bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2024–06–02
six papers selected by
Sergio Marchini, Humanitas Research
  1. Harmonization of homologous recombination deficiency testing in ovarian cancer: Results from the MITO16A/MaNGO-OV2 trial.
  2. Homologous recombination deficiency should be tested for in patients with advanced stage high-grade serous ovarian cancer aged 70 years and over.
  3. Generalizable transcriptome-based tumor malignant level evaluation and molecular subtyping towards precision oncology.
  4. Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients.
  5. The association of body composition phenotypes before chemotherapy with epithelial ovarian cancer mortality.
  6. Exploring combined effects of DNA methylation and copy number on gene expression with a two-stage approach.
  1. Eur J Cancer. 2024 May 23. pii: S0959-8049(24)00783-4. [Epub ahead of print]206 114127
    Harmonization of homologous recombination deficiency testing in ovarian cancer: Results from the MITO16A/MaNGO-OV2 trial.
    Cristin Roma, Riziero Esposito Abate, Alessandra Sacco, Daniela Califano, Laura Arenare, Francesca Bergantino, Carmela Pisano, Sabrina Chiara Cecere, Giovanni Scambia, Domenica Lorusso, Grazia Artioli, Giulia Tasca, Anna Spina, Daniela Russo, Angiolo Gadducci, Carmine De Angelis, Alessandra Bologna, Sergio Marchini, Ettore Domenico Capoluongo, Francesco Perrone, Sandro Pignata, Nicola Normanno.
       BACKGROUND: Homologous Recombination Deficiency (HRD) status predicts response to treatment with poly(ADP-ribose) polymerase inhibitors in Ovarian Cancer (OC) patients. The Myriad myChoiceCDx Assay is approved by Food and Drug Agency for the HRD assessment. Here we compared the HRD status obtained by three commercial panels with the results from Myriad reference test.
    METHODS: The HRD analysis was performed on DNA from formalin-fixed and paraffin-embedded tumor samples of 100 untreated OC patients for which Myriad assay results were available, using TruSight Oncology 500 HRD assay (Illumina), Oncomine Comprehensive Assay Plus (Thermo Fisher Scientific) and SOPHiA DDM HRD solution panel (SOPHiA Genetics).
    RESULTS: A good overall concordance with the reference method was demonstrated at three different levels: BRCA mutational status (from 94.4 % to 97.7 %), the genomic instability value (from 88.2 % to 95.3 %) and for the HRD status (from 90.4 % to 97.6 %). Moreover, a trend in favour of HRD positive patients for response rate, progression-free survival and overall survival similar to Myriad was observed for all three tests.
    DISCUSSION: Our data suggest the feasibility of commercial testing for assessing HRD status, with a good concordance with the reference method and association with clinical outcome.
    Keywords:  Homologous Recombination Deficiency; Ovarian Cancer; Targeted resequencing
    DOI:  https://doi.org/10.1016/j.ejca.2024.114127
  2. Gynecol Oncol. 2024 May 30. pii: S0090-8258(24)00239-7. [Epub ahead of print]187 221-226
    Homologous recombination deficiency should be tested for in patients with advanced stage high-grade serous ovarian cancer aged 70 years and over.
    Omali Pitiyarachchi, Peter J Ansell, Robert L Coleman, Minh H Dinh, Laura Holman, Charles A Leath, Theresa Werner, Paul DiSilvestro, Mark Morgan, William Tew, Christine Lee, Mary Cunningham, Meredith Newton, Babak Edraki, Peter Lim, Joyce Barlin, Nicola M Spirtos, Krishnansu S Tewari, Mitchell Edelson, Thomas Reid, Jay Carlson, Michael Friedlander.
       OBJECTIVE: Due to limited data on homologous recombination deficiency (HRD) in older patients (≥ 70 years) with advanced stage high grade serous ovarian cancer (HGSC), we aimed to determine the rates of HRD at diagnosis in this age group.
    METHODS: From the Phase 3 trial VELIA the frequency of HRD and BRCA1/2 pathogenic variants (PVs) was compared between younger (< 70 years) and older participants. HRD and somatic(s) BRCA1/2 pathogenic variants (PVs) were determined at diagnosis using Myriad myChoice® CDx and germline(g) BRCA1/2 PVs using Myriad BRACAnalysis CDx®. HRD was defined if a BRCA PV was present, or the genomic instability score (GIS) met threshold (GIS ≥ 33 & ≥ 42 analyzed).
    RESULTS: Of 1140 participants, 21% were ≥ 70 years. In total, 26% (n = 298) had a BRCA1/2 PV and HRD, 29% (n = 329) were HRD/BRCA wild-type, 33% (n = 372) non-HRD, and 12% HR-status unknown (n = 141). HRD rates were higher in younger participants, 59% (n = 476/802), compared to 40% (n = 78/197) of older participants (GIS ≥ 42) [p < 0.001]; similar rates demonstrated with GIS ≥ 33, 66% vs 48% [p < 0.001]. gBRCA PVs observed in 24% younger vs 8% of older participants (p < 0.001); sBRCA in 8% vs 10% (p = 0.2559), and HRD (GIS ≥ 42) not due to gBRCA was 35% vs 31% (p = 0.36).
    CONCLUSIONS: HRD frequency was similar in participants aged < 70 and ≥ 70 years (35% vs 31%) when the contribution of gBRCA was excluded; rates of sBRCA PVs were also similar (8% v 10%), thus underscoring the importance of HRD and BRCA testing at diagnosis in older patients with advanced HGSC given the therapeutic implications.
    Keywords:  HRD testing; Homologous Recombination Deficiency (HRD); Older patients; Ovarian cancer; PARP inhibitors
    DOI:  https://doi.org/10.1016/j.ygyno.2024.05.021
  3. J Transl Med. 2024 May 28. 22(1): 512
    Generalizable transcriptome-based tumor malignant level evaluation and molecular subtyping towards precision oncology.
    Dingxue Hu, Ziteng Zhang, Xiaoyi Liu, Youchun Wu, Yunyun An, Wanqiu Wang, Mengqi Yang, Yuqi Pan, Kun Qiao, Changzheng Du, Yu Zhao, Yan Li, Jianqiang Bao, Tao Qin, Yue Pan, Zhaohua Xia, Xin Zhao, Kun Sun.
      In cancer treatment, therapeutic strategies that integrate tumor-specific characteristics (i.e., precision oncology) are widely implemented to provide clinical benefits for cancer patients. Here, through in-depth integration of tumor transcriptome and patients' prognoses across cancers, we investigated dysregulated and prognosis-associated genes and catalogued such important genes in a cancer type-dependent manner. Utilizing the expression matrices of these genes, we built models to quantitatively evaluate the malignant levels of tumors across cancers, which could add value to the clinical staging system for improved prediction of patients' survival. Furthermore, we performed a transcriptome-based molecular subtyping on hepatocellular carcinoma, which revealed three subtypes with significantly diversified clinical outcomes, mutation landscapes, immune microenvironment, and dysregulated pathways. As tumor transcriptome was commonly profiled in clinical practice with low experimental complexity and cost, this work proposed easy-to-perform approaches for practical clinical promotion towards better healthcare and precision oncology of cancer patients.
    Keywords:  Hepatocellular carcinoma; Oncogene; Survival analysis; Tumor suppressor
    DOI:  https://doi.org/10.1186/s12967-024-05326-0
  4. NPJ Genom Med. 2024 May 29. 9(1): 33
    Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients.
    Tom Venken, Ian S Miller, Ingrid Arijs, Valentina Thomas, Ana Barat, Johannes Betge, Tianzuo Zhan, Timo Gaiser, Matthias P Ebert, Alice C O'Farrell, Jochen Prehn, Rut Klinger, Darran P O'Connor, Brian Moulton, Verena Murphy, Garazi Serna, Paolo G Nuciforo, Ray McDermott, Brian Bird, Gregory Leonard, Liam Grogan, Anne Horgan, Nadine Schulte, Markus Moehler, Diether Lambrechts, Annette T Byrne.
      To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment.
    DOI:  https://doi.org/10.1038/s41525-024-00415-x
  5. J Natl Cancer Inst. 2024 May 28. pii: djae112. [Epub ahead of print]
    The association of body composition phenotypes before chemotherapy with epithelial ovarian cancer mortality.
    Evan W Davis, Kristopher Attwood, Joseph Prunier, Gyorgy Paragh, Janine M Joseph, André Klein, Charles Roche, Nancy Barone, John Lewis Etter, Andrew D Ray, Britton Trabert, Matthew B Schabath, Lauren C Peres, Rikki Cannioto.
       BACKGROUND: The association of body composition with epithelial ovarian carcinoma (EOC) mortality is poorly understood. To date, evidence suggests high adiposity associates with decreased mortality (an obesity paradox), but the impact of muscle on this association has not been investigated. Herein, we define associations of muscle and adiposity joint-exposure body composition phenotypes with EOC mortality.
    METHODS: Body composition from 500 women in The Body Composition and Epithelial Ovarian Cancer Survival Study was dichotomized as normal/low skeletal muscle index (SMI), a proxy for sarcopenia and high/low adiposity. Four phenotypes were classified as fit/reference (normal SMI/low adiposity; 16.2%), overweight/obese (normal SMI/high adiposity; 51.2%), sarcopenia/overweight-obese (low SMI/high adiposity; 15.6%), and sarcopenia/cachexia (low SMI/low adiposity; 17%). We used multivariable Cox models to estimate associations of each phenotype with mortality for EOC overall and high-grade serous ovarian carcinoma (HGSOC).
    RESULTS: Overweight/obesity was associated with up to 51% and 104% increased mortality in EOC and HGSOC (HR = 1.51, 95% CI: 1.05-2.19 and HR = 2.04, 95% CI: 1.29-3.21). Sarcopenia/overweight-obesity was associated with up to 66% and 67% increased mortality in EOC and HGSOC (HR = 1.66, 95% CI: 1.13-2.45 and HR = 1.67, 95% CI: 1.05-2.68). Sarcopenia/cachexia was associated with up to 73% and 109% increased mortality in EOC and HGSOC (HR = 1.73, 95% CI: 1.14-2.63 and HR = 2.09, 95% CI: 1.25-3.50).
    CONCLUSIONS: Overweight/obesity, sarcopenia/overweight-obesity and sarcopenia/cachexia phenotypes were each associated with increased mortality in EOC and HGSOC. Exercise and dietary interventions could be leveraged as ancillary treatment strategies for improving outcomes in the most fatal gynecological malignancy with no previously established modifiable prognostic factors.
    DOI:  https://doi.org/10.1093/jnci/djae112
  6. IEEE/ACM Trans Comput Biol Bioinform. 2024 May 29. PP
    Exploring combined effects of DNA methylation and copy number on gene expression with a two-stage approach.
    Henry Claussen, Santu Ghosh, Jie Chen.
      DNA methylation and copy number may be associated with each other to some extent, in positive or negative ways. Whether differential methylation and copy number variation have combined effects on gene expression is largely unknown. We use a multivariate linear model to formulate the relationship among the three genomic measurements, gene expression, copy number, and methylation levels. We propose a method that combines a distance covariance measure and the group LASSO to analyze multiple types of genomic data collectively for the purpose of insightfully revealing how gene expression is potentially affected by both copy number variation and differential methylation levels in cellular process. Our approach is of two stages, the first is a variable screening process in which a variable selection method is utilized by employing the concept of joint distance covariance (JdCov) of random vectors, and the second is to implement a penalized regression approach, a group LASSO, on the screened data of much lower dimension. The two-stage approach is tested in extensive simulation studies and shown to be effective. The approach is then applied to the TCGA Melanoma data, which consists of gene expression, methylation and copy number measurements of more than 300 patients and relationship of some genes with methylation and copy number measurements were revealed for the involved subjects.
    DOI:  https://doi.org/10.1109/TCBB.2024.3406969
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