bims-tumhet 2022-06-05 papers

Issue of 2022–06–05
six papers selected by
Sergio Marchini, Humanitas Research

BMC Cancer. 2022 May 28. 22(1): 587

Validation of genomic and transcriptomic models of homologous recombination deficiency in a real-world pan-cancer cohort.

Benjamin D Leibowitz, Bonnie V Dougherty, Joshua S K Bell, Joshuah Kapilivsky, Jackson Michuda, Andrew J Sedgewick, Wesley A Munson, Tushar A Chandra, Jonathan R Dry, Nike Beaubier, Catherine Igartua, Timothy Taxter.

BACKGROUND: With the introduction of DNA-damaging therapies into standard of care cancer treatment, there is a growing need for predictive diagnostics assessing homologous recombination deficiency (HRD) status across tumor types. Following the strong clinical evidence for the utility of DNA-sequencing-based HRD testing in ovarian cancer, and growing evidence in breast cancer, we present analytical validation of the Tempus HRD-DNA test. We further developed, validated, and explored the Tempus HRD-RNA model, which uses gene expression data from 16,750 RNA-seq samples to predict HRD status from formalin-fixed paraffin-embedded tumor samples across numerous cancer types.
METHODS: Genomic and transcriptomic profiling was performed using next-generation sequencing from Tempus xT, Tempus xO, Tempus xE, Tempus RS, and Tempus RS.v2 assays on 48,843 samples. Samples were labeled based on their BRCA1, BRCA2 and selected Homologous Recombination Repair pathway gene (CDK12, PALB2, RAD51B, RAD51C, RAD51D) mutational status to train and validate HRD-DNA, a genome-wide loss-of-heterozygosity biomarker, and HRD-RNA, a logistic regression model trained on gene expression.
RESULTS: In a sample of 2058 breast and 1216 ovarian tumors, BRCA status was predicted by HRD-DNA with F1-scores of 0.98 and 0.96, respectively. Across an independent set of 1363 samples across solid tumor types, the HRD-RNA model was predictive of BRCA status in prostate, pancreatic, and non-small cell lung cancer, with F1-scores of 0.88, 0.69, and 0.62, respectively.
CONCLUSIONS: We predict HRD-positive patients across many cancer types and believe both HRD models may generalize to other mechanisms of HRD outside of BRCA loss. HRD-RNA complements DNA-based HRD detection methods, especially for indications with low prevalence of BRCA alterations.

Keywords: Diagnostic biomarkers; Gene expression profiling; Homologous recombination\

DOI: https://doi.org/10.1186/s12885-022-09669-z

Biomark Med. 2022 Jun 01.

Homologous recombination deficiency and molecular subtype are associated with immunogenicity in ovarian cancer.

Charlene M Fares, Kathleen E Fenerty, Cinthiya Chander, Matthew K Theisen, Gottfried E Konecny.

Aim: There is an unmet need for predictive biomarkers for immune checkpoint blockade in ovarian cancer. Homologous recombination deficiency (HRD) and immunoreactive molecular subtype may be associated with determinants of immunogenicity. Materials & methods: Neoantigen load, tumor inflammation signature (TIS), immune cell infiltrates and individual immune checkpoints were assessed based on HRD status and molecular subtype. Results: Tumors with HRD demonstrated significantly higher expression of neoantigens and multiple immune check points, but not higher TIS scores or increased immune cell infiltrates. Immunoreactive tumors had significantly higher neoantigen expression, TIS scores, immune cell infiltrate and immune checkpoint expression compared with other subtypes. Conclusion: HRD and the immunoreactive molecular subtype signature were associated with multiple determinants of immunogenicity and deserve further exploration as predictive biomarkers.

Keywords: biomarkers; homologous recombination deficiency; immune checkpoint blockade; molecular subtype; ovarian cancer

DOI: https://doi.org/10.2217/bmm-2022-0044

Bioinformatics. 2022 May 31. pii: btac371. [Epub ahead of print]

CNpare: matching DNA copy number profiles.

Blas Chaves-Urbano, Barbara Hernando, Maria J Garcia, Geoff Macintyre.

SUMMARY: Selecting the optimal cancer cell line for an experiment can be challenging given the diversity of lines available. Here, we present CNpare, which identifies similar cell line models based on genome-wide DNA copy number.
AVAILABILITY: CNpare is available as an R package at https://github.com/macintyrelab/CNpare. All analysis performed in the manuscript can be reproduced via the code found at https://github.com/macintyrelab/CNpare_analyses.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

DOI: https://doi.org/10.1093/bioinformatics/btac371

Am J Obstet Gynecol. 2022 May 28. pii: S0002-9378(22)00412-4. [Epub ahead of print]

Is there a "Low Risk" Patient Population in Advanced Epithelial Ovarian Cancer?: A Critical Analysis.

Laura M Chambers, David M O'Malley, Robert L Coleman, Thomas J Herzog.

Ovarian cancer is the leading cause of gynecologic cancer-related death in the United States. Historically, studies have demonstrated that ovarian cancer is a heterogeneous disease with several patient and oncologic characteristics, including BRCA status and residual disease at surgery, known to be predictive of clinical outcomes. However, over the last decade, the discovery and approval of bevacizumab and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors have moved the front-line treatment paradigm beyond platinum-doublet therapy for women with advanced ovarian cancer. Subsequently, investigators have sought to assess the therapeutic efficacy of these agents in women who are considered "high" and "low" risk to determine which patients may benefit the most from aggressive therapy and in whom additional treatment may be avoided. We review historical and contemporary definitions of "high" and "low" risk ovarian cancer and how this has been incorporated into the subset analyses of randomized, clinical trials of therapeutic agents, including bevacizumab and PARP inhibitors. Next, we provide an in-depth discussion of landmark trials for front-line maintenance therapy with bevacizumab and/or PARP inhibitors, focusing on the impact of treatment efficacy according to a "high"- and "low"- risk paradigm. Further, we highlight that recent data have challenged this dichotomous classification, notably from the GOG-0218, ICON7, SOLO-1 and PAOLA-1 trials. While some studies have suggested that certain populations of women with advanced ovarian cancer may have a more favorable prognosis and be considered "low risk", the risk of progression and death remains unacceptably high in all women. Furthermore, in many cases, those considered lowest risk have the most treatment benefit from maintenance therapy with PARP inhibitors and/or bevacizumab. From this data, we advocate that that virtually all women with advanced ovarian cancer are high-risk and that use of our most effective therapies in the front-line setting holds promise for potentially curing more patients. Lastly, we critically discuss the practice of utilizing sub-analyses in clinical trials, with emphasis that while this practice is important for hypothesis generation, caution must be taken prior to accepting findings from sub-analyses as actual treatment effects.

Keywords: BRCA; HRD; PARP inhibitors; bevacizumab; high-risk; low-risk; maintenance therapy; ovarian cancer

DOI: https://doi.org/10.1016/j.ajog.2022.05.047

Nat Commun. 2022 May 31. 13(1): 3016

BRD4 promotes resection and homology-directed repair of DNA double-strand breaks.

John K Barrows, Baicheng Lin, Colleen E Quaas, George Fullbright, Elizabeth N Wallace, David T Long.

Double-strand breaks (DSBs) are one of the most toxic forms of DNA damage and represent a major source of genomic instability. Members of the bromodomain and extra-terminal (BET) protein family are characterized as epigenetic readers that regulate gene expression. However, evidence suggests that BET proteins also play a more direct role in DNA repair. Here, we establish a cell-free system using Xenopus egg extracts to elucidate the gene expression-independent functions of BET proteins in DSB repair. We identify the BET protein BRD4 as a critical regulator of homologous recombination and describe its role in stimulating DNA processing through interactions with the SWI/SNF chromatin remodeling complex and resection machinery. These results establish BRD4 as a multifunctional regulator of chromatin binding that links transcriptional activity and homology-directed repair.

DOI: https://doi.org/10.1038/s41467-022-30787-6

Cancer. 2022 Jun 03.

Molecular classification in endometrial cancer: Opportunities for precision oncology in a changing landscape.

Amy Jamieson, Lisa M Barroilhet, Jessica N McAlpine.

Endometrial carcinoma (EC) classification and risk stratification have undergone a global transformation in the last decade, shifting from a reliance on poorly reproducible histomorphological parameters such as grade and histotype, toward a molecular classification that is consistent and biologically informative. Molecular classification enables reliable categorization of ECs, provides prognostic information, and is now beginning to drive clinical management, including surgery and adjuvant therapy. Within this framework, we now have the ability to further refine both the prognostic and predictive value of molecular classification. As we move toward the routine implementation of this classification system as a stratification tool for research, clinical trials, and patient care, it is imperative that access to these tests be equitable. Furthermore, continued education will be critical for patients and providers to understand the value that this molecular information provides.

DOI: https://doi.org/10.1002/cncr.34328