bims-tumhet 2022-12-18 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2022–12–18
eight papers selected by
Sergio Marchini, Humanitas Research

The cGAS-STING pathway and cancer.
Homologous Recombination Deficiency and Cyclin E1 Amplification Are Correlated with Immune Cell Infiltration and Survival in High-Grade Serous Ovarian Cancer.
Ovarian cancer mutational processes drive site-specific immune evasion.
Genetics and anatomy sculpt immune-cell partners of ovarian cancer.
Low grade serous ovarian cancer - A rare disease with increasing therapeutic options.
DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities.
Concordance between single-nucleotide polymorphism-based genomic instability assays and a next-generation sequencing-based homologous recombination deficiency test.
Combining Inhibition of Immune Checkpoints and PARP: Rationale and Perspectives in Cancer Treatment.

Nat Cancer. 2022 Dec 12.

The cGAS-STING pathway and cancer.

Natasha Samson, Andrea Ablasser.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a critical innate immune pathway that, following engagement by DNA, promotes distinct immune effector responses that can impact virtually all aspects of tumorigenesis, from malignant cell transformation to metastasis. Here we address how natural tumor-associated processes and traditional cancer therapies are shaped by cGAS-STING signaling, and how this contributes to beneficial or detrimental outcomes of cancer. We consider current efforts to target the cGAS-STING axis in tumors and highlight new frontiers in cGAS-STING biology to inspire thinking about their connection to cancer.

DOI: https://doi.org/10.1038/s43018-022-00468-w
Cancers (Basel). 2022 Dec 02. pii: 5965. [Epub ahead of print]14(23):

Homologous Recombination Deficiency and Cyclin E1 Amplification Are Correlated with Immune Cell Infiltration and Survival in High-Grade Serous Ovarian Cancer.

Lilian van Wagensveld, Juliette O A M van Baal, Maite Timmermans, Duco Gaillard, Lauri Borghuis, Seth B Coffelt, Efraim H Rosenberg, Christianne A R Lok, Hans W Nijman, Loes F S Kooreman, Joyce Sanders, Marco de Bruijn, Lodewyk F A Wessels, Rianne van der Wiel, Christian Rausch, Annegien Broeks, Roy F P M Kruitwagen, Maaike A van der Aa, Gabe S Sonke, Philip C Schouten, Koen K Van de Vijver, Hugo M Horlings.

   BACKGROUND: How molecular profiles are associated with tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC) is incompletely understood. Therefore, we analyzed the TME and molecular profiles of HGSOC and assessed their associations with overall survival (OS).
METHODS: Patients with advanced-stage HGSOC treated in three Dutch hospitals between 2008-2015 were included. Patient data were collected from medical records. BRCA1/2 mutation, BRCA1 promotor methylation analyses, and copy number variations were used to define molecular profiles. Immune cells were assessed with immunohistochemical staining.
RESULTS: 348 patients were categorized as BRCA mutation (BRCAm) (BRCAm or promotor methylation) (30%), non-BRCA mutated HRD (19%), Cyclin E1 (CCNE1)-amplification (13%), non-BRCAmut HRD and CCNE1-amplification (double classifier) (20%), and no specific molecular profile (NSMP) (18%). BRCAm showed highest immune cell densities and CCNE1-amplification lowest. BRCAm showed the most favorable OS (52.5 months), compared to non-BRCAmut HRD (41.0 months), CCNE1-amplification (28.0 months), double classifier (27.8 months), and NSMP (35.4 months). Higher immune cell densities showed a favorable OS compared to lower, also within the profiles. CD8+, CD20+, and CD103+ cells remained associated with OS in multivariable analysis.
CONCLUSIONS: Molecular profiles and TME are associated with OS. TME differs per profile, with higher immune cell densities showing a favorable OS, even within the profiles. HGSOC does not reflect one entity but comprises different entities based on molecular profiles and TME.

Keywords:  epithelial ovarian carcinoma; homologous; microenvironment; ovarian neoplasms/genetics; prognosis; recombination; tumor

DOI:  https://doi.org/10.3390/cancers14235965
Nature. 2022 Dec 14.

Ovarian cancer mutational processes drive site-specific immune evasion.

Ignacio Vázquez-García, Florian Uhlitz, Nicholas Ceglia, Jamie L P Lim, Michelle Wu, Neeman Mohibullah, Juliana Niyazov, Arvin Eric B Ruiz, Kevin M Boehm, Viktoria Bojilova, Christopher J Fong, Tyler Funnell, Diljot Grewal, Eliyahu Havasov, Samantha Leung, Arfath Pasha, Druv M Patel, Maryam Pourmaleki, Nicole Rusk, Hongyu Shi, Rami Vanguri, Marc J Williams, Allen W Zhang, Vance Broach, Dennis S Chi, Arnaud Da Cruz Paula, Ginger J Gardner, Sarah H Kim, Matthew Lennon, Kara Long Roche, Yukio Sonoda, Oliver Zivanovic, Ritika Kundra, Agnes Viale, Fatemeh N Derakhshan, Luke Geneslaw, Shirin Issa Bhaloo, Ana Maroldi, Rahelly Nunez, Fresia Pareja, Anthe Stylianou, Mahsa Vahdatinia, Yonina Bykov, Rachel N Grisham, Ying L Liu, Yulia Lakhman, Ines Nikolovski, Daniel Kelly, Jianjiong Gao, Andrea Schietinger, Travis J Hollmann, Samuel F Bakhoum, Robert A Soslow, Lora H Ellenson, Nadeem R Abu-Rustum, Carol Aghajanian, Claire F Friedman, Andrew McPherson, Britta Weigelt, Dmitriy Zamarin, Sohrab P Shah.

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1-4 patterned by distinct mutational processes5,6, tumour heterogeneity7-9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11-13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFβ signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research.

DOI: https://doi.org/10.1038/s41586-022-05496-1
Nature. 2022 Dec;612(7941): 634-636

Genetics and anatomy sculpt immune-cell partners of ovarian cancer.

Denarda Dangaj Laniti, George Coukos.



Keywords:  Cancer; Medical research

DOI:  https://doi.org/10.1038/d41586-022-04169-3
Cancer Treat Rev. 2022 Dec 10. pii: S0305-7372(22)00173-6. [Epub ahead of print]112 102497

Low grade serous ovarian cancer - A rare disease with increasing therapeutic options.

Tibor A Zwimpfer, Ori Tal, Franziska Geissler, Ricardo Coelho, Natalie Rimmer, Francis Jacob, Viola Heinzelmann-Schwarz.

  High-grade serous ovarian cancers (HGSOCs) most commonly arise from the fimbrial end of the fallopian tube and harbor TP53 gene mutations. In contrast, low-grade serous ovarian cancers (LGSOCs) appear to have different pathological, epidemiological, and clinical features and should be seen as a distinct serous epithelial ovarian cancer subtype. Our current understanding of LGSOC is limited, and treatment has generally been derived from the more common HGSOCs due to a lack of separate trial data. LGSOCs are characterized by slow tumor growth and are assumed to develop from serous borderline ovarian tumors as precursors. These cancers are often estrogen-receptor positive and show an activated mitogen-activated protein kinase pathway together with KRAS and BRAF mutations and, rarely, TP53 mutations. These characteristics are now commonly used to guide therapeutical decision making and, consequently, a substantial part of treatment consists of maintenance with endocrine treatment, thus balancing disease stabilization and mild toxicity. Additionally, new trials are ongoing that examine the role of targeted therapies such as MEK inhibitors in combination with endocrine treatments. The purpose of this work is to summarize current knowledge and present ongoing trial efforts for LGSOCs.

Keywords:  BRAF inhibitors; CDK 4/6; ER; Endocrine treatment; KRAS; MEK inhibitors

DOI:  https://doi.org/10.1016/j.ctrv.2022.102497
Int J Mol Sci. 2022 Nov 24. pii: 14672. [Epub ahead of print]23(23):

DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities.

Dana Jurkovicova, Christiana M Neophytou, Ana Čipak Gašparović, Ana Cristina Gonçalves.

  Resistance to chemo- and radiotherapy is a common event among cancer patients and a reason why new cancer therapies and therapeutic strategies need to be in continuous investigation and development. DNA damage response (DDR) comprises several pathways that eliminate DNA damage to maintain genomic stability and integrity, but different types of cancers are associated with DDR machinery defects. Many improvements have been made in recent years, providing several drugs and therapeutic strategies for cancer patients, including those targeting the DDR pathways. Currently, poly (ADP-ribose) polymerase inhibitors (PARP inhibitors) are the DDR inhibitors (DDRi) approved for several cancers, including breast, ovarian, pancreatic, and prostate cancer. However, PARPi resistance is a growing issue in clinical settings that increases disease relapse and aggravate patients' prognosis. Additionally, resistance to other DDRi is also being found and investigated. The resistance mechanisms to DDRi include reversion mutations, epigenetic modification, stabilization of the replication fork, and increased drug efflux. This review highlights the DDR pathways in cancer therapy, its role in the resistance to conventional treatments, and its exploitation for anticancer treatment. Biomarkers of treatment response, combination strategies with other anticancer agents, resistance mechanisms, and liabilities of treatment with DDR inhibitors are also discussed.

Keywords:  DNA damage repair inhibitors; DNA damage response; biomarkers; drug resistance

DOI:  https://doi.org/10.3390/ijms232314672
BMC Cancer. 2022 Dec 14. 22(1): 1310

Concordance between single-nucleotide polymorphism-based genomic instability assays and a next-generation sequencing-based homologous recombination deficiency test.

Razvan Cristescu, Xiao Qiao Liu, Gladys Arreaza, Cai Chen, Andrew Albright, Ping Qiu, Matthew J Marton.

   BACKGROUND: We evaluated the performance of single-nucleotide polymorphism (SNP) genotyping arrays OncoScan (Thermo Fisher Scientific, San Diego, CA) and Infinium CytoSNP-850K (CytoSNP; Illumina, Waltham, MA) for assessing homologous recombination deficiency (HRD) genomic instability.
METHODS: DNA (pretreatment samples) across 20 tumor types was evaluated with OncoScan, CytoSNP, and the clinically validated HRD test. Copy number variation (CNV) and loss of heterozygosity (LOH) analyses were performed with ASCATv2.5.1. Aggregate HRD genomic metrics included LOH, telomeric-allelic imbalance number (TAI), and large-scale state transition (LST). Associations between BRCA mutation (BRCAm) status and the clinically validated HRD test metric (dichotomized at a clinical cut-off) were evaluated using area under the receiver operating characteristic (AUROC); Spearman ρ was calculated for continuous metrics. CNV segmentation and HRD genomic metrics were calculated (n = 120, n = 106, and n = 126 for OncoScan, CytoSNP and clinically validated HRD test, respectively).
RESULTS: When assessed by SNP arrays, the genomic metric demonstrated good association with BRCAm (AUROC of HRD: OncoScan, 0.87; CytoSNP, 0.75) and the clinically validated test (cut-off, 42; AUROC of HRD: OncoScan, 0.92; CytoSNP, 0.91). The genomic metrics demonstrated good correlation with the clinically validated aggregate HRD test metric (ρ: OncoScan, 0.82; CytoSNP, 0.81) and for each component (ρ: OncoScan, 0.68 [LOH], 0.76 [TAI], and 0.78 [LST]; CytoSNP, 0.59 [LOH], 0.77 [TAI], and 0.82 [LST]). HRD assessed by SNP genotyping arrays and the clinically validated test showed good correlation.
CONCLUSION: OncoScan and CytoSNP may potentially identify most HRD-positive tumors with appropriate clinically relevant cut-offs.

Keywords:  BRCA; Homologous recombination deficiency; Large-scale state transition; Loss of heterozygosity; Telomeric-allelic imbalance number

DOI:  https://doi.org/10.1186/s12885-022-10197-z
Expert Opin Ther Targets. 2022 Dec 15.

Combining Inhibition of Immune Checkpoints and PARP: Rationale and Perspectives in Cancer Treatment.

Martina Catalano, Luigi Francesco Iannone, Federica Cosso, Daniele Generali, Enrico Mini, Giandomenico Roviello.

   INTRODUCTION: Genomic instability resulting from the inability of cells to repair DNA damage is a breeding ground for immune checkpoint inhibitors (ICIs) and targeted treatments. Poly (ADP-ribose) polymerase inhibitors (PARPi) interfere with the efficient repair of DNA single-strand break damage inducing, mainly in tumors with existing defects in double strand DNA repair system, synthetic lethality.
AREAS COVERED: : By amplifying the DNA damage and inducing immunogenic cell death PARPi leads tumor neoantigens to increase, upregulation of programmed death-ligand 1, and modulation of the tumor microenvironment facilitating a more intense antitumor immune response. In this review, we reported the immunological role of PARPi and the rational use of the combination with ICIs, evaluating data from combination clinical trials and discussing perspectives.
EXPERT OPINION: Several prospective combination studies to overcome existing limitations to PARPi and ICI single agents are currently ongoing. The identification of the different resistance mechanisms to PARPi and ICI as well as the development of accurate and predictive biomarkers of response should be a priority to identify the patients who may most benefit from this combination. Similarly, clarifying the role and interaction between the DNA damage repair pathways and the tumor immune microenvironment would increase success of the combination.

Keywords:  PARP inhibitors; combined therapy; immune checkpoint inhibitors; solid tumors; synergistic effect

DOI:  https://doi.org/10.1080/14728222.2022.2158813