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1. Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS

Author

Cho Mar Myint Wai, Shangying Chen, The Phyu, Shuangyi Fan, Sai Mun Leong, Wenning Zheng, Louis Ching Yi Low, Shoa-Nian Choo, Chi-Kuen Lee, Tae-Hoon Chung, Kenneth Hon Kim Ban, Soumita Ghosh, Stefanus Lie, Seiichi Kato, Shigeo Nakamura, Emiko Takahashi, Young-Hyeh Ko, Joseph D. Khoury, Shih-Sung Chuang, Rex K.H. Au-Yeung, Soo-Yong Tan, Soon-Thye Lim, Choon-Kiat Ong, Yong-Howe Ho, Li Mei Poon, Sanjay de Mel, Anand D. Jeyasekharan, Wee-Joo Chng, Franziska Otto, Leticia Quintanilla-Martinez, Federica Zanardi, Fabio Iannelli, Claudio Tripodo, Jason J. Pitt, and Siok-Bian Ng

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Primary Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of primary T-cell lymphoma not otherwise specified (PTCL-NOS). Herein, we analyzed copynumber aberrations (n=77) with a focus on global measures of genomic instability and homologous recombination deficiency and performed gene expression (n=84) and EBV miRNA expression (n=24) profiling as well as targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed that patients with PTCL-EBV had a significantly worse outcome compared to patients with PTCL-NOS (P=0.002) but not to those with ENKTL. Remarkably, PTCL-EBV exhibited significantly lower genomic instability and homologous recombination deficiency scores compared to ENKTL and PTCL-NOS. Gene set enrichment analysis revealed that many immune-related pathways, interferon α/γ response, and IL6_JAK_STAT3 signaling were significantly upregulated in PTCLEBV and correlated with lower genomic instability scores. We also identified that NFκB-associated genes, BIRC3, NFKB1 (P50) and CD27, and their proteins are upregulated in PTCL-EBV. Most PTCL-EBV demonstrated a type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNA compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are characterized by microsatellite stability. Overall, poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNA are distinctive features of PTCL-EBV. Our data support the concept that PTCL-EBV could be considered as a distinct entity, provide novel insights into the pathogenesis of the disease and offer potential new therapeutic targets for this tumor.

Published
2022
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2. Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer

Author

Michal M Hoppe, Patrick Jaynes, Joanna D Wardyn, Sai Srinivas Upadhyayula, Tuan Zea Tan, Stefanus Lie, Diana G Z Lim, Brendan N K Pang, Sherlly Lim, Joe P S Yeong, Anthony Karnezis, Derek S Chiu, Samuel Leung, David G Huntsman, Anna S Sedukhina, Ko Sato, Monique D Topp, Clare L Scott, Hyungwon Choi, Naina R Patel, Robert Brown, Stan B Kaye, Jason J Pitt, David S P Tan, and Anand D Jeyasekharan

Subjects
HRD, immune exclusion, multiplexed IHC, ovarian cancer, RAD51, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A‐priori identification of platinum resistance is therefore crucial to improve on standard first‐line carboplatin–paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum‐induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK‐compliant study of pre‐treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51‐High tumours had shorter progression‐free and overall survival compared to RAD51‐Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR‐proficient cancers (Myriad HRDscore

Published
2021
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3. Supplementary Table 1 from Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma

Author

Patrick Tan, Bin Tean Teh, Chawalit Pairojkul, Tatsuhiro Shibata, Steven G. Rozen, Raluca Gordân, Ludmil B. Alexandrov, Young Nyun Park, Hyungjin Rhee, André Luiz Vettore, André Lopes Carvalho, Di-Xian Luo, Jiaming Lai, Aldo Scarpa, Ming-Chin Yu, Sen-Yung Hsieh, Philippe Broet, Irinel Popescu, Dan G. Duda, Simona Dima, Kiat Hon Lim, London Lucien Peng Jin Ooi, Alexander Yaw Fui Chung, Pierce Kah-Hoe Chow, Satoshi Yamasaki, Yasuhito Arai, Hiromi Nakamura, Yasushi Totoki, Sopit Wongkham, Puangrat Yongvanit, Vajaraphongsa Bhudhisawasdi, Narong Khuntikeo, John R. McPherson, Jia Liang Loh, Jing Tan, Tse Hui Lim, Alvin Soon Tiong Lim, Stefanus Lie, Vikneswari Rajasegaran, Choon Kiat Ong, Mo Liu, Arnoud Boot, Cedric Chuan Young Ng, Weng Khong Lim, Sanjanaa Nagarajan, Raynoo Thanan, Swe Swe Myint, Su Pin Choo, Ley Moy Ng, Alvin Wei Tian Ng, Sarinya Kongpetch, Vishwa Nellore, Nisha Padmanabhan, Mi Ni Huang, Jing Quan Lim, Chern Han Yong, Ioana Cutcutache, and Apinya Jusakul

Abstract

Summary of Patients and Clinical Data.

Published
2023

4. Supplementary Figures 1-6 from Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma

Author

Patrick Tan, Bin Tean Teh, Chawalit Pairojkul, Tatsuhiro Shibata, Steven G. Rozen, Raluca Gordân, Ludmil B. Alexandrov, Young Nyun Park, Hyungjin Rhee, André Luiz Vettore, André Lopes Carvalho, Di-Xian Luo, Jiaming Lai, Aldo Scarpa, Ming-Chin Yu, Sen-Yung Hsieh, Philippe Broet, Irinel Popescu, Dan G. Duda, Simona Dima, Kiat Hon Lim, London Lucien Peng Jin Ooi, Alexander Yaw Fui Chung, Pierce Kah-Hoe Chow, Satoshi Yamasaki, Yasuhito Arai, Hiromi Nakamura, Yasushi Totoki, Sopit Wongkham, Puangrat Yongvanit, Vajaraphongsa Bhudhisawasdi, Narong Khuntikeo, John R. McPherson, Jia Liang Loh, Jing Tan, Tse Hui Lim, Alvin Soon Tiong Lim, Stefanus Lie, Vikneswari Rajasegaran, Choon Kiat Ong, Mo Liu, Arnoud Boot, Cedric Chuan Young Ng, Weng Khong Lim, Sanjanaa Nagarajan, Raynoo Thanan, Swe Swe Myint, Su Pin Choo, Ley Moy Ng, Alvin Wei Tian Ng, Sarinya Kongpetch, Vishwa Nellore, Nisha Padmanabhan, Mi Ni Huang, Jing Quan Lim, Chern Han Yong, Ioana Cutcutache, and Apinya Jusakul

Abstract

Supplementary Figure 1. Unsupervised Clustering on CCA samples. Supplementary Figure 2. Alterations Found in CCA Clusters. Supplementary Figure 3. MAP2K4 Homozygous Deletions and ERBB2 Amplifications. Supplementary Figure 4. Alterations Related to Structural Variations Found in CCAs. Supplementary Figure 5. FIREFLY Analysis of Pathways Systematically Dysregulated by Somatic Promoter Mutations that Alter Transcription Factor Binding. Supplementary Figure 6. Epigenetic Clusters and Mutation Signatures.

Published
2023

5. Supplementary Table 4 from Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma

Author

Patrick Tan, Bin Tean Teh, Chawalit Pairojkul, Tatsuhiro Shibata, Steven G. Rozen, Raluca Gordân, Ludmil B. Alexandrov, Young Nyun Park, Hyungjin Rhee, André Luiz Vettore, André Lopes Carvalho, Di-Xian Luo, Jiaming Lai, Aldo Scarpa, Ming-Chin Yu, Sen-Yung Hsieh, Philippe Broet, Irinel Popescu, Dan G. Duda, Simona Dima, Kiat Hon Lim, London Lucien Peng Jin Ooi, Alexander Yaw Fui Chung, Pierce Kah-Hoe Chow, Satoshi Yamasaki, Yasuhito Arai, Hiromi Nakamura, Yasushi Totoki, Sopit Wongkham, Puangrat Yongvanit, Vajaraphongsa Bhudhisawasdi, Narong Khuntikeo, John R. McPherson, Jia Liang Loh, Jing Tan, Tse Hui Lim, Alvin Soon Tiong Lim, Stefanus Lie, Vikneswari Rajasegaran, Choon Kiat Ong, Mo Liu, Arnoud Boot, Cedric Chuan Young Ng, Weng Khong Lim, Sanjanaa Nagarajan, Raynoo Thanan, Swe Swe Myint, Su Pin Choo, Ley Moy Ng, Alvin Wei Tian Ng, Sarinya Kongpetch, Vishwa Nellore, Nisha Padmanabhan, Mi Ni Huang, Jing Quan Lim, Chern Han Yong, Ioana Cutcutache, and Apinya Jusakul

Abstract

Structural Variations across 71 WGS CCAs.

Published
2023

6. Supplementary Table 3 from Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma

Author

Patrick Tan, Bin Tean Teh, Chawalit Pairojkul, Tatsuhiro Shibata, Steven G. Rozen, Raluca Gordân, Ludmil B. Alexandrov, Young Nyun Park, Hyungjin Rhee, André Luiz Vettore, André Lopes Carvalho, Di-Xian Luo, Jiaming Lai, Aldo Scarpa, Ming-Chin Yu, Sen-Yung Hsieh, Philippe Broet, Irinel Popescu, Dan G. Duda, Simona Dima, Kiat Hon Lim, London Lucien Peng Jin Ooi, Alexander Yaw Fui Chung, Pierce Kah-Hoe Chow, Satoshi Yamasaki, Yasuhito Arai, Hiromi Nakamura, Yasushi Totoki, Sopit Wongkham, Puangrat Yongvanit, Vajaraphongsa Bhudhisawasdi, Narong Khuntikeo, John R. McPherson, Jia Liang Loh, Jing Tan, Tse Hui Lim, Alvin Soon Tiong Lim, Stefanus Lie, Vikneswari Rajasegaran, Choon Kiat Ong, Mo Liu, Arnoud Boot, Cedric Chuan Young Ng, Weng Khong Lim, Sanjanaa Nagarajan, Raynoo Thanan, Swe Swe Myint, Su Pin Choo, Ley Moy Ng, Alvin Wei Tian Ng, Sarinya Kongpetch, Vishwa Nellore, Nisha Padmanabhan, Mi Ni Huang, Jing Quan Lim, Chern Han Yong, Ioana Cutcutache, and Apinya Jusakul

Abstract

Summary of CCA Alterations.

Published
2023

7. Supplementary Methods and Supplementary Figure and Table Legends from Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma

Author

Patrick Tan, Bin Tean Teh, Chawalit Pairojkul, Tatsuhiro Shibata, Steven G. Rozen, Raluca Gordân, Ludmil B. Alexandrov, Young Nyun Park, Hyungjin Rhee, André Luiz Vettore, André Lopes Carvalho, Di-Xian Luo, Jiaming Lai, Aldo Scarpa, Ming-Chin Yu, Sen-Yung Hsieh, Philippe Broet, Irinel Popescu, Dan G. Duda, Simona Dima, Kiat Hon Lim, London Lucien Peng Jin Ooi, Alexander Yaw Fui Chung, Pierce Kah-Hoe Chow, Satoshi Yamasaki, Yasuhito Arai, Hiromi Nakamura, Yasushi Totoki, Sopit Wongkham, Puangrat Yongvanit, Vajaraphongsa Bhudhisawasdi, Narong Khuntikeo, John R. McPherson, Jia Liang Loh, Jing Tan, Tse Hui Lim, Alvin Soon Tiong Lim, Stefanus Lie, Vikneswari Rajasegaran, Choon Kiat Ong, Mo Liu, Arnoud Boot, Cedric Chuan Young Ng, Weng Khong Lim, Sanjanaa Nagarajan, Raynoo Thanan, Swe Swe Myint, Su Pin Choo, Ley Moy Ng, Alvin Wei Tian Ng, Sarinya Kongpetch, Vishwa Nellore, Nisha Padmanabhan, Mi Ni Huang, Jing Quan Lim, Chern Han Yong, Ioana Cutcutache, and Apinya Jusakul

Abstract

Further details of methods, in addition to the supplementary figure and table legends.

Published
2023

8. Supplementary Table 2 from Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma

Author

Patrick Tan, Bin Tean Teh, Chawalit Pairojkul, Tatsuhiro Shibata, Steven G. Rozen, Raluca Gordân, Ludmil B. Alexandrov, Young Nyun Park, Hyungjin Rhee, André Luiz Vettore, André Lopes Carvalho, Di-Xian Luo, Jiaming Lai, Aldo Scarpa, Ming-Chin Yu, Sen-Yung Hsieh, Philippe Broet, Irinel Popescu, Dan G. Duda, Simona Dima, Kiat Hon Lim, London Lucien Peng Jin Ooi, Alexander Yaw Fui Chung, Pierce Kah-Hoe Chow, Satoshi Yamasaki, Yasuhito Arai, Hiromi Nakamura, Yasushi Totoki, Sopit Wongkham, Puangrat Yongvanit, Vajaraphongsa Bhudhisawasdi, Narong Khuntikeo, John R. McPherson, Jia Liang Loh, Jing Tan, Tse Hui Lim, Alvin Soon Tiong Lim, Stefanus Lie, Vikneswari Rajasegaran, Choon Kiat Ong, Mo Liu, Arnoud Boot, Cedric Chuan Young Ng, Weng Khong Lim, Sanjanaa Nagarajan, Raynoo Thanan, Swe Swe Myint, Su Pin Choo, Ley Moy Ng, Alvin Wei Tian Ng, Sarinya Kongpetch, Vishwa Nellore, Nisha Padmanabhan, Mi Ni Huang, Jing Quan Lim, Chern Han Yong, Ioana Cutcutache, and Apinya Jusakul

Abstract

Alterations in CCA Clusters.

Published
2023

9. Supplementary Table 5 from Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma

Author

Patrick Tan, Bin Tean Teh, Chawalit Pairojkul, Tatsuhiro Shibata, Steven G. Rozen, Raluca Gordân, Ludmil B. Alexandrov, Young Nyun Park, Hyungjin Rhee, André Luiz Vettore, André Lopes Carvalho, Di-Xian Luo, Jiaming Lai, Aldo Scarpa, Ming-Chin Yu, Sen-Yung Hsieh, Philippe Broet, Irinel Popescu, Dan G. Duda, Simona Dima, Kiat Hon Lim, London Lucien Peng Jin Ooi, Alexander Yaw Fui Chung, Pierce Kah-Hoe Chow, Satoshi Yamasaki, Yasuhito Arai, Hiromi Nakamura, Yasushi Totoki, Sopit Wongkham, Puangrat Yongvanit, Vajaraphongsa Bhudhisawasdi, Narong Khuntikeo, John R. McPherson, Jia Liang Loh, Jing Tan, Tse Hui Lim, Alvin Soon Tiong Lim, Stefanus Lie, Vikneswari Rajasegaran, Choon Kiat Ong, Mo Liu, Arnoud Boot, Cedric Chuan Young Ng, Weng Khong Lim, Sanjanaa Nagarajan, Raynoo Thanan, Swe Swe Myint, Su Pin Choo, Ley Moy Ng, Alvin Wei Tian Ng, Sarinya Kongpetch, Vishwa Nellore, Nisha Padmanabhan, Mi Ni Huang, Jing Quan Lim, Chern Han Yong, Ioana Cutcutache, and Apinya Jusakul

Abstract

Coverage Statistics and List of Genes for Targeted Sequencing.

Published
2023

10. Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer

Author

Samuel Leung, Sai Srinivas Upadhyayula, Anna S. Sedukhina, Anthony N. Karnezis, Diana G Z Lim, Clare L. Scott, Stefanus Lie, Sherlly Lim, Derek S. Chiu, Joanna D. Wardyn, David S.P. Tan, Joe P S Yeong, Ko Sato, Michal Marek Hoppe, Monique Topp, Stan B. Kaye, Brendan Pang, Robert S. Brown, Tuan Zea Tan, Hyungwon Choi, Anand D. Jeyasekharan, Jason J. Pitt, David G. Huntsman, Naina Patel, and Patrick Jaynes

Subjects
0301 basic medicine, Medicine (General), endocrine system diseases, medicine.medical_treatment, RAD51, QH426-470, Carcinoma, Ovarian Epithelial, Medical and Health Sciences, chemistry.chemical_compound, 0302 clinical medicine, Ovarian Epithelial, News & Views, Cancer, Ovarian Neoplasms, Articles, Biological Sciences, female genital diseases and pregnancy complications, Ovarian Cancer, ovarian cancer, Local, Paclitaxel, 5.1 Pharmaceuticals, Molecular Medicine, Female, Development of treatments and therapeutic interventions, multiplexed IHC, endocrine system, DNA repair, Article, 03 medical and health sciences, Rare Diseases, R5-920, immune exclusion, medicine, Carcinoma, Genetics, Humans, Platinum, Biomarkers & Diagnostic Imaging, Chemotherapy, Radar, business.industry, medicine.disease, Carboplatin, enzymes and coenzymes (carbohydrates), Neoplasm Recurrence, 030104 developmental biology, chemistry, HRD, Cancer research, Rad51 Recombinase, Neoplasm Recurrence, Local, Ovarian cancer, business, 030217 neurology & neurosurgery
Abstract

Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A‐priori identification of platinum resistance is therefore crucial to improve on standard first‐line carboplatin–paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum‐induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK‐compliant study of pre‐treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51‐High tumours had shorter progression‐free and overall survival compared to RAD51‐Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR‐proficient cancers (Myriad HRDscore, Quantitative immunohistochemistry (qIHC) reveals that high expression of the DNA repair protein RAD51 in epithelial ovarian cancer (EOC) is associated with early relapse after platinum chemotherapy, and also with decreased cytotoxic T‐cell infiltration into tumors.

Published
2021

11. Primary platinum resistance and immune exclusion in ovarian carcinomas with high expression of the homologous recombination mediator RAD51

Author

Anand D. Jeyasekharan, Sherlly Lim, Jason J. Pitt, Joanna D. Wardyn, Stefanus Lie, Robert M Brown, Stan B. Kaye, Michal Marek Hoppe, Derek S. Chiu, David G. Huntsman, Ko Sato, Brendan Pang, Samuel Leung, David S.P. Tan, Anthony N. Karnezis, Joe Ps Yeong, Anna S. Sedukhina, Diana Gz Lim, Tuan Zea Tan, Hyungwon Choi, Naina Patel, and Patrick Jaynes

Subjects
Messenger RNA, Chemotherapy, Immune system, medicine.medical_treatment, RAD51, medicine, Cancer research, Immunohistochemistry, Cancer, Biology, Homologous recombination, Ovarian cancer, medicine.disease
Abstract

BackgroundHomologous recombination deficiency (HRD) in ovarian cancer confers increased sensitivity to Poly-ADP-Ribose-Polymerase (PARP) inhibitors and platinum. The homologous recombination (HR) mediator RAD51, however, is commonly overexpressed, potentially driving unregulated HR. Due to non-quantitative measurements and heterogeneous cohorts, the clinical relevance of RAD51 expression in ovarian cancer is unclear.MethodsFluorescent immunohistochemistry and multispectral imaging were used to quantitate RAD51 expression, in relation to other markers, in independent cohorts of ovarian carcinomas from British Columbia Cancer (BCC n=284) and the phase III SCOTROC4 trial (n=268). Independent cohorts (TCGA n=566, GSE9891 n=267, GSE26712 n=185 and GSE3149 n=146) were used for mRNA expression and immune infiltration analyses.ResultsRAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in both BCC and SCOTROC4. The negative prognostic significance of high RAD51 was primarily evident in cases classified “HRD negative” by the Myriad genomic scar assay. Unexpectedly, overexpression of RAD51 in ovarian cancer cell lines did not affect sensitivity to platinum or PARP inhibitors, but modified the expression of immune-regulatory genes. Accordingly, tumours with high RAD51 mRNA showed consistent changes in immunomodulatory transcripts across four independent ovarian cancer cohorts. In-situ multiplexed imaging confirmed that high RAD51 tumours correlated with tumour exclusion of cytotoxic-T-cells, possibly explaining their poor outcomes after chemotherapy.ConclusionsHigh RAD51 expression, in conjunction with a HRD score Statement of Translational RelevanceHomologous recombination deficiency (HRD) in ovarian cancer confers increased sensitivity to Poly-ADP-Ribose-Polymerase (PARP) inhibitors and platinum. Currently, methods to identify patients who do poorly on first-line platinum based chemotherapy in ovarian cancer represent an unmet clinical need. In this report we show that RAD51 expression can identify patients with primary platinum resistance in two large cohorts, including a unique phase-III trial of carboplatin as adjuvant monotherapy. The clinical relevance of a positive genomic scar HRD score, a biomarker for assessing HRD status, in predicting benefit to PARP inhibitors has been established following recent phase 3 trials in first line and 2nd line maintenance treatment of ovarian cancer. Our findings suggest that HRD negative ovarian tumours may be further stratified by RAD51 expression status in the context of platinum sensitivity, and may serve to guide future trials of HRD targeted agents.

Published
2020

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