bims-tumhet 2022-06-19 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2022‒06‒19
eight papers selected by
Sergio Marchini
Humanitas Research

Homologous Recombination Deficiency and Ovarian Cancer Treatment Decisions: Practical Implications for Pathologists for Tumor Typing and Reporting.
Multiomic characterisation of high grade serous ovarian carcinoma enables high resolution patient stratification.
Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma.
Signatures of copy number alterations in human cancer.
Circulating DNA and Liquid Biopsies in the Management of Patients with Cancer.
A pan-cancer compendium of chromosomal instability.
cGAS-STING drives the IL-6-dependent survival of chromosomally instable cancers.
Circulating tumor DNA: current challenges for clinical utility.

Surg Pathol Clin. 2022 Jun;pii: S1875-9181(22)00013-7. [Epub ahead of print]15(2): 219-234

Homologous Recombination Deficiency and Ovarian Cancer Treatment Decisions: Practical Implications for Pathologists for Tumor Typing and Reporting.

Joseph T Rabban, Lee-May Chen, W Patrick Devine.

  Clinical testing for homologous repair (HR) deficiency (HRD) in ovarian cancers has emerged as a means to tailor the use of poly(ADP-ribose)polymerase (PARP) inhibitor therapy to the patients most likely to respond. The currently available HRD tests evaluate tumor tissue for genomic evidence of impairment of the HR pathway of DNA damage repair, which, if present, renders the tumor vulnerable to PARP inhibitors in conjunction with platinum chemotherapy. Germline or somatic mutation of BRCA1/2 is a major contributor HRD. Thus, tubo-ovarian/peritoneal high-grade serous carcinoma (HGSC) is enriched by HRD. After highlighting the general concepts underlying HRD testing and PARP inhibitor therapy, this review discusses practical roles for pathologists to maximize the opportunities for eligible patients with ovarian cancer to benefit from HRD testing, chiefly by applying contemporary diagnostic criteria for ovarian cancer tumor typing and navigating through potential pitfalls of tumor types that may mimic HGSC but are unlikely to harbor HRD.

Keywords:  DNA repair; High-grade serous carcinoma; Homologous recombination deficiency; Ovarian cancer; PARP inhibitor

DOI:  https://doi.org/10.1016/j.path.2022.02.003
Clin Cancer Res. 2022 Jun 13. pii: clincanres.0368.2022-2-2 06:00:14.580. [Epub ahead of print]

Multiomic characterisation of high grade serous ovarian carcinoma enables high resolution patient stratification.

Robert L Hollis, Alison M Meynert, Caroline O Michie, Tzyvia Rye, Michael Churchman, Amelia Hallas-Potts, Ian Croy, W Glenn McCluggage, Alistair R W Williams, Clare Bartos, Yasushi Iida, Aikou Okamoto, Brian Dougherty, J Carl Barrett, Ruth March, Athena Matakidou, Patricia Roxburgh, Colin A Semple, D Paul Harkin, Richard Kennedy, C Simon Herrington, Charlie Gourley.

PURPOSE: High grade serous ovarian carcinoma (HGSOC) is the most common ovarian cancer type; most patients experience disease recurrence which accumulates chemoresistance, leading to treatment failure. Genomic and transcriptomic features have been associated with differential outcome and treatment response. However, the relationship between events at the gene sequence, copy number and gene expression levels remains poorly defined.EXPERIMENTAL DESIGN: We perform multiomic characterisation of a large HGSOC cohort (n=362) with detailed clinical annotation to interrogate the relationship between patient subgroups defined by specific molecular events.
RESULTS: BRCA2-mutant (BRCA2m) and EMSY-overexpressing cases demonstrated prolonged survival (multivariable HR 0.40 and 0.51) and significantly higher first- and second-line chemotherapy response rate. CCNE1-gained (CCNE1g) cases demonstrated under-representation of FIGO stage IV cases, with shorter survival but no significant difference in treatment response. We demonstrate marked overlap between the TCGA- and Tothill-derived subtypes. IMR/C2 cases displayed higher BRCA1/2m frequency (25.5%, 32.5%) and significantly greater immune cell infiltration, while PRO/C5 cases had the highest CCNE1g rate (23.9%, 22.2%) and were uniformly low in immune cell infiltration. The survival benefit for cases with aberrations in homologous recombination repair(HRR) genes was apparent across all transcriptomic subtypes (HR range 0.48-0.68). There was significant co-occurrence of RB loss and HRR gene aberrations; RB loss was further associated with favourable survival within HRR-aberrant cases (multivariable HR 0.50).
CONCLUSIONS: These data paint a high resolution picture of the molecular landscape in HGSOC, better defining patients who may benefit most from specific molecular therapeutics and highlighting those for whom novel treatment strategies are needed to improve outcomes.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-0368
Nat Commun. 2022 Jun 15. 13(1): 3406

Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma.

Mrinal M Gounder, Narasimhan P Agaram, Sally E Trabucco, Victoria Robinson, Richard A Ferraro, Sherri Z Millis, Anita Krishnan, Jessica Lee, Steven Attia, Wassim Abida, Alexander Drilon, Ping Chi, Sandra P D' Angelo, Mark A Dickson, Mary Lou Keohan, Ciara M Kelly, Mark Agulnik, Sant P Chawla, Edwin Choy, Rashmi Chugh, Christian F Meyer, Parvathi A Myer, Jessica L Moore, Ross A Okimoto, Raphael E Pollock, Vinod Ravi, Arun S Singh, Neeta Somaiah, Andrew J Wagner, John H Healey, Garrett M Frampton, Jeffrey M Venstrom, Jeffrey S Ross, Marc Ladanyi, Samuel Singer, Murray F Brennan, Gary K Schwartz, Alexander J Lazar, David M Thomas, Robert G Maki, William D Tap, Siraj M Ali, Dexter X Jin.

There are more than 70 distinct sarcomas, and this diversity complicates the development of precision-based therapeutics for these cancers. Prospective comprehensive genomic profiling could overcome this challenge by providing insight into sarcomas' molecular drivers. Through targeted panel sequencing of 7494 sarcomas representing 44 histologies, we identify highly recurrent and type-specific alterations that aid in diagnosis and treatment decisions. Sequencing could lead to refinement or reassignment of 10.5% of diagnoses. Nearly one-third of patients (31.7%) harbor potentially actionable alterations, including a significant proportion (2.6%) with kinase gene rearrangements; 3.9% have a tumor mutational burden ≥10 mut/Mb. We describe low frequencies of microsatellite instability (<0.3%) and a high degree of genome-wide loss of heterozygosity (15%) across sarcomas, which are not readily explained by homologous recombination deficiency (observed in 2.5% of cases). In a clinically annotated subset of 118 patients, we validate actionable genetic events as therapeutic targets. Collectively, our findings reveal the genetic landscape of human sarcomas, which may inform future development of therapeutics and improve clinical outcomes for patients with these rare cancers.

DOI: https://doi.org/10.1038/s41467-022-30496-0
Nature. 2022 Jun 15.

Signatures of copy number alterations in human cancer.

Christopher D Steele, Ammal Abbasi, S M Ashiqul Islam, Amy L Bowes, Azhar Khandekar, Kerstin Haase, Shadi Hames-Fathi, Dolapo Ajayi, Annelien Verfaillie, Pawan Dhami, Alex McLatchie, Matt Lechner, Nicholas Light, Adam Shlien, David Malkin, Andrew Feber, Paula Proszek, Tom Lesluyes, Fredrik Mertens, Adrienne M Flanagan, Maxime Tarabichi, Peter Van Loo, Ludmil B Alexandrov, Nischalan Pillay.

Gains and losses of DNA are prevalent in cancer and emerge as a consequence of inter-related processes of replication stress, mitotic errors, spindle multipolarity and breakage-fusion-bridge cycles, among others, which may lead to chromosomal instability and aneuploidy1,2. These copy number alterations contribute to cancer initiation, progression and therapeutic resistance3-5. Here we present a conceptual framework to examine the patterns of copy number alterations in human cancer that is widely applicable to diverse data types, including whole-genome sequencing, whole-exome sequencing, reduced representation bisulfite sequencing, single-cell DNA sequencing and SNP6 microarray data. Deploying this framework to 9,873 cancers representing 33 human cancer types from The Cancer Genome Atlas6 revealed a set of 21 copy number signatures that explain the copy number patterns of 97% of samples. Seventeen copy number signatures were attributed to biological phenomena of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, chromothripsis and haploidization. The aetiologies of four copy number signatures remain unexplained. Some cancer types harbour amplicon signatures associated with extrachromosomal DNA, disease-specific survival and proto-oncogene gains such as MDM2. In contrast to base-scale mutational signatures, no copy number signature was associated with many known exogenous cancer risk factors. Our results synthesize the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes that give rise to these alterations.

DOI: https://doi.org/10.1038/s41586-022-04738-6
Cancer Res. 2022 Jun 15. 82(12): 2213-2215

Circulating DNA and Liquid Biopsies in the Management of Patients with Cancer.

Simon A Joosse, Klaus Pantel.

Forty-five years ago, Cancer Research published the study by Leon and colleagues in which the authors described the observation of increased levels of cell-free DNA (cfDNA) in the serum of patients with cancer as compared with healthy individuals, with the highest serum levels in patients with metastatic cancer. Most interestingly was the correlation between serum DNA concentrations and therapy outcome: Increased serum DNA levels were associated with poor response to treatment, whereas decreases in DNA levels during treatment appeared to be a sign of better prognosis. Since the discovery of the prognostic value of blood DNA, much research has been focused on the characterization of cfDNA to understand its origins and increase the sensitivity and specificity of using cfDNA as a prognostic and predictive marker in the battle against cancer. Tumor-specific cfDNA markers that were discovered include genetic alterations, chromosomal aberrations, epigenetic modifications, and DNA fragmentation size. In recent years, due to the development of highly sensitive molecular technologies, cfDNA-based assays are now being introduced into the clinic as the so called "liquid biopsy." The advantages of a liquid biopsy over traditional biopsy and imaging have led to the implementation in the clinic for early cancer detection, improved cancer staging, early detection of relapse, real-time monitoring of therapeutic efficacy, and detection of therapeutic targets and resistance mechanisms. Despite Leon and colleagues' initial skepticism about the potential diagnostic value of serum DNA, cfDNA-based liquid biopsy has become one of the most important tools for personalized cancer treatment. See related article by Leon and colleagues, Cancer Res 1977;37:646-50.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-1405
Nature. 2022 Jun 15.

A pan-cancer compendium of chromosomal instability.

Ruben M Drews, Barbara Hernando, Maxime Tarabichi, Kerstin Haase, Tom Lesluyes, Philip S Smith, Lena Morrill Gavarró, Dominique-Laurent Couturier, Lydia Liu, Michael Schneider, James D Brenton, Peter Van Loo, Geoff Macintyre, Florian Markowetz.

Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA1. The broad genomic complexity caused by CIN is a hallmark of cancer2; however, there is no systematic framework to measure different types of CIN and their effect on clinical phenotypes pan-cancer. Here we evaluate the extent, diversity and origin of CIN across 7,880 tumours representing 33 cancer types. We present a compendium of 17 copy number signatures that characterize specific types of CIN, with putative aetiologies supported by multiple independent data sources. The signatures predict drug response and identify new drug targets. Our framework refines the understanding of impaired homologous recombination, which is one of the most therapeutically targetable types of CIN. Our results illuminate a fundamental structure underlying genomic complexity in human cancers and provide a resource to guide future CIN research.

DOI: https://doi.org/10.1038/s41586-022-04789-9
Nature. 2022 Jun 15.

cGAS-STING drives the IL-6-dependent survival of chromosomally instable cancers.

Christy Hong, Michael Schubert, Andréa E Tijhuis, Marta Requesens, Maurits Roorda, Anouk van den Brink, Lorena Andrade Ruiz, Petra L Bakker, Tineke van der Sluis, Wietske Pieters, Mengting Chen, René Wardenaar, Bert van der Vegt, Diana C J Spierings, Marco de Bruyn, Marcel A T M van Vugt, Floris Foijer.

Chromosomal instability (CIN) drives cancer cell evolution, metastasis and therapy resistance, and is associated with poor prognosis1. CIN leads to micronuclei that release DNA into the cytoplasm after rupture, which triggers activation of inflammatory signalling mediated by cGAS and STING2,3. These two proteins are considered to be tumour suppressors as they promote apoptosis and immunosurveillance. However, cGAS and STING are rarely inactivated in cancer4, and, although they have been implicated in metastasis5, it is not known why loss-of-function mutations do not arise in primary tumours4. Here we show that inactivation of cGAS-STING signalling selectively impairs the survival of triple-negative breast cancer cells that display CIN. CIN triggers IL-6-STAT3-mediated signalling, which depends on the cGAS-STING pathway and the non-canonical NF-κB pathway. Blockade of IL-6 signalling by tocilizumab, a clinically used drug that targets the IL-6 receptor (IL-6R), selectively impairs the growth of cultured triple-negative breast cancer cells that exhibit CIN. Moreover, outgrowth of chromosomally instable tumours is significantly delayed compared with tumours that do not display CIN. Notably, this targetable vulnerability is conserved across cancer types that express high levels of IL-6 and/or IL-6R in vitro and in vivo. Together, our work demonstrates pro-tumorigenic traits of cGAS-STING signalling and explains why the cGAS-STING pathway is rarely inactivated in primary tumours. Repurposing tocilizumab could be a strategy to treat cancers with CIN that overexpress IL-6R.

DOI: https://doi.org/10.1038/s41586-022-04847-2
J Clin Invest. 2022 Jun 15. pii: e154941. [Epub ahead of print]132(12):

Circulating tumor DNA: current challenges for clinical utility.

Donna K Dang, Ben H Park.

Cancer cells shed naked DNA molecules into the circulation. This circulating tumor DNA (ctDNA) has become the predominant analyte for liquid biopsies to understand the mutational landscape of cancer. Coupled with next-generation sequencing, ctDNA can serve as an alternative substrate to tumor tissues for mutation detection and companion diagnostic purposes. In fact, recent advances in precision medicine have rapidly enabled the use of ctDNA to guide treatment decisions for predicting response and resistance to targeted therapies and immunotherapies. An advantage of using ctDNA over conventional tissue biopsies is the relatively noninvasive approach of obtaining peripheral blood, allowing for simple repeated and serial assessments. Most current clinical practice using ctDNA has endeavored to identify druggable and resistance mutations for guiding systemic therapy decisions, albeit mostly in metastatic disease. However, newer research is evaluating potential for ctDNA as a marker of minimal residual disease in the curative setting and as a useful screening tool to detect cancer in the general population. Here we review the history of ctDNA and liquid biopsies, technologies to detect ctDNA, and some of the current challenges and limitations in using ctDNA as a marker of minimal residual disease and as a general blood-based cancer screening tool. We also discuss the need to develop rigorous clinical studies to prove the clinical utility of ctDNA for future applications in oncology.

DOI: https://doi.org/10.1172/JCI154941