bims-ovdlit 2023-05-21 papers

Issue of 2023–05–21
seven papers selected by
Lara Paracchini, Humanitas Research

Commun Biol. 2023 May 16. 6(1): 527

Copy number alteration features in pan-cancer homologous recombination deficiency prediction and biology.

Huizi Yao, Huimin Li, Jinyu Wang, Tao Wu, Wei Ning, Kaixuan Diao, Chenxu Wu, Guangshuai Wang, Ziyu Tao, Xiangyu Zhao, Jing Chen, Xiaoqin Sun, Xue-Song Liu.

Homologous recombination deficiency (HRD) renders cancer cells vulnerable to unrepaired double-strand breaks and is an important therapeutic target as exemplified by the clinical efficacy of poly ADP-ribose polymerase (PARP) inhibitors as well as the platinum chemotherapy drugs applied to HRD patients. However, it remains a challenge to predict HRD status precisely and economically. Copy number alteration (CNA), as a pervasive trait of human cancers, can be extracted from a variety of data sources, including whole genome sequencing (WGS), SNP array, and panel sequencing, and thus can be easily applied clinically. Here we systematically evaluate the predictive performance of various CNA features and signatures in HRD prediction and build a gradient boosting machine model (HRDCNA) for pan-cancer HRD prediction based on these CNA features. CNA features BP10MB[1] (The number of breakpoints per 10MB of DNA is 1) and SS[ > 7 & <=8] (The log10-based size of segments is greater than 7 and less than or equal to 8) are identified as the most important features in HRD prediction. HRDCNA suggests the biallelic inactivation of BRCA1, BRCA2, PALB2, RAD51C, RAD51D, and BARD1 as the major genetic basis for human HRD, and may also be applied to effectively validate the pathogenicity of BRCA1/2 variants of uncertain significance (VUS). Together, this study provides a robust tool for cost-effective HRD prediction and also demonstrates the applicability of CNA features and signatures in cancer precision medicine.

DOI: https://doi.org/10.1038/s42003-023-04901-3

Gynecol Oncol. 2023 May 11. pii: S0090-8258(23)00179-8. [Epub ahead of print]173 138-150

Tissue factor as a novel diagnostic target for early detection of ovarian cancer using ultrasound microbubbles.

Meghan M Newcomer, Kalpana Deepa Priya Dorayappan, Vincent Wagner, Adrian A Suarez, Corinne A Calo, Eileen L Kalmar, G Larry Maxwell, David O'Malley, David E Cohn, Michael F Tweedle, Karuppaiyah Selvendiran.

INTRODUCTION: Ovarian cancer (OC) is the deadliest gynecologic malignancy, with an overall 5-year survival rate of less than 30%. The existing paradigm for OC detection involves a serum marker, CA125, and ultrasound examination, neither of which is sufficiently specific for OC. This study addresses this deficiency through the use of a targeted ultrasound microbubble directed against tissue factor (TF).
METHODS: TF expression was examined in both OC cell lines and patient-derived tumor samples via western blotting and IHC. In vivo microbubble ultrasound imaging was analyzed using high grade serous ovarian carcinoma orthotopic mouse models.
RESULTS: While TF expression has previously been described on angiogenic, tumor-associated vascular endothelial cells (VECs) of several tumor types, this is first study to show TF expression on both murine and patient-derived ovarian tumor-associated VECs. Biotinylated anti-TF antibody was conjugated to streptavidin-coated microbubbles and in vitro binding assays were performed to assess the binding efficacy of these agents. TF-targeted microbubbles successfully bound to TF-expressing OC cells, as well as an in vitro model of angiogenic endothelium. In vivo, these microbubbles bound to the tumor-associated VECs of a clinically relevant orthotopic OC mouse model.
CONCLUSION: Development of a TF-targeted microbubble capable of successfully detecting ovarian tumor neovasculature could have significant implications towards increasing the number of early-stage OC diagnoses. This preclinical study shows potential for translation to clinical use, which could ultimately help increase the number of early OC detections and decrease the mortality associated with this disease.

Keywords: Early detection; Ovarian cancer; Tissue factor; Ultrasound microbubbles; Vascular endothelial cells

DOI: https://doi.org/10.1016/j.ygyno.2023.04.008

Br J Cancer. 2023 Apr 25.

Modelled mortality benefits of multi-cancer early detection screening in England.

Peter Sasieni, Rebecca Smittenaar, Earl Hubbell, John Broggio, Richard D Neal, Charles Swanton.

BACKGROUND: Screening programmes utilising blood-based multi-cancer early detection (MCED) tests, which can detect a shared cancer signal from any site in the body with a single, low false-positive rate, could reduce cancer burden through early diagnosis.
METHODS: A natural history ('interception') model of cancer was previously used to characterise potential benefits of MCED screening (based on published performance of an MCED test). We built upon this using a two-population survival model to account for an increased risk of death from cfDNA-detectable cancers relative to cfDNA-non-detectable cancers. We developed another model allowing some cancers to metastasise directly from stage I, bypassing intermediate tumour stages. We used incidence and survival-by-stage data from the National Cancer Registration and Analysis Service in England to estimate longer-term benefits to a cohort screened between ages 50-79 years.
RESULTS: Estimated late-stage and mortality reductions were robust to a range of assumptions. With the least favourable dwell (sojourn) time and cfDNA status hazard ratio assumptions, we estimated, among 100,000 screened individuals, 67 (17%) fewer cancer deaths per year corresponding to 2029 fewer deaths in those screened between ages 50-79 years.
CONCLUSION: Realising the potential benefits of MCED tests could substantially reduce late-stage cancer diagnoses and mortality.

DOI: https://doi.org/10.1038/s41416-023-02243-9

Int J Mol Sci. 2023 Apr 25. pii: 7811. [Epub ahead of print]24(9):

The Potential of Liquid Biopsy in Detection of Endometrial Cancer Biomarkers: A Pilot Study.

Dominik Kodada, Michaela Hyblova, Patrik Krumpolec, Nikola Janostiakova, Peter Barath, Marian Grendar, Gabriela Blandova, Oliver Petrovic, Pavol Janega, Vanda Repiska, Gabriel Minarik.

Endometrial cancer belongs to the most common gynecologic cancer types globally, with increasing incidence. There are numerous ways of classifying different cases. The most recent decade has brought advances in molecular classification, which show more accurate prognostic factors and the possibility of personalised adjuvant treatment. In addition, diagnostic approaches lag behind these advances, with methods causing patients discomfort while lacking the reproducibility of tissue sampling for biopsy. Minimally invasive liquid biopsies could therefore represent an alternative screening and diagnostic approach in patients with endometrial cancer. The method could potentially detect molecular changes in this cancer type and identify patients at early stages. In this pilot study, we tested such a detection method based on circulating tumour DNA isolated from the peripheral blood plasma of 21 Slovak endometrial cancer patients. We successfully detected oncomutations in the circulating DNA of every single patient, although the prognostic value of the detected mutations failed to offer certainty. Furthermore, we detected changes associated with clonal hematopoiesis, including DNMT3A mutations, which were present in the majority of circulating tumour DNA samples.

Keywords: DNMT3A mutations; ctDNA; endometrial cancer; liquid biopsy

DOI: https://doi.org/10.3390/ijms24097811

Health Technol Assess. 2023 May 11. 1-81

Mortality impact, risks, and benefits of general population screening for ovarian cancer: the UKCTOCS randomised controlled trial.

Usha Menon, Aleksandra Gentry-Maharaj, Matthew Burnell, Andy Ryan, Jatinderpal K Kalsi, Naveena Singh, Anne Dawnay, Lesley Fallowfield, Alistair J McGuire, Stuart Campbell, Steven J Skates, Mahesh Parmar, Ian J Jacobs.

Background: Ovarian and tubal cancers are lethal gynaecological cancers, with over 50% of the patients diagnosed at advanced stage.
Trial design: Randomised controlled trial involving 27 primary care trusts adjacent to 13 trial centres based at NHS Trusts in England, Wales and Northern Ireland.
Methods: Postmenopausal average-risk women, aged 50-74, with intact ovaries and no previous ovarian or current non-ovarian cancer.
Interventions: One of two annual screening strategies: (1) multimodal screening (MMS) using a longitudinal CA125 algorithm with repeat CA125 testing and transvaginal scan (TVS) as second line test (2) ultrasound screening (USS) using TVS alone with repeat scan to confirm any abnormality. The control (C) group had no screening. Follow-up was through linkage to national registries, postal follow-up questionnaires and direct communication with trial centres and participants.
Objective: To assess comprehensively risks and benefits of ovarian cancer screening in the general population.
Outcome: Primary outcome was death due to ovarian or tubal cancer as assigned by an independent outcomes review committee. Secondary outcomes included incidence and stage at diagnosis of ovarian and tubal cancer, compliance, performance characteristics, harms and cost-effectiveness of the two screening strategies and a bioresource for future research.
Randomisation: The trial management system confirmed eligibility and randomly allocated participants using computer-generated random numbers to MMS, USS and C groups in a 1:1:2 ratio.
Blinding: Investigators and participants were unblinded and outcomes review committee was masked to randomisation group.
Analyses: Primary analyses were by intention to screen, comparing separately MMS and USS with C using the Versatile test.
Results: 1,243,282 women were invited and 205,090 attended for recruitment between April 2001 and September 2005.
Randomised: 202,638 women: 50,640 MMS, 50,639 USS and 101,359 C group.
Numbers analysed for primary outcome: 202,562 (>99.9%): 50,625 (>99.9%) MMS, 50,623 (>99.9%) USS, and 101,314 (>99.9%) C group.
Outcome: Women in MMS and USS groups underwent 345,570 and 327,775 annual screens between randomisation and 31 December 2011. At median follow-up of 16.3 (IQR 15.1-17.3) years, 2055 women developed ovarian or tubal cancer: 522 (1.0% of 50,625) MMS, 517 (1.0% of 50,623) USS, and 1016 (1.0% of 101314) in C group. Compared to the C group, in the MMS group, the incidence of Stage I/II disease was 39.2% (95% CI 16.1 to 66.9) higher and stage III/IV 10.2% (95% CI -21.3 to 2.4) lower. There was no difference in stage in the USS group. 1206 women died of the disease: 296 (0.6%) MMS, 291 (0.6%) USS, and 619 (0.6%) C group. There was no significant reduction in ovarian and tubal cancer deaths in either MMS (p = 0.580) or USS (p = 0.360) groups compared to the C group. Overall compliance with annual screening episode was 80.8% (345,570/420,047) in the MMS and 78.0% (327,775/420,047) in the USS group. For ovarian and tubal cancers diagnosed within one year of the last test in a screening episode, in the MMS group, the sensitivity, specificity and positive predictive values were 83.8% (95% CI 78.7 to 88.1), 99.8% (95% CI 99.8 to 99.9), and 28.8% (95% CI 25.5 to 32.2) and in the USS group, 72.2% (95% CI 65.9 to 78.0), 99.5% (95% CI 99.5 to 99.5), and 9.1% (95% CI 7.8 to 10.5) respectively. The final within-trial cost-effectiveness analysis was not undertaken as there was no mortality reduction. A bioresource (UKCTOCS Longitudinal Women's Cohort) of longitudinal outcome data and over 0.5 million serum samples including serial annual samples in women in the MMS group was established and to date has been used in many new studies, mainly focused on early detection of cancer.
Harms: Both screening tests (venepuncture and TVS) were associated with minor complications with low (8.6/100,000 screens MMS; 18.6/100,000 screens USS) complication rates. Screening itself did not cause anxiety unless more intense repeat testing was required following abnormal screens. In the MMS group, for each screen-detected ovarian or tubal cancer, an additional 2.3 (489 false positives; 212 cancers) women in the MMS group had unnecessary false-positive (benign adnexal pathology or normal adnexa) surgery. Overall, 14 (489/345,572 annual screens) underwent unnecessary surgery per 10,000 screens. In the USS group, for each screen-detected ovarian or tubal cancer, an additional 10 (1630 false positives; 164 cancers) underwent unnecessary false-positive surgery. Overall, 50 (1630/327,775 annual screens) women underwent unnecessary surgery per 10,000 screens.
Conclusions: Population screening for ovarian and tubal cancer for average-risk women using these strategies should not be undertaken. Decreased incidence of Stage III/IV cancers during multimodal screening did not translate to mortality reduction. Researchers should be cautious about using early stage as a surrogate outcome in screening trials. Meanwhile the bioresource provides a unique opportunity to evaluate early cancer detection tests.
Funding: Long-term follow-up UKCTOCS (2015-2020) - National Institute for Health and Care Research (NIHR HTA grant 16/46/01), Cancer Research UK, and The Eve Appeal. UKCTOCS (2001-2014) - Medical Research Council (MRC) (G9901012/G0801228), Cancer Research UK (C1479/A2884), and the UK Department of Health, with additional support from The Eve Appeal. Researchers at UCL were supported by the NIHR UCL Hospitals Biomedical Research Centre and by MRC Clinical Trials Unit at UCL core funding (MR_UU_12023).

Keywords: CA-125 ANTIGEN; CANCER SCREENING; EARLY DETECTION OF CANCER; GENERAL POPULATION; OVARIAN CANCER; OVARIAN EPITHELIAL CARCINOMA; OVARIAN NEOPLASMS; RANDOMISED CONTROLLED TRIAL; RCT; TRANSVAGINAL ULTRASOUND; UKCTOCS; ULTRASONOGRAPHY

DOI: https://doi.org/10.3310/BHBR5832

Nat Commun. 2023 May 12. 14(1): 2744

Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response.

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.

DOI: https://doi.org/10.1038/s41467-023-38271-5