from WES samples using a signal from T cell receptor excision circle (TREC) loss during V(D)J recombination of the T cell receptor-α gene (TCRA (also known as TRA)). TCRA T cell fraction correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females than in males and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma. Using a meta-analysis of tumours treated with immunotherapy, we show that tumour TCRA T cell fraction predicts immunotherapy response, providing value beyond measuring tumour mutational burden. Applying T cell ExTRECT to a multi-sample pan-cancer cohort reveals a high diversity of the degree of immune infiltration within tumours. Subclonal loss of 12q24.31-32, encompassing SPPL3, is associated with reduced TCRA T cell fraction. T cell ExTRECT provides a cost-effective technique to characterize immune infiltrate alongside somatic changes.

DOI: https://doi.org/10.1038/s41586-021-03894-5