Pub Date : 2024-09-11DOI: 10.1101/2024.09.10.24313398
Simon Deacon, Inswasti Cahyani, Nadine Holmes, Graeme Fox, Rory Munro, Satrio Wibowo, Thomas Murray, Hannah Mason, Mark Housley, Daniel Martin, Abid Sharif, Areeba Patel, Robert Goldspring, Sebastian Brandner, Felix Sahm, Stuart Smith, Simon Paine, Matthew Loose
Background Advances in our technological capacity to interrogate brain tumour biology has led to the ever-increasing use of genomic sequencing in routine diagnostic decision making. Presently, brain tumours are routinely classified based on their epigenetic signatures, leading to a paradigm shift in diagnostic pathways. Such testing can be performed so rapidly using nanopore sequencing that results can be provided intraoperatively. This information greatly improves upon the fidelity of smear diagnosis and can help surgeons tailor their approach, balancing the risks of surgery with the likely benefit. Nevertheless, full integrated diagnosis may require subsequent additional assays to detect pathognomonic somatic mutations and structural variants, thereby delaying the time to final diagnosis. Methods Here, we present ROBIN, a tool based upon PromethION nanopore sequencing technology that can provide both real-time, intraoperative methylome classification and next-day comprehensive molecular profiling within a single assay. ROBIN uniquely integrates three methylation classifiers to improve diagnostic performance in the intraoperative setting. Findings We demonstrate classifier performance on 50 prospective intraoperative cases, achieving a diagnostic turnaround time under 2 hours and generating robust tumour classifications within minutes of sequencing. Furthermore, ROBIN can detect single nucleotide variants (SNVs), copy number variants (CNVs) and structural variants (SVs) in real-time, and is able to inform a complete integrated diagnosis within 24 hours. Classifier performance demonstrated concordance with final integrated diagnosis in 90% of prospective cases. Interpretation Nanopore sequencing can greatly improve upon the turnaround times for standard of care diagnostic testing, including sequencing, and is furthermore able to reliably provide clinically actionable intraoperative tumour classification. Funding The Jean-Shanks Foundation, the Pathological Society of Great Britain and Ireland, the British Neuropathological Society, and the Wellcome Trust.
{"title":"ROBIN: A unified nanopore-based sequencing assay integrating real-time, intraoperative methylome classification and next-day comprehensive molecular brain tumour profiling for ultra-rapid tumour diagnostics","authors":"Simon Deacon, Inswasti Cahyani, Nadine Holmes, Graeme Fox, Rory Munro, Satrio Wibowo, Thomas Murray, Hannah Mason, Mark Housley, Daniel Martin, Abid Sharif, Areeba Patel, Robert Goldspring, Sebastian Brandner, Felix Sahm, Stuart Smith, Simon Paine, Matthew Loose","doi":"10.1101/2024.09.10.24313398","DOIUrl":"https://doi.org/10.1101/2024.09.10.24313398","url":null,"abstract":"Background\u0000Advances in our technological capacity to interrogate brain tumour biology has led to the ever-increasing use of genomic sequencing in routine diagnostic decision making. Presently, brain tumours are routinely classified based on their epigenetic signatures, leading to a paradigm shift in diagnostic pathways. Such testing can be performed so rapidly using nanopore sequencing that results can be provided intraoperatively. This information greatly improves upon the fidelity of smear diagnosis and can help surgeons tailor their approach, balancing the risks of surgery with the likely benefit. Nevertheless, full integrated diagnosis may require subsequent additional assays to detect pathognomonic somatic mutations and structural variants, thereby delaying the time to final diagnosis. Methods\u0000Here, we present ROBIN, a tool based upon PromethION nanopore sequencing technology that can provide both real-time, intraoperative methylome classification and next-day comprehensive molecular profiling within a single assay. ROBIN uniquely integrates three methylation classifiers to improve diagnostic performance in the intraoperative setting. Findings\u0000We demonstrate classifier performance on 50 prospective intraoperative cases, achieving a diagnostic turnaround time under 2 hours and generating robust tumour classifications within minutes of sequencing. Furthermore, ROBIN can detect single nucleotide variants (SNVs), copy number variants (CNVs) and structural variants (SVs) in real-time, and is able to inform a complete integrated diagnosis within 24 hours. Classifier performance demonstrated concordance with final integrated diagnosis in 90% of prospective cases. Interpretation\u0000Nanopore sequencing can greatly improve upon the turnaround times for standard of care diagnostic testing, including sequencing, and is furthermore able to reliably provide clinically actionable intraoperative tumour classification. Funding\u0000The Jean-Shanks Foundation, the Pathological Society of Great Britain and Ireland, the British Neuropathological Society, and the Wellcome Trust.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1101/2024.09.09.24313308
Casey R Ager, Aleksandar Obradovic, Patrick McCann, Matthew Chaimowitz, Alexander L.E. Wang, Neha Shaikh, Parin Shah, Samuel Pan, Caroline J Laplaca, Renu K Virk, Jessica C Hill, Collin Jugler, Grace DeFranco, Nilika Bhattacharya, Howard I Scher, Guarionex Joel Decastro, Christopher B Anderson, James M McKiernan, Catherine S Spina, Mark N Stein, Karie Runcie, Charles G Drake, Andrea Califano, Matthew C Dallos
Men with high-risk localized prostate cancer exhibit high rates of post-surgical recurrence. In these patients, androgen deprivation therapy (ADT) is immunomodulatory, however increased infiltration of regulatory T cells (Tregs) may limit the antitumor immune effects of ADT. We designed a neoadjuvant clinical trial to test whether BMS-986218, a next-generation non-fucosylated anti-CTLA-4 antibody engineered for enhanced antibody-dependent cellular cytotoxicity or phagocytosis (ADCC/P), depletes intratumoral Tregs and augments the response to ADT. In this single-center, two-arm, open-label study, 24 men with high-risk localized prostate cancer were randomized to receive a single dose of ADT with or without two pre-operative doses of BMS-986218 (anti-CTLA4-NF) prior to radical prostatectomy. Treatment was well tolerated and feasible in the neoadjuvant setting. A secondary clinical outcome was the rate of disease recurrence, which was lower than predicted in both arms. Mechanistically, anti-CTLA4-NF reduced ADT-induced Treg accumulation through engagement of CD16a/FCGR3A on tumor macrophages, and depth of Treg depletion was quantitatively associated with clinical outcome. Increased intratumoral dendritic cell (DC) frequencies also associated with lack of recurrence, and pre-clinical data suggest ADCC/P-competent anti-CTLA-4 antibodies elicit activation and expansion of tumor DCs. Patients receiving anti-CTLA4-NF also exhibited phenotypic signatures of enhanced antitumor T cell priming. In total, this study provides the first-in-human evidence of Treg depletion by glycoengineered antibodies targeting CTLA-4 in humans and their potential in combination with ADT in prostate cancer patients with high-risk of recurrence.
{"title":"Neoadjuvant androgen deprivation therapy with or without Fc-enhanced non-fucosylated anti-CTLA-4 (BMS-986218) in high risk localized prostate cancer: a randomized phase 1 trial","authors":"Casey R Ager, Aleksandar Obradovic, Patrick McCann, Matthew Chaimowitz, Alexander L.E. Wang, Neha Shaikh, Parin Shah, Samuel Pan, Caroline J Laplaca, Renu K Virk, Jessica C Hill, Collin Jugler, Grace DeFranco, Nilika Bhattacharya, Howard I Scher, Guarionex Joel Decastro, Christopher B Anderson, James M McKiernan, Catherine S Spina, Mark N Stein, Karie Runcie, Charles G Drake, Andrea Califano, Matthew C Dallos","doi":"10.1101/2024.09.09.24313308","DOIUrl":"https://doi.org/10.1101/2024.09.09.24313308","url":null,"abstract":"Men with high-risk localized prostate cancer exhibit high rates of post-surgical recurrence. In these patients, androgen deprivation therapy (ADT) is immunomodulatory, however increased infiltration of regulatory T cells (Tregs) may limit the antitumor immune effects of ADT. We designed a neoadjuvant clinical trial to test whether BMS-986218, a next-generation non-fucosylated anti-CTLA-4 antibody engineered for enhanced antibody-dependent cellular cytotoxicity or phagocytosis (ADCC/P), depletes intratumoral Tregs and augments the response to ADT. In this single-center, two-arm, open-label study, 24 men with high-risk localized prostate cancer were randomized to receive a single dose of ADT with or without two pre-operative doses of BMS-986218 (anti-CTLA4-NF) prior to radical prostatectomy. Treatment was well tolerated and feasible in the neoadjuvant setting. A secondary clinical outcome was the rate of disease recurrence, which was lower than predicted in both arms. Mechanistically, anti-CTLA4-NF reduced ADT-induced Treg accumulation through engagement of CD16a/FCGR3A on tumor macrophages, and depth of Treg depletion was quantitatively associated with clinical outcome. Increased intratumoral dendritic cell (DC) frequencies also associated with lack of recurrence, and pre-clinical data suggest ADCC/P-competent anti-CTLA-4 antibodies elicit activation and expansion of tumor DCs. Patients receiving anti-CTLA4-NF also exhibited phenotypic signatures of enhanced antitumor T cell priming. In total, this study provides the first-in-human evidence of Treg depletion by glycoengineered antibodies targeting CTLA-4 in humans and their potential in combination with ADT in prostate cancer patients with high-risk of recurrence.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"167 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1101/2024.09.10.24313140
Brian Y. Zhao, Shun Hirayama, Deborah Goss, Yan Zhao, Daniel L. Faden
Objective: Human papillomavirus (HPV) is known to affect head and neck sites beyond the oropharynx, including the nasopharynx. Unlike HPV-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC), HPV-associated nasopharyngeal carcinoma (HPV+NPC) is not well characterized and the true prevalence in non-endemic regions is poorly described. Here, we sought to obtain a global point prevalence of HPV in NPC, stratified by geographic region. Data Sources: EMBASE, OVID Medline, and Web of Science were systematically searched for available evidence on September 21, 2022 for articles published between January 1, 1990 and September 21, 2022. Review Methods: We reviewed the literature for all studies examining NPC and HPV status in adult patients that provided a quantitative HPV prevalence. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Main outcome and measures included HPV+NPC prevalence estimates stratified by geographic region, along with other clinical and demographic features. Results: Of the 1567 citations retrieved, 46 studies encompassing 6314 NPC patients were eligible for statistical analysis. The global prevalence of HPV+NPC was 0.18 (95% CI 0.14-0.23). When stratified by geographic region, prevalence was highest in North America (0.25, 95% CI 0.17-0.36), which is a non-endemic region for NPC and also has highest prevalence for HPV+OPSCC. Asia, an endemic area, had the lowest HPV prevalence estimate (0.13, 95% CI 0.08-0.22). HPV 16 (44%) and 18 (33%) were the predominant genotypes in HPV+NPC, dissimilar to HPV+OPSCC. Conclusion: This systematic review and meta-analysis provides a global point prevalence of HPV+NPC stratified by geographic region and suggests that HPV is a significant etiological factor of NPC in North America.
目的：已知人类乳头瘤病毒（HPV）会影响口咽以外的头颈部位，包括鼻咽。与人乳头瘤病毒相关的口咽鳞状细胞癌（HPV+OPSCC）不同，人乳头瘤病毒相关的鼻咽癌（HPV+NPC）并没有很好的特征，非流行地区的真实发病率也很少被描述。在此，我们试图获得鼻咽癌中 HPV 的全球点流行率，并按地理区域进行分层。数据来源：于 2022 年 9 月 21 日系统检索了 EMBASE、OVID Medline 和 Web of Science 中 1990 年 1 月 1 日至 2022 年 9 月 21 日期间发表的文章，以获取可用证据。审查方法：我们查阅了所有研究成人患者鼻咽癌和 HPV 感染状况的文献，这些研究提供了 HPV 感染率的定量数据。研究遵循了系统综述和荟萃分析首选报告项目 (PRISMA) 指南。主要结果和衡量标准包括按地理区域分层的 HPV+NPC 流行率估计值，以及其他临床和人口特征。结果：在检索到的 1567 篇引文中，有 46 项研究（涵盖 6314 名鼻咽癌患者）符合统计分析条件。HPV+NPC的全球患病率为0.18（95% CI 0.14-0.23）。如果按地理区域分层，北美洲的患病率最高（0.25，95% CI 0.17-0.36），该地区是鼻咽癌的非流行区，同时也是HPV+OPSCC患病率最高的地区。亚洲是HPV流行地区，其HPV流行率估计值最低（0.13，95% CI 0.08-0.22）。HPV16（44%）和18（33%）是HPV+NPC的主要基因型，这与HPV+OPSCC不同。结论本系统综述和荟萃分析提供了按地理区域分层的HPV+NPC全球点流行率，并表明HPV是北美NPC的一个重要病因。
{"title":"Human Papillomavirus-Associated Nasopharyngeal Carcinoma: A Systematic Review and Meta-Analysis","authors":"Brian Y. Zhao, Shun Hirayama, Deborah Goss, Yan Zhao, Daniel L. Faden","doi":"10.1101/2024.09.10.24313140","DOIUrl":"https://doi.org/10.1101/2024.09.10.24313140","url":null,"abstract":"Objective: Human papillomavirus (HPV) is known to affect head and neck sites beyond the oropharynx, including the nasopharynx. Unlike HPV-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC), HPV-associated nasopharyngeal carcinoma (HPV+NPC) is not well characterized and the true prevalence in non-endemic regions is poorly described. Here, we sought to obtain a global point prevalence of HPV in NPC, stratified by geographic region. Data Sources: EMBASE, OVID Medline, and Web of Science were systematically searched for available evidence on September 21, 2022 for articles published between January 1, 1990 and September 21, 2022. Review Methods: We reviewed the literature for all studies examining NPC and HPV status in adult patients that provided a quantitative HPV prevalence. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Main outcome and measures included HPV+NPC prevalence estimates stratified by geographic region, along with other clinical and demographic features. Results: Of the 1567 citations retrieved, 46 studies encompassing 6314 NPC patients were eligible for statistical analysis. The global prevalence of HPV+NPC was 0.18 (95% CI 0.14-0.23). When stratified by geographic region, prevalence was highest in North America (0.25, 95% CI 0.17-0.36), which is a non-endemic region for NPC and also has highest prevalence for HPV+OPSCC. Asia, an endemic area, had the lowest HPV prevalence estimate (0.13, 95% CI 0.08-0.22). HPV 16 (44%) and 18 (33%) were the predominant genotypes in HPV+NPC, dissimilar to HPV+OPSCC. Conclusion: This systematic review and meta-analysis provides a global point prevalence of HPV+NPC stratified by geographic region and suggests that HPV is a significant etiological factor of NPC in North America.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1101/2024.09.10.24313378
Thien-Phuc Hoang Nguyen, Nam HB Tran, Tien Anh Nguyen, My TT Ngo, Anh Duong Doan, Du Quyen Nguyen, Hung Sang Tang, Duy Sinh Nguyen, Cam Tu Nguyen Thi, Thanh Thuy Do Thi, Hoai-Nghia Nguyen, Hoa Giang, Lan N Tu
Backgrounds: Assessing homologous recombination deficiency (HRD) has been recommended by clinical guidelines for patients with ovarian cancer (OC) as it predicts sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi). However, HRD testing is complex and either inaccessible or unaffordable for majority of OC patients in developing countries. Consequently, the prevalence of HRD in OC remains unknown. Methods: We examined HRD status of 77 Vietnamese patients with OC using a new laboratory-developed test (HRD Insight, Gene Solutions). Tumor DNA was extracted from FFPE samples, followed by next-generation sequencing to detect deleterious or suspected deleterious variants in BRCA1/2 genes. Shallow whole genome sequencing was performed to determine the whole Genomic Instability (wGI) score by assessing the presence of large-scale intra-chromosomal copy number alterations. Results: The assay was first benchmarked against commercial HRD kits including TruSight Oncology 500 HRD (Illumina), SOPHiA DDM HRD Solutions (Sophia Genetics) and HRD Focus Panel (AmoyDx), and showed an overall percent agreement of 90.0%, 96.3%, and 96.4% respectively. The successful rate of sequencing was 94.8% (73/77) and the prevalence of HRD in OC patients was 54.8% (40/73). BRCA mutations and positive wGI scores were found in 16.4% (12/73) and 47.9% (35/73) of the patients respectively. Among those with wild-type BRCA1/2, 40.5% of them had positive wGI scores and hence positive HRD. Age at diagnosis was not affected by both BRCA and wGI status. Conclusions: HRD Insight assay could accurately and robustly determine the HRD status of ovarian tissue samples, including those with low quality.
{"title":"Combination of BRCA deep targeted sequencing and shallow whole genome sequencing to detect homologous recombination deficiency in ovarian cancer","authors":"Thien-Phuc Hoang Nguyen, Nam HB Tran, Tien Anh Nguyen, My TT Ngo, Anh Duong Doan, Du Quyen Nguyen, Hung Sang Tang, Duy Sinh Nguyen, Cam Tu Nguyen Thi, Thanh Thuy Do Thi, Hoai-Nghia Nguyen, Hoa Giang, Lan N Tu","doi":"10.1101/2024.09.10.24313378","DOIUrl":"https://doi.org/10.1101/2024.09.10.24313378","url":null,"abstract":"Backgrounds: Assessing homologous recombination deficiency (HRD) has been recommended by clinical guidelines for patients with ovarian cancer (OC) as it predicts sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi). However, HRD testing is complex and either inaccessible or unaffordable for majority of OC patients in developing countries. Consequently, the prevalence of HRD in OC remains unknown.\u0000Methods: We examined HRD status of 77 Vietnamese patients with OC using a new laboratory-developed test (HRD Insight, Gene Solutions). Tumor DNA was extracted from FFPE samples, followed by next-generation sequencing to detect deleterious or suspected deleterious variants in BRCA1/2 genes. Shallow whole genome sequencing was performed to determine the whole Genomic Instability (wGI) score by assessing the presence of large-scale intra-chromosomal copy number alterations.\u0000Results: The assay was first benchmarked against commercial HRD kits including TruSight Oncology 500 HRD (Illumina), SOPHiA DDM HRD Solutions (Sophia Genetics) and HRD Focus Panel (AmoyDx), and showed an overall percent agreement of 90.0%, 96.3%, and 96.4% respectively. The successful rate of sequencing was 94.8% (73/77) and the prevalence of HRD in OC patients was 54.8% (40/73). BRCA mutations and positive wGI scores were found in 16.4% (12/73) and 47.9% (35/73) of the patients respectively. Among those with wild-type BRCA1/2, 40.5% of them had positive wGI scores and hence positive HRD. Age at diagnosis was not affected by both BRCA and wGI status. Conclusions: HRD Insight assay could accurately and robustly determine the HRD status of ovarian tissue samples, including those with low quality.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1101/2024.09.08.24313260
Nawaf Alanazi, Abdulkareem AlGarni, Sarah Almukhaylid, Maryam AlMajed, Sabreen Alanazi, Muhammad Khan, Muhammad Sabar, Mudassar Iqbal, Abid Jameel, Akhtar Hussian, Dhay Almaghlouth, Alhanoof Alsuwaidani, Ghala Alsalem, Nouf AlMutairi, Hassan Almasoudi, Buthainah AlShehab, Sarah Alfayez, Maryam Butwyibah, Batool Alnajad, Fatimah Alali, Anwar Al-Rasasi, Kanza Adeel, Sahar Al Hakeem, Tarig Karar, Fahad Alsaab, Yaqob Taleb, Sana Shahbaz, Sumyiea Malik, Amer Mahmood, Sulman Basit, Muhammad Anharullah, Aamer Aleem, Irtaza Fatima Zafar, Rizwan Naeem, Masood Shamas, Zafar Iqbal
Background: Chronic Myeloid Leukemia (CML) is a myeloproliferative stem cell malignancy. Chronic Phase CML (CP) is treatable with overall survival equivalent to general public. Nevertheless, a proportion of CP-CML progresses to the accelerated phase (AP-) and ultimately blast crisis (BC), with the later having an overall survival of 3-23 months, making it almost a fatal manifestation. Therefore, treatment of BC-CML is of the biggest challenges in modern cancer medicine. FDA-approved drugs are available against a large number of mutated genes reported in AML and ALL. As BC-CML resembles AML (myeloid BC) or ALL (lymphoid BC), this study was designed to find out AML-/ALL lineage gene mutations in BC-CML, find their druggability and feasibility of their utilization in patient-tailored treatment of BC-CML. Patients & Methods: The study included 141 CML patients (123 CP-CML as control groups; 6 AP-CML and 12 BC-CML as experimental groups). Most of the patients received imatinib mesylate (IM) as first-line treatment. All response criteria were per European LeukemiaNet (ELN) guidelines 2020. Whole exome sequencing (WES) was carried out to find out druggable gene mutations and the druggability of the mutated genes was determined using online tool www.pandrugs.com. SAS/STAT software version 9.4 was used for data analysis (SAS Institute Inc., Cary, NC, USA). For statistical computing, the R package was employed (Vienna, Austria). The study was approved by ethical committee of KAIMRC and carried out per guidelines o of the Helsinki Declaration Results: Overall male-to-female ratio was 1.6:1 and the mean age was 36.4 (range: 9 -67) years. Eighteen (12.8%) patients progressed to AP-CML while 12 (8.5%) to BC-CML finally. BC-ML patients had overall poorer response to TKIs and higher mortality rate (75%) that prompted to look for druggable gene mutations in advanced phase CML. WES showed overall 64 AML-/ALL- associated gene mutated in advanced phase CML patients. AP-CML had 1644 variants, whereas BC-CML had 2531 variants, with a 54% gain in mutations from AP-CML to BC-CML (P< 0.000001). Among AML-/ALL- related mutated genes were NPM1 (%1.98), DNMT3A (%1.86), PML (%1.82), AKT1 (%1.62), CBL (%1.30), JAK2 (%0.71), TET2 (%0.59), IDH1 (%0.32), and BCL2, which have FDA-approved drug to target them. Conclusions: NGS found druggable mutations in many AML-/ALL-lineage genes. Many of the corresponding drugs are either already approved for BC-CML treatment or in clinical trial phase. We conclude that our approach can help in finding druggable gene mutations related to AML-/ALL-lineage genes in almost every BC-CML patients and provide a practical guidance for drug repurposing to individualize BC-CML patient treatment. Keywords: Blast crisis Chronic Myeloid Leukemia; druggable mutations; pa-tient-tailored treatment; AML lineage genes; ALL lineage genes.
{"title":"Investigations on druggable gene mutations related to AML/ALL lineage genes in Advanced Phases of CML: Implications in patient-tailored therapy of blast crisis CML in TKI era","authors":"Nawaf Alanazi, Abdulkareem AlGarni, Sarah Almukhaylid, Maryam AlMajed, Sabreen Alanazi, Muhammad Khan, Muhammad Sabar, Mudassar Iqbal, Abid Jameel, Akhtar Hussian, Dhay Almaghlouth, Alhanoof Alsuwaidani, Ghala Alsalem, Nouf AlMutairi, Hassan Almasoudi, Buthainah AlShehab, Sarah Alfayez, Maryam Butwyibah, Batool Alnajad, Fatimah Alali, Anwar Al-Rasasi, Kanza Adeel, Sahar Al Hakeem, Tarig Karar, Fahad Alsaab, Yaqob Taleb, Sana Shahbaz, Sumyiea Malik, Amer Mahmood, Sulman Basit, Muhammad Anharullah, Aamer Aleem, Irtaza Fatima Zafar, Rizwan Naeem, Masood Shamas, Zafar Iqbal","doi":"10.1101/2024.09.08.24313260","DOIUrl":"https://doi.org/10.1101/2024.09.08.24313260","url":null,"abstract":"Background: Chronic Myeloid Leukemia (CML) is a myeloproliferative stem cell malignancy. Chronic Phase CML (CP) is treatable with overall survival equivalent to general public. Nevertheless, a proportion of CP-CML progresses to the accelerated phase (AP-) and ultimately blast crisis (BC), with the later having an overall survival of 3-23 months, making it almost a fatal manifestation. Therefore, treatment of BC-CML is of the biggest challenges in modern cancer medicine. FDA-approved drugs are available against a large number of mutated genes reported in AML and ALL. As BC-CML resembles AML (myeloid BC) or ALL (lymphoid BC), this study was designed to find out AML-/ALL lineage gene mutations in BC-CML, find their druggability and feasibility of their utilization in patient-tailored treatment of BC-CML. Patients & Methods: The study included 141 CML patients (123 CP-CML as control groups; 6 AP-CML and 12 BC-CML as experimental groups). Most of the patients received imatinib mesylate (IM) as first-line treatment. All response criteria were per European LeukemiaNet (ELN) guidelines 2020. Whole exome sequencing (WES) was carried out to find out druggable gene mutations and the druggability of the mutated genes was determined using online tool www.pandrugs.com. SAS/STAT software version 9.4 was used for data analysis (SAS Institute Inc., Cary, NC, USA). For statistical computing, the R package was employed (Vienna, Austria). The study was approved by ethical committee of KAIMRC and carried out per guidelines o of the Helsinki Declaration Results: Overall male-to-female ratio was 1.6:1 and the mean age was 36.4 (range: 9 -67) years. Eighteen (12.8%) patients progressed to AP-CML while 12 (8.5%) to BC-CML finally. BC-ML patients had overall poorer response to TKIs and higher mortality rate (75%) that prompted to look for druggable gene mutations in advanced phase CML. WES showed overall 64 AML-/ALL- associated gene mutated in advanced phase CML patients. AP-CML had 1644 variants, whereas BC-CML had 2531 variants, with a 54% gain in mutations from AP-CML to BC-CML (P< 0.000001). Among AML-/ALL- related mutated genes were NPM1 (%1.98), DNMT3A (%1.86), PML (%1.82), AKT1 (%1.62), CBL (%1.30), JAK2 (%0.71), TET2 (%0.59), IDH1 (%0.32), and BCL2, which have FDA-approved drug to target them. Conclusions: NGS found druggable mutations in many AML-/ALL-lineage genes. Many of the corresponding drugs are either already approved for BC-CML treatment or in clinical trial phase. We conclude that our approach can help in finding druggable gene mutations related to AML-/ALL-lineage genes in almost every BC-CML patients and provide a practical guidance for drug repurposing to individualize BC-CML patient treatment. Keywords: Blast crisis Chronic Myeloid Leukemia; druggable mutations; pa-tient-tailored treatment; AML lineage genes; ALL lineage genes.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1101/2024.08.14.24311973
Oluwadamilare I. Afolabi
Lung cancer is the leading cause of cancer deaths, with lung squamous cell carcinoma (LUSC) accounting for a substantial proportion of cases. LUSC exhibits significant variability in patient outcomes, influenced by clinicopathological factors such as stage, age, and sex, with men exhibiting higher rates of incidence and poorer outcomes compared to women. Therefore, prognosis modeling and customized approaches to LUSC therapy require the characterization of the biological mechanisms that differentiate tumors and patient outcomes across sexes. Using data from The Cancer Genome Atlas (TCGA), this study characterized gene expression patterns that distinguish male and female LUSC. Specifically, differential expression, survival, and Cox regression analyses assessed the prognostic value of ANO1 (Anoctamin 1) expression and methylation in LUSC. Analyses uncovered a significant overexpression of ANO1 in a subset of male LUSC tumors compared to a much lower expression in normal lung and female LUSC tumors. High ANO1 expression was associated with poor survival outcomes in male subjects. High ANO1 gene body methylation mirrored gene expression and was similarly associated with poor survival outcomes. ANO1’s prognostic value remained significant in a multivariate Cox regression analysis, establishing it as an independent prognostic biomarker. ANO1’s marked sex-specific differences in expression and prognostic value indicate its role in the sex disparity of LUSC survival, highlighting its potential as a biomarker and a target for sex-specific customized therapies.
{"title":"ANO1 expression is associated with male survival in lung squamous cell carcinoma","authors":"Oluwadamilare I. Afolabi","doi":"10.1101/2024.08.14.24311973","DOIUrl":"https://doi.org/10.1101/2024.08.14.24311973","url":null,"abstract":"Lung cancer is the leading cause of cancer deaths, with lung squamous cell carcinoma (LUSC) accounting for a substantial proportion of cases. LUSC exhibits significant variability in patient outcomes, influenced by clinicopathological factors such as stage, age, and sex, with men exhibiting higher rates of incidence and poorer outcomes compared to women. Therefore, prognosis modeling and customized approaches to LUSC therapy require the characterization of the biological mechanisms that differentiate tumors and patient outcomes across sexes. Using data from The Cancer Genome Atlas (TCGA), this study characterized gene expression patterns that distinguish male and female LUSC. Specifically, differential expression, survival, and Cox regression analyses assessed the prognostic value of ANO1 (Anoctamin 1) expression and methylation in LUSC. Analyses uncovered a significant overexpression of ANO1 in a subset of male LUSC tumors compared to a much lower expression in normal lung and female LUSC tumors. High ANO1 expression was associated with poor survival outcomes in male subjects. High ANO1 gene body methylation mirrored gene expression and was similarly associated with poor survival outcomes. ANO1’s prognostic value remained significant in a multivariate Cox regression analysis, establishing it as an independent prognostic biomarker. ANO1’s marked sex-specific differences in expression and prognostic value indicate its role in the sex disparity of LUSC survival, highlighting its potential as a biomarker and a target for sex-specific customized therapies.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1101/2024.08.26.24312568
Oluwadamilare I. Afolabi
Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and is characterized by significant molecular heterogeneity and poor prognosis, primarily due to late-stage diagnoses. Therefore, detailed molecular characterization of LUAD is crucial for developing biomarkers to accurately detect the disease in its early stages. This study investigates the role of DNA methylation in LUAD, emphasizing its potential as a biomarker for cancer detection and as a tool for understanding tumor biology. The study identified 4,925 differentially methylated sites (DMSs) and prioritized the top 200 DMSs for downstream analyses. Functional enrichment analysis revealed that site-specific hypermethylation in exon 1 and distal promoter regions are linked to critical developmental processes, including morphogenesis, pattern specification, stem cell differentiation, and synaptic transmission, suggesting that these epigenetic changes may disrupt normal cellular functions and contribute to tumorigenesis. Support vector machines demonstrated the diagnostic potential of these hypermethylated sites, achieving perfect classification of LUAD and normal adjacent tissues with as few as five features. Additionally, the strong correlation between methylation levels and feature importance scores further explained the predictive accuracy of these methylation markers. The study also identified distinct methylation subgroups within LUAD tumors, independent of traditional staging, each associated with unique transcriptional dysregulation and biological processes, such as DNA repair, immune response, and ribosome biogenesis. These findings not only enhance our understanding of LUAD pathophysiology but also underscore the clinical utility of DNA methylation as a diagnostic tool and guide for patient management.
肺腺癌（LUAD）是肺癌中最常见的亚型，具有明显的分子异质性和预后不良的特点，这主要是由于晚期诊断所致。因此，详细描述 LUAD 的分子特征对于开发生物标记物以在早期阶段准确检测该疾病至关重要。本研究调查了 DNA 甲基化在 LUAD 中的作用，强调其作为癌症检测生物标记物和了解肿瘤生物学的工具的潜力。研究确定了 4,925 个差异甲基化位点（DMSs），并优先选择了前 200 个 DMSs 进行下游分析。功能富集分析表明，外显子1和远端启动子区域的位点特异性高甲基化与关键的发育过程有关，包括形态发生、模式规范、干细胞分化和突触传递，这表明这些表观遗传变化可能会破坏正常的细胞功能并导致肿瘤发生。支持向量机证明了这些高甲基化位点的诊断潜力，只需五个特征就能对 LUAD 和正常邻近组织进行完美分类。此外，甲基化水平与特征重要性得分之间的强相关性进一步说明了这些甲基化标记的预测准确性。研究还发现了 LUAD 肿瘤中不同的甲基化亚群，这些亚群与传统的分期无关，每个亚群都与独特的转录失调和生物过程（如 DNA 修复、免疫反应和核糖体生物发生）相关。这些发现不仅加深了我们对LUAD病理生理学的理解，还强调了DNA甲基化作为诊断工具和患者管理指南的临床实用性。
{"title":"DNA Methylation Analysis Identifies Clinically Relevant Lung Adenocarcinoma Subgroups","authors":"Oluwadamilare I. Afolabi","doi":"10.1101/2024.08.26.24312568","DOIUrl":"https://doi.org/10.1101/2024.08.26.24312568","url":null,"abstract":"Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and is characterized by significant molecular heterogeneity and poor prognosis, primarily due to late-stage diagnoses. Therefore, detailed molecular characterization of LUAD is crucial for developing biomarkers to accurately detect the disease in its early stages. This study investigates the role of DNA methylation in LUAD, emphasizing its potential as a biomarker for cancer detection and as a tool for understanding tumor biology. The study identified 4,925 differentially methylated sites (DMSs) and prioritized the top 200 DMSs for downstream analyses. Functional enrichment analysis revealed that site-specific hypermethylation in exon 1 and distal promoter regions are linked to critical developmental processes, including morphogenesis, pattern specification, stem cell differentiation, and synaptic transmission, suggesting that these epigenetic changes may disrupt normal cellular functions and contribute to tumorigenesis. Support vector machines demonstrated the diagnostic potential of these hypermethylated sites, achieving perfect classification of LUAD and normal adjacent tissues with as few as five features. Additionally, the strong correlation between methylation levels and feature importance scores further explained the predictive accuracy of these methylation markers. The study also identified distinct methylation subgroups within LUAD tumors, independent of traditional staging, each associated with unique transcriptional dysregulation and biological processes, such as DNA repair, immune response, and ribosome biogenesis. These findings not only enhance our understanding of LUAD pathophysiology but also underscore the clinical utility of DNA methylation as a diagnostic tool and guide for patient management.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1101/2024.09.05.24313092
Xingyuan Li, Hui Li
Purpose To determine whether genetic predisposition to various skin diseases influences the risk of non-small cell lung cancer (NSCLC) through Mendelian randomization (MR).
{"title":"Impact of 26 Skin Diseases on the Risk of Non-Small Cell Lung Cancer: A Mendelian Randomization Study Using FinnGen R11 Data","authors":"Xingyuan Li, Hui Li","doi":"10.1101/2024.09.05.24313092","DOIUrl":"https://doi.org/10.1101/2024.09.05.24313092","url":null,"abstract":"<strong>Purpose</strong> To determine whether genetic predisposition to various skin diseases influences the risk of non-small cell lung cancer (NSCLC) through Mendelian randomization (MR).","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1101/2024.09.05.24313109
Iulian Emil Tampu, Tamara Bianchessi, Ida Blystad, Peter Lundberg, Per Nyman, Anders Eklund, Neda Haj-Hosseini
Purpose To implement and evaluate deep learning-based methods for the classification of pediatric brain tumors in MR data.
目的 实施和评估基于深度学习的方法，对磁共振数据中的小儿脑肿瘤进行分类。
{"title":"Pediatric brain tumor classification using deep learning on MR-images with age fusion","authors":"Iulian Emil Tampu, Tamara Bianchessi, Ida Blystad, Peter Lundberg, Per Nyman, Anders Eklund, Neda Haj-Hosseini","doi":"10.1101/2024.09.05.24313109","DOIUrl":"https://doi.org/10.1101/2024.09.05.24313109","url":null,"abstract":"<strong>Purpose</strong> To implement and evaluate deep learning-based methods for the classification of pediatric brain tumors in MR data.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1101/2024.09.04.24313032
Mark Zobeck, Javed Khan, Rajkumar Venkatramani, M. Fatih Okcu, Michael E. Scheurer, Philip J. Lupo
Purpose Molecular markers, such as FOXO1 fusion genes and TP53 and MYOD1 mutations, increasingly influence risk-stratified treatment selection for pediatric rhabdomyosarcoma (RMS). This study aims to integrate molecular and clinical data to produce individualized prognosis predictions that can further improve treatment selection.
{"title":"Improving Individualized Rhabdomyosarcoma Prognosis Predictions Using Somatic Molecular Biomarkers","authors":"Mark Zobeck, Javed Khan, Rajkumar Venkatramani, M. Fatih Okcu, Michael E. Scheurer, Philip J. Lupo","doi":"10.1101/2024.09.04.24313032","DOIUrl":"https://doi.org/10.1101/2024.09.04.24313032","url":null,"abstract":"<strong>Purpose</strong> Molecular markers, such as <em>FOXO1</em> fusion genes and <em>TP53</em> and <em>MYOD1</em> mutations, increasingly influence risk-stratified treatment selection for pediatric rhabdomyosarcoma (RMS). This study aims to integrate molecular and clinical data to produce individualized prognosis predictions that can further improve treatment selection.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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