bims-tumhet 2024-07-21 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2024–07–21
seven papers selected by
Sergio Marchini, Humanitas Research

Recent Advances in Genomic Approaches for the Detection of Homologous Recombination Deficiency.
Timing of whole genome duplication is associated with tumor-specific MHC-II depletion in serous ovarian cancer.
Targeting DNA Damage Response Deficiency in Thoracic Cancers.
Spatial tumor immune microenvironment phenotypes in ovarian cancer.
HRD testing for all advanced high-grade ovarian carcinoma in first line?
Quantification method of ctDNA using cell-free DNA methylation profile for noninvasive screening and monitoring of colon cancer.
Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma.

Cancer Res Treat. 2024 Jul 17.

Recent Advances in Genomic Approaches for the Detection of Homologous Recombination Deficiency.

Yoo-Na Kim, Doga C Gulhan, Hu Jin, Dominik Glodzik, Peter J Park.

  Accurate detection of homologous recombination deficiency (HRD) in cancer patients is paramount in clinical applications, as HRD confers sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. With the advances in genome sequencing technology, mutational profiling on a genome-wide scale has become readily accessible, and our knowledge of the genomic consequences of HRD has been greatly expanded and refined. Here, we review the recent advances in HRD detection methods. We examine the copy number and structural alterations that often accompany the genome instability that results from HRD, describe the advantages of mutational signature-based methods that do not rely on specific gene mutations, and review some of the existing algorithms used for HRD detection. We also discuss the choice of sequencing platforms (panel, exome, or whole-genome) and catalog the HRD detection assays used in key PARP inhibitor trials.

Keywords:  Copy number analysis; DNA repair; Genomic instability; Mutational signature analysis; PARP inhibitor; Recombinational DNA repair

DOI:  https://doi.org/10.4143/crt.2024.154
Nat Commun. 2024 Jul 18. 15(1): 6069

Timing of whole genome duplication is associated with tumor-specific MHC-II depletion in serous ovarian cancer.

Australian Ovarian Cancer Study Group

Whole genome duplication is frequently observed in cancer, and its prevalence in our prior analysis of end-stage, homologous recombination deficient high grade serous ovarian cancer (almost 80% of samples) supports the notion that whole genome duplication provides a fitness advantage under the selection pressure of therapy. Here, we therefore aim to identify potential therapeutic vulnerabilities in primary high grade serous ovarian cancer with whole genome duplication by assessing differentially expressed genes and pathways in 79 samples. We observe that MHC-II expression is lowest in tumors which have acquired whole genome duplication early in tumor evolution, and further demonstrate that reduced MHC-II expression occurs in subsets of tumor cells rather than in canonical antigen-presenting cells. Early whole genome duplication is also associated with worse patient survival outcomes. Our results suggest an association between the timing of whole genome duplication, MHC-II expression and clinical outcome in high grade serous ovarian cancer that warrants further investigation for therapeutic targeting.

DOI: https://doi.org/10.1038/s41467-024-50137-y
Drugs. 2024 Jul 13.

Targeting DNA Damage Response Deficiency in Thoracic Cancers.

Aleksandra Bzura, Jake B Spicer, Sean Dulloo, Timothy A Yap, Dean A Fennell.

Thoracic cancers comprise non-small cell lung cancers (NSCLCs), small cell lung cancers (SCLCs) and malignant pleural mesotheliomas (MPM). Collectively, they account for the highest rate of death from malignancy worldwide. Genomic instability is a universal feature of cancer, which fuels mutations and tumour evolution. Deficiencies in DNA damage response (DDR) genes amplify genomic instability. Homologous recombination deficiency (HRD), resulting from BRCA1/BRCA2 inactivation, is exploited for therapeutic synthetic lethality with poly-ADP ribose polymerase (PARP) inhibitors in breast and ovarian cancers, as well as in prostate and pancreatic cancers. However, DDR deficiency and its therapeutic implications are less well established in thoracic cancers. Emerging evidence suggests that a subset of thoracic cancers may harbour DDR deficiency and may, thus, be effectively targeted with DDR agents. Here, we review the current evidence surrounding DDR in thoracic cancers and discuss the challenges and promise for achieving clinical benefit with such therapeutics.

DOI: https://doi.org/10.1007/s40265-024-02066-9
NPJ Precis Oncol. 2024 Jul 18. 8(1): 148

Spatial tumor immune microenvironment phenotypes in ovarian cancer.

Claudia Mateiou, Lavanya Lokhande, Lan Hoa Diep, Mattis Knulst, Elias Carlsson, Sara Ek, Karin Sundfeldt, Anna Gerdtsson.

Immunotherapy has largely failed in ovarian carcinoma (OC), likely due to that the vast tumor heterogeneity and variation in immune response have hampered clinical trial outcomes. Tumor-immune microenvironment (TIME) profiling may aid in stratification of OC tumors for guiding treatment selection. Here, we used Digital Spatial Profiling combined with image analysis to characterize regions of spatially distinct TIME phenotypes in OC to assess whether immune infiltration pattern can predict presence of immuno-oncology targets. Tumors with diffuse immune infiltration and increased tumor-immune spatial interactions had higher presence of IDO1, PD-L1, PD-1 and Tim-3, while focal immune niches had more CD163 macrophages and a preliminary worse outcome. Immune exclusion was associated with presence of Tregs and Fibronectin. High-grade serous OC showed an overall stronger immune response and presence of multiple targetable checkpoints. Low-grade serous OC was associated with diffuse infiltration and a high expression of STING, while endometrioid OC had higher presence of CTLA-4. Mucinous and clear cell OC were dominated by focal immune clusters and immune-excluded regions, with mucinous tumors displaying T-cell rich immune niches.

DOI: https://doi.org/10.1038/s41698-024-00640-8
ESMO Open. 2024 Jul 17. pii: S2059-7029(24)01396-6. [Epub ahead of print]9(7): 103627

HRD testing for all advanced high-grade ovarian carcinoma in first line?

S Puglisi, I A McNeish, A G Martin.

DOI: https://doi.org/10.1016/j.esmoop.2024.103627
Clin Epigenetics. 2024 Jul 19. 16(1): 95

Quantification method of ctDNA using cell-free DNA methylation profile for noninvasive screening and monitoring of colon cancer.

Hyojung Ryu, Ji-Hoon Kim, Yeo Jin Kim, Hahyeon Jeon, Byoung-Chul Kim, Yeonsu Jeon, Yeonkyung Kim, Hyebin Bak, Younghui Kang, Changjae Kim, Hyojin Um, Ji-Hye Ahn, Hwi Hyun, Byung Chul Kim, Inho Song, Sungwon Jeon, Jong Bhak, Eon Chul Han.

   BACKGROUND: Colon cancer ranks as the second most lethal form of cancer globally. In recent years, there has been active investigation into using the methylation profile of circulating tumor DNA (ctDNA), derived from blood, as a promising indicator for diagnosing and monitoring colon cancer.
RESULTS: We propose a liquid biopsy-based epigenetic method developed by utilizing 49 patients and 260 healthy controls methylation profile data to screen and monitor colon cancer. Our method initially identified 901 colon cancer-specific hypermethylated (CaSH) regions in the tissues of the 49 cancer patients. We then used these CaSH regions to accurately quantify the amount of circulating tumor DNA (ctDNA) in the blood samples of these same patients, utilizing cell-free DNA methylation profiles. Notably, the methylation profiles of ctDNA in the blood exhibited high sensitivity (82%) and specificity (93%) in distinguishing patients with colon cancer from the control group, with an area under the curve of 0.903. Furthermore, we confirm that our method for ctDNA quantification is effective for monitoring cancer patients and can serve as a valuable tool for postoperative prognosis.
CONCLUSIONS: This study demonstrated a successful application of the quantification of ctDNA among cfDNA using the original cancer tissue-derived CaSH region for screening and monitoring colon cancer.

Keywords:  Colon cancer; Epigenetic diagnosis; Liquid biopsy; Postoperative monitoring; ctDNA

DOI:  https://doi.org/10.1186/s13148-024-01708-9
Nat Commun. 2024 Jul 16. 15(1): 5932

Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma.

Olivia Le Saux, Maude Ardin, Justine Berthet, Sarah Barrin, Morgane Bourhis, Justine Cinier, Yasmine Lounici, Isabelle Treilleux, Pierre-Alexandre Just, Guillaume Bataillon, Aude-Marie Savoye, Marie-Ange Mouret-Reynier, Elodie Coquan, Olfa Derbel, Louis Jeay, Suliman Bouizaguen, Intidhar Labidi-Galy, Séverine Tabone-Eglinger, Anthony Ferrari, Emilie Thomas, Christine Ménétrier-Caux, Eric Tartour, Isabelle Galy-Fauroux, Marc-Henri Stern, Magali Terme, Christophe Caux, Bertrand Dubois, Isabelle Ray-Coquard.

PD-1/PD-L1 blockade has so far shown limited survival benefit for high-grade ovarian carcinomas. By using paired samples from the NeoPembrOv randomized phase II trial (NCT03275506), for which primary outcomes are published, and by combining RNA-seq and multiplexed immunofluorescence staining, we explore the impact of NeoAdjuvant ChemoTherapy (NACT) ± Pembrolizumab (P) on the tumor environment, and identify parameters that correlated with response to immunotherapy as a pre-planned exploratory analysis. Indeed, i) combination therapy results in a significant increase in intraepithelial CD8+PD-1+ T cells, ii) combining endothelial and monocyte gene signatures with the CD8B/FOXP3 expression ratio is predictive of response to NACT + P with an area under the curve of 0.93 (95% CI 0.85-1.00) and iii) high CD8B/FOXP3 and high CD8B/ENTPD1 ratios are significantly associated with positive response to NACT + P, while KDR and VEGFR2 expression are associated with resistance. These results indicate that targeting regulatory T cells and endothelial cells, especially VEGFR2+ endothelial cells, could overcome immune resistance of ovarian cancers.

DOI: https://doi.org/10.1038/s41467-024-47000-5