Pub Date : 2024-09-05DOI: 10.1101/2024.08.29.24312813
Alexandre Matov
Prostate cancer (PC), which is a disease driven by the activity of the androgen receptor (AR), is the most commonly diagnosed malignancy and despite advances in diagnostic and treatment strategies, PC is the second most common cause of cancer mortality in men (Bray et al., 2018). Taxane-based chemotherapy is the only chemotherapy that prolongs survival in metastatic PC patients (Petrylak et al., 2004; Tannock et al., 2004). At the cellular level, taxanes bind to and stabilize microtubules (MTs) inhibiting all MT-dependent intracellular pathways. MTs are highly dynamic polymers that stochastically switch between phases of growth, shrinkage, and pause (Jordan and Wilson, 2004). Altered MT dynamics endow cancer cells with both survival and migratory advantages (Mitchison, 2012). Taxanes inhibit MT dynamics and alter the spatial organization of the MT network, thereby inhibiting intracellular trafficking of molecular cargo critical for tumor survival. In PC specifically, taxanes inhibit transcriptional activity downstream of MT stabilization (Thadani-Mulero et al., 2012) and AR nuclear accumulation (Darshan et al., 2011; Zhu et al., 2010). Different tubulin inhibitors, even from within the same structural class as the taxanes, affect distinct parameters of MT dynamics (Jordan and Wilson, 2004), yet the selection of taxane for chemotherapy is not based on the particular patterns of dynamic behavior of the MT cytoskeleton in individual patients. We envisage that systematic characterization using quantitative analysis of MT dynamics in PC patient cells expressing clinically relevant protein isoforms (Matov et al., 2024; Thoma et al., 2010), before and after treatment with each of the taxanes, will allow us to identify criteria for the selection of the most suitable drug combination at the onset of treatment. We link MT dynamics in the presence of AR variants and sensitivity/resistance to taxanes and connect fundamental research with clinically relevant concepts to elucidate cellular mechanisms of clinical response to taxanes and, thus, advance the customization of therapy. Our computational live-cell analysis addresses questions in the context of the inherent differences in MT homeostasis as a function of AR content in PC cells, the specific parameters of MT dynamics each of the taxanes affects, and how can this information be used to match endogenous patterns of MT dynamics with drug-modulated MT behavior. We investigate whether the sensitivity to taxanes, evaluated by computational analysis of MTs, can be linked to gene expression driven by AR and its variants, and whether the resistance to taxanes be linked to the presence of a specific AR splice variant, and can we identify which of the taxanes will be most effective based on the endogenous patterns of MT dynamics.
{"title":"Computational Analysis of Treatment Resistant Cancer Cells","authors":"Alexandre Matov","doi":"10.1101/2024.08.29.24312813","DOIUrl":"https://doi.org/10.1101/2024.08.29.24312813","url":null,"abstract":"Prostate cancer (PC), which is a disease driven by the activity of the androgen receptor (AR), is the most commonly diagnosed malignancy and despite advances in diagnostic and treatment strategies, PC is the second most common cause of cancer mortality in men (Bray et al., 2018). Taxane-based chemotherapy is the only chemotherapy that prolongs survival in metastatic PC patients (Petrylak et al., 2004; Tannock et al., 2004). At the cellular level, taxanes bind to and stabilize microtubules (MTs) inhibiting all MT-dependent intracellular pathways. MTs are highly dynamic polymers that stochastically switch between phases of growth, shrinkage, and pause (Jordan and Wilson, 2004). Altered MT dynamics endow cancer cells with both survival and migratory advantages (Mitchison, 2012). Taxanes inhibit MT dynamics and alter the spatial organization of the MT network, thereby inhibiting intracellular trafficking of molecular cargo critical for tumor survival. In PC specifically, taxanes inhibit transcriptional activity downstream of MT stabilization (Thadani-Mulero et al., 2012) and AR nuclear accumulation (Darshan et al., 2011; Zhu et al., 2010). Different tubulin inhibitors, even from within the same structural class as the taxanes, affect distinct parameters of MT dynamics (Jordan and Wilson, 2004), yet the selection of taxane for chemotherapy is not based on the particular patterns of dynamic behavior of the MT cytoskeleton in individual patients. We envisage that systematic characterization using quantitative analysis of MT dynamics in PC patient cells expressing clinically relevant protein isoforms (Matov et al., 2024; Thoma et al., 2010), before and after treatment with each of the taxanes, will allow us to identify criteria for the selection of the most suitable drug combination at the onset of treatment. We link MT dynamics in the presence of AR variants and sensitivity/resistance to taxanes and connect fundamental research with clinically relevant concepts to elucidate cellular mechanisms of clinical response to taxanes and, thus, advance the customization of therapy. Our computational live-cell analysis addresses questions in the context of the inherent differences in MT homeostasis as a function of AR content in PC cells, the specific parameters of MT dynamics each of the taxanes affects, and how can this information be used to match endogenous patterns of MT dynamics with drug-modulated MT behavior. We investigate whether the sensitivity to taxanes, evaluated by computational analysis of MTs, can be linked to gene expression driven by AR and its variants, and whether the resistance to taxanes be linked to the presence of a specific AR splice variant, and can we identify which of the taxanes will be most effective based on the endogenous patterns of MT dynamics.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202866","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}
Background Approximately one-third of patients with HER2-positive breast cancer experienced recurrence within 10 years after receiving 1 year of adjuvant trastuzumab. The ExteNET study showed that 1 year of extended adjuvant neratinib after trastuzumab-based adjuvant therapy could reduce invasive disease-free survival (iDFS) events compared with placebo. This study investigated the efficacy and safety of pyrotinib, an irreversible pan-HER receptor tyrosine kinase inhibitor, after trastuzumab-based adjuvant therapy in patients with high-risk, HER2-positive early or locally advanced breast cancer.
{"title":"Pyrotinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (PERSIST): A multicenter phase II trial","authors":"Feilin Cao, Zhaosheng Ma, Zenggui Wu, Weizhu Wu, Ouchen Wang, Binbin Cui, Xiaotao Zhu, Jing Hao, Xiaochun Ji, Zhanwen Li, Deyou Tao, Qingjing Feng, Wei Lin, Dongbo Shi, Jingde Shu, Jichun Zhou, Shifen Huang","doi":"10.1101/2024.09.05.24313095","DOIUrl":"https://doi.org/10.1101/2024.09.05.24313095","url":null,"abstract":"<strong>Background</strong> Approximately one-third of patients with HER2-positive breast cancer experienced recurrence within 10 years after receiving 1 year of adjuvant trastuzumab. The ExteNET study showed that 1 year of extended adjuvant neratinib after trastuzumab-based adjuvant therapy could reduce invasive disease-free survival (iDFS) events compared with placebo. This study investigated the efficacy and safety of pyrotinib, an irreversible pan-HER receptor tyrosine kinase inhibitor, after trastuzumab-based adjuvant therapy in patients with high-risk, HER2-positive early or locally advanced breast cancer.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202865","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 : 2024-09-04DOI: 10.1101/2024.09.03.24312978
Simon Skau, Marianne Jarfelt, Gustaf Glavå, Laura Jess, H. Georg Kuhn
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Due to the drastic increase in survivor rate over the last 50 years, long lasting treatment effect on moods and neurocognitive function has become a present issue. Most studies of late effects of treatment of ALL survivors investigate patients in their adolescents. This pilot study aims to identify measurements for evaluating late effect of childhood ALL survivors regarding neurocognitive and mood problems in adulthood. ALL survivors who received neurotoxic treatment with high-dose methotrexate and cranial radiotherapy (Chemo+CRT) (n=10) and ALL survivors only treated with high-dose methotrexate (Chemo) (n=10), plus age and sex match controls (n=20) where recruited to the study. The study protocol involved questionnaires, neurocognitive tests and optical brain imaging with functional near infrared spectroscopy (fNIRS) over the frontal and parietal cortex. The fNIRS results indicate a reduced involvement of the parietal cortex during conflict processing for the ALL survivors compared to controls. The study protocol shows promising results for identifying subgroups that suffers from neurocognitive and mood problems and we aim to expand upon it in a larger study. As our results indicate increased challenges among female ALL survivors, especially pathological fatigue, anxiety, and information processing, it is important to explore in future investigations the interplay between the risk of hormonal interaction with chemotherapy during development and occupational and social pressure during adulthood.
急性淋巴细胞白血病（ALL）是最常见的儿童恶性肿瘤。由于过去 50 年来存活率的急剧上升，长期治疗对情绪和神经认知功能的影响已成为当前的一个问题。大多数关于 ALL 存活者治疗后期影响的研究都是针对青少年患者的。本试验性研究旨在确定评估儿童期 ALL 存活者成年后神经认知和情绪问题的晚期影响的测量方法。研究招募了接受大剂量甲氨蝶呤和头颅放疗（化疗+CRT）神经毒性治疗的ALL幸存者（10人）、仅接受大剂量甲氨蝶呤（化疗）治疗的ALL幸存者（10人）以及年龄和性别匹配的对照组（20人）。研究方案包括问卷调查、神经认知测试以及额叶和顶叶皮层的功能性近红外光谱（fNIRS）光学脑成像。fNIRS 的结果表明，与对照组相比，ALL 幸存者在冲突处理过程中顶叶皮层的参与程度降低。该研究方案在识别患有神经认知和情绪问题的亚组方面显示出良好的效果，我们希望在更大规模的研究中进一步扩展该方案。我们的研究结果表明，女性ALL幸存者面临的挑战越来越多，尤其是病理性疲劳、焦虑和信息处理，因此，在未来的研究中探索发育期荷尔蒙与化疗相互作用的风险与成年期职业和社会压力之间的相互作用非常重要。
{"title":"Using functional near-infrared spectroscopy to explore neurocognitive function in adult survivors of childhood acute lymphoblastic leukemia","authors":"Simon Skau, Marianne Jarfelt, Gustaf Glavå, Laura Jess, H. Georg Kuhn","doi":"10.1101/2024.09.03.24312978","DOIUrl":"https://doi.org/10.1101/2024.09.03.24312978","url":null,"abstract":"Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Due to the drastic increase in survivor rate over the last 50 years, long lasting treatment effect on moods and neurocognitive function has become a present issue. Most studies of late effects of treatment of ALL survivors investigate patients in their adolescents. This pilot study aims to identify measurements for evaluating late effect of childhood ALL survivors regarding neurocognitive and mood problems in adulthood. ALL survivors who received neurotoxic treatment with high-dose methotrexate and cranial radiotherapy (Chemo+CRT) (n=10) and ALL survivors only treated with high-dose methotrexate (Chemo) (n=10), plus age and sex match controls (n=20) where recruited to the study. The study protocol involved questionnaires, neurocognitive tests and optical brain imaging with functional near infrared spectroscopy (fNIRS) over the frontal and parietal cortex. The fNIRS results indicate a reduced involvement of the parietal cortex during conflict processing for the ALL survivors compared to controls. The study protocol shows promising results for identifying subgroups that suffers from neurocognitive and mood problems and we aim to expand upon it in a larger study. As our results indicate increased challenges among female ALL survivors, especially pathological fatigue, anxiety, and information processing, it is important to explore in future investigations the interplay between the risk of hormonal interaction with chemotherapy during development and occupational and social pressure during adulthood.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227682","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 : 2024-09-04DOI: 10.1101/2024.09.03.24311998
Maximilian Unfried, Amaury Cazenave-Gassiot, Evelyne Bischof, Michal Holcapek, Morten Scheibye-Knudsen, Markus R. Wenk, Jan Gruber, Brian K. Kennedy
Lipids are a heterogenous class of molecules involved in signaling, cell structure and energy storage. Lipid metabolism is dysregulated in aging and aging-related diseases such as cancer, metabolic disorders, and neurodegeneration. In this study, we developed a biological age predictor – a Lipid Aging Clock - based on human serum lipidome data of pancreatic ductal adenocarcinoma (PDAC) patients, that has a Pearson correlation coefficient of 0.81 to chronological age with a median absolute error of 4.5 years. This shows that it is possible to build aging clocks measuring aging from pathological cohorts.
{"title":"Lipid Aging Clocks as predictive and prognostic biomarker in cancer and inflammaging","authors":"Maximilian Unfried, Amaury Cazenave-Gassiot, Evelyne Bischof, Michal Holcapek, Morten Scheibye-Knudsen, Markus R. Wenk, Jan Gruber, Brian K. Kennedy","doi":"10.1101/2024.09.03.24311998","DOIUrl":"https://doi.org/10.1101/2024.09.03.24311998","url":null,"abstract":"Lipids are a heterogenous class of molecules involved in signaling, cell structure and energy storage. Lipid metabolism is dysregulated in aging and aging-related diseases such as cancer, metabolic disorders, and neurodegeneration. In this study, we developed a biological age predictor – a Lipid Aging Clock - based on human serum lipidome data of pancreatic ductal adenocarcinoma (PDAC) patients, that has a Pearson correlation coefficient of 0.81 to chronological age with a median absolute error of 4.5 years. This shows that it is possible to build aging clocks measuring aging from pathological cohorts.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202867","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 : 2024-09-03DOI: 10.1101/2024.08.25.24312201
Bezhou Feng, Eashwar Somasundaram, Vishhvaan Gopalakrishnan, Julia Pelesko, Kevin Stephans, Anthony Magnelli, Shlomo Koyfman, Gregory Videtic, Peng Qi, Jonathan W. Piper, Richard L.J. Qiu, Jacob G. Scott
In modern radiotherapy, multiple courses of radiation are becoming increasingly common as a treatment regimen to extend progression-free and overall survival in patients with oligometastatic disease. However, normal tissue recovery over time has not been well characterized, and there are few models for clinicians to use when evaluating potential toxicities in subsequent radiation treatments. The lack of standardization when documenting a patient’s radiotherapy history presents a major barrier to conducting large scale studies. To advance our understanding of normal tissue recovery post-radiation, we propose the addition of a new object accompanied by a suite of mathematical models linked to toxicity information in a patient’s medical record. This object leverages the Digital Imaging and Communications in Medicine (DICOM) standard to serve as a centralized data store for radiotherapy planning and treatment, thereby facilitating a better analysis of therapeutic outcomes and tissue response over the course of radiotherapy.
{"title":"Temporally Corrected Dose Accumulation – Next Steps in the Biology of Reirradiation","authors":"Bezhou Feng, Eashwar Somasundaram, Vishhvaan Gopalakrishnan, Julia Pelesko, Kevin Stephans, Anthony Magnelli, Shlomo Koyfman, Gregory Videtic, Peng Qi, Jonathan W. Piper, Richard L.J. Qiu, Jacob G. Scott","doi":"10.1101/2024.08.25.24312201","DOIUrl":"https://doi.org/10.1101/2024.08.25.24312201","url":null,"abstract":"In modern radiotherapy, multiple courses of radiation are becoming increasingly common as a treatment regimen to extend progression-free and overall survival in patients with oligometastatic disease. However, normal tissue recovery over time has not been well characterized, and there are few models for clinicians to use when evaluating potential toxicities in subsequent radiation treatments. The lack of standardization when documenting a patient’s radiotherapy history presents a major barrier to conducting large scale studies. To advance our understanding of normal tissue recovery post-radiation, we propose the addition of a new object accompanied by a suite of mathematical models linked to toxicity information in a patient’s medical record. This object leverages the Digital Imaging and Communications in Medicine (DICOM) standard to serve as a centralized data store for radiotherapy planning and treatment, thereby facilitating a better analysis of therapeutic outcomes and tissue response over the course of radiotherapy.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"4683 4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202868","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}
Background Both neoadjuvant chemotherapy and endocrine therapy only result in trivial pathological complete response rates and moderate objective response rates (ORR) in hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer, more promising alternatives are urgently needed. With proven synergistic effect of cyclin dependent kinase 4/6 (CDK4/6) inhibitor and radiotherapy in preclinical studies, this pilot study aimed to explore the efficacy and safety of neoadjuvant stereotactic body radiation therapy (SBRT) followed by dalpiciclib and exemestane in HR-positive, HER2-negative breast cancer.
{"title":"Efficacy and safety of neoadjuvant stereotactic body radiation therapy plus dalpiciclib and exemestane for hormone receptor-positive, HER2-negative breast cancer: A prospective pilot study","authors":"Yu Zhang, Shuo Cao, Nan Niu, Huilian Shan, Jinqi Xue, Guanglei Chen, Yongqing Xu, Jianqiao Yin, Chao Liu, Lisha Sun, Xiaofan Jiang, Meiyue Tang, Qianshi Xu, Mingxuan Jia, Xu Zhang, Zhenyong Zhang, Qingfu Zhang, Jianfei Wang, Ailin Li, Yongliang Yang, Caigang Liu","doi":"10.1101/2024.08.31.24312890","DOIUrl":"https://doi.org/10.1101/2024.08.31.24312890","url":null,"abstract":"<strong>Background</strong> Both neoadjuvant chemotherapy and endocrine therapy only result in trivial pathological complete response rates and moderate objective response rates (ORR) in hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer, more promising alternatives are urgently needed. With proven synergistic effect of cyclin dependent kinase 4/6 (CDK4/6) inhibitor and radiotherapy in preclinical studies, this pilot study aimed to explore the efficacy and safety of neoadjuvant stereotactic body radiation therapy (SBRT) followed by dalpiciclib and exemestane in HR-positive, HER2-negative breast cancer.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202881","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 : 2024-09-01DOI: 10.1101/2024.09.01.24312783
Julie W. Reeser, Michele R. Wing, Eric Samorodnitsky, Thuy Dao, Amy Smith, Leah Stein, Anoosha Paruchuri, Jharna Miya, Russell Bonneville, Yi-Seok Chang, Matthew Avenarius, Aharon G. Freud, Lianbo Yu, Sameek Roychowdhury
Commercial liquid biopsy assays are routinely used by oncologists to monitor disease response and resistance to therapy. Additionally, in cases where tumor tissue is not available, clinicians may rely on cell-free DNA (cfDNA) testing as a surrogate for comprehensive tumor testing. While some gene rearrangements are well detected, current commercial liquid biopsy assays exhibit low sensitivity for fibroblast growth factor receptor (FGFR) rearrangements. FGFRs are altered in ∼2.5% of all cancers, including FGFR2 rearrangements in 10% of intrahepatic cholangiocarcinoma and FGFR3 point mutations and rearrangements in 10-15% of urothelial carcinoma. Therefore, we developed and analytically validated FGFR-Dx, an FGFR-focused cfDNA assay with improved sensitivity for FGFR rearrangements. FGFR-Dx comprehensively targets the introns in FGFR1-3 previously shown to be involved in gene fusions as well as all coding exons. Custom FGFR synthetic reference standards representing both single nucleotide variants (SNVs) and gene rearrangements were utilized at a range of variant frequencies and revealed a detection limit of 0.5% with sensitivities of 97.2% and 92.9% for SNVs and rearrangements, respectively. Furthermore, FGFR-Dx detected rearrangements and identified the intronic breakpoints from cfDNA collected from 13 of 15 patients with known FGFR fusions.
{"title":"Analytic validation of an FGFR-focused cell-free DNA liquid biopsy assay (FGFR-Dx)","authors":"Julie W. Reeser, Michele R. Wing, Eric Samorodnitsky, Thuy Dao, Amy Smith, Leah Stein, Anoosha Paruchuri, Jharna Miya, Russell Bonneville, Yi-Seok Chang, Matthew Avenarius, Aharon G. Freud, Lianbo Yu, Sameek Roychowdhury","doi":"10.1101/2024.09.01.24312783","DOIUrl":"https://doi.org/10.1101/2024.09.01.24312783","url":null,"abstract":"Commercial liquid biopsy assays are routinely used by oncologists to monitor disease response and resistance to therapy. Additionally, in cases where tumor tissue is not available, clinicians may rely on cell-free DNA (cfDNA) testing as a surrogate for comprehensive tumor testing. While some gene rearrangements are well detected, current commercial liquid biopsy assays exhibit low sensitivity for fibroblast growth factor receptor (<em>FGFR</em>) rearrangements. <em>FGFRs</em> are altered in ∼2.5% of all cancers, including <em>FGFR2</em> rearrangements in 10% of intrahepatic cholangiocarcinoma and <em>FGFR3</em> point mutations and rearrangements in 10-15% of urothelial carcinoma. Therefore, we developed and analytically validated FGFR-Dx, an <em>FGFR</em>-focused cfDNA assay with improved sensitivity for <em>FGFR</em> rearrangements. FGFR-Dx comprehensively targets the introns in <em>FGFR1-3</em> previously shown to be involved in gene fusions as well as all coding exons. Custom <em>FGFR</em> synthetic reference standards representing both single nucleotide variants (SNVs) and gene rearrangements were utilized at a range of variant frequencies and revealed a detection limit of 0.5% with sensitivities of 97.2% and 92.9% for SNVs and rearrangements, respectively. Furthermore, FGFR-Dx detected rearrangements and identified the intronic breakpoints from cfDNA collected from 13 of 15 patients with known FGFR fusions.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202869","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 : 2024-09-01DOI: 10.1101/2024.08.31.24312756
Ryan D. Chow, Priya Velu, Safoora Deihimi, Jonathan Belman, Angela Youn, Nisargbhai Shah, Selina M. Luger, Martin P. Carroll, Jennifer Morrissette, Robert L Bowman
Mutations commonly found in AML such as DNMT3A, TET2 and ASXL1 can be found in the peripheral blood of otherwise healthy adults – a phenomenon referred to as clonal hematopoiesis (CH). These mutations are thought to represent the earliest genetic events in the evolution of AML. Genomic studies on samples acquired at diagnosis, remission, and at relapse have demonstrated significant stability of CH mutations following induction chemotherapy. Meanwhile, later mutations in genes such as NPM1 and FLT3, have been shown to contract at remission and in the case of FLT3 often are absent at relapse. We sought to understand how early CH mutations influence subsequent evolutionary trajectories throughout remission and relapse in response to induction chemotherapy. Here, we assembled a retrospective cohort of patients diagnosed with de novo AML at our institution that underwent genomic sequencing at diagnosis as well as at the time of remission and/or relapse (total n = 182 patients). Corroborating prior studies, FLT3 and NPM1 mutations were generally eliminated at the time of cytologic complete remission but subsequently reemerged upon relapse, whereas DNMT3A, TET2 and ASXL1 mutations often persisted through remission. Early CH-related mutations exhibited distinct constellations of co-occurring genetic alterations, with NPM1 and FLT3 mutations enriched in DNMT3Amut AML, while CBL and SRSF2 mutations were enriched in TET2mut and ASXL1mut AML, respectively. In the case of NPM1 and FLT3 mutations, these differences vanished at the time of complete remission yet readily reemerged upon relapse, indicating the reproducible nature of these genetic interactions. Thus, early CH-associated mutations that precede malignant transformation subsequently shape the evolutionary trajectories of AML through diagnosis, therapy, and relapse.
{"title":"Early drivers of clonal hematopoiesis shape the evolutionary trajectories of de novo acute myeloid leukemia","authors":"Ryan D. Chow, Priya Velu, Safoora Deihimi, Jonathan Belman, Angela Youn, Nisargbhai Shah, Selina M. Luger, Martin P. Carroll, Jennifer Morrissette, Robert L Bowman","doi":"10.1101/2024.08.31.24312756","DOIUrl":"https://doi.org/10.1101/2024.08.31.24312756","url":null,"abstract":"Mutations commonly found in AML such as <em>DNMT3A</em>, <em>TET2</em> and <em>ASXL1</em> can be found in the peripheral blood of otherwise healthy adults – a phenomenon referred to as clonal hematopoiesis (CH). These mutations are thought to represent the earliest genetic events in the evolution of AML. Genomic studies on samples acquired at diagnosis, remission, and at relapse have demonstrated significant stability of CH mutations following induction chemotherapy. Meanwhile, later mutations in genes such as <em>NPM1</em> and <em>FLT3</em>, have been shown to contract at remission and in the case of <em>FLT3</em> often are absent at relapse. We sought to understand how early CH mutations influence subsequent evolutionary trajectories throughout remission and relapse in response to induction chemotherapy. Here, we assembled a retrospective cohort of patients diagnosed with <em>de novo</em> AML at our institution that underwent genomic sequencing at diagnosis as well as at the time of remission and/or relapse (total n = 182 patients). Corroborating prior studies, <em>FLT3</em> and <em>NPM1</em> mutations were generally eliminated at the time of cytologic complete remission but subsequently reemerged upon relapse, whereas <em>DNMT3A</em>, <em>TET2</em> and <em>ASXL1</em> mutations often persisted through remission. Early CH-related mutations exhibited distinct constellations of co-occurring genetic alterations, with <em>NPM1</em> and <em>FLT3</em> mutations enriched in <em>DNMT3A</em><sup>mut</sup> AML, while <em>CBL</em> and <em>SRSF2</em> mutations were enriched in <em>TET2</em><sup>mut</sup> and <em>ASXL1<sup>mut</sup></em> AML, respectively. In the case of <em>NPM1</em> and <em>FLT3</em> mutations, these differences vanished at the time of complete remission yet readily reemerged upon relapse, indicating the reproducible nature of these genetic interactions. Thus, early CH-associated mutations that precede malignant transformation subsequently shape the evolutionary trajectories of AML through diagnosis, therapy, and relapse.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"736 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202870","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 : 2024-08-31DOI: 10.1101/2024.08.30.24312735
Itzel Valencia, Pier Vitale Nuzzo, Edoardo Francini, Francesco Ravera, Giuseppe Nicolò Fanelli, Sara Bleve, Cristian Scatena, Luigi Marchionni, Mohamed Omar
Prostate cancer (PCa) is currently the most commonly diagnosed cancer and second leading cause of cancer-related death in men in the United States. The development of metastases is associated with a poor prognosis in PCa patients. Since current clinicopathological classification schemes are unable to accurately prognosticate the risk of metastasis for those diagnosed with localized PCa, there is a pressing need for precise and easily attainable biomarkers of metastatic risk in these patients. Primary tumor samples from 1239 individuals with PCa were divided into development (n=1000) and validation (n=239) cohorts. In the development cohort, we utilized a meta-analysis workflow on retrospective primary tumor gene expression profiles to identify a subset of genes predictive of metastasis. For each gene, we computed Hedges’ g effect size and combined their p-values using Fisher’s combined probability test. We then adjusted for multiple hypothesis testing using the Benjamini-Hochberg method. Our developed gene signature, termed Meta-Score, achieved a robust performance at predicting metastasis from primary tumor gene expression profiles, with an AUC of 0.72 in the validation cohort. In addition to its robust predictive power, Meta-Score also demonstrated a significant prognostic utility in two independent cohorts. Specifically, patients with a higher risk-score had a significantly worse metastasis-free survival and progression-free survival compared to those with lower score. Multivariate cox proportional hazards model showed that Meta-Score is significantly associated with worse survival even after adjusting for Gleason score. Our findings suggest that our primary tumor transcriptional signature, Meta-Score, could be a valuable tool to assess the risk of metastasis in PCa patients with localized disease, pending validation in large prospective studies.
{"title":"Gene Signature for Predicting Metastasis in Prostate Cancer Using Primary Tumor Expression Profiles","authors":"Itzel Valencia, Pier Vitale Nuzzo, Edoardo Francini, Francesco Ravera, Giuseppe Nicolò Fanelli, Sara Bleve, Cristian Scatena, Luigi Marchionni, Mohamed Omar","doi":"10.1101/2024.08.30.24312735","DOIUrl":"https://doi.org/10.1101/2024.08.30.24312735","url":null,"abstract":"Prostate cancer (PCa) is currently the most commonly diagnosed cancer and second leading cause of cancer-related death in men in the United States. The development of metastases is associated with a poor prognosis in PCa patients. Since current clinicopathological classification schemes are unable to accurately prognosticate the risk of metastasis for those diagnosed with localized PCa, there is a pressing need for precise and easily attainable biomarkers of metastatic risk in these patients. Primary tumor samples from 1239 individuals with PCa were divided into development (n=1000) and validation (n=239) cohorts. In the development cohort, we utilized a meta-analysis workflow on retrospective primary tumor gene expression profiles to identify a subset of genes predictive of metastasis. For each gene, we computed Hedges’ g effect size and combined their p-values using Fisher’s combined probability test. We then adjusted for multiple hypothesis testing using the Benjamini-Hochberg method. Our developed gene signature, termed Meta-Score, achieved a robust performance at predicting metastasis from primary tumor gene expression profiles, with an AUC of 0.72 in the validation cohort. In addition to its robust predictive power, Meta-Score also demonstrated a significant prognostic utility in two independent cohorts. Specifically, patients with a higher risk-score had a significantly worse metastasis-free survival and progression-free survival compared to those with lower score. Multivariate cox proportional hazards model showed that Meta-Score is significantly associated with worse survival even after adjusting for Gleason score. Our findings suggest that our primary tumor transcriptional signature, Meta-Score, could be a valuable tool to assess the risk of metastasis in PCa patients with localized disease, pending validation in large prospective studies.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202887","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 : 2024-08-31DOI: 10.1101/2024.08.30.24312793
Raylane Adrielle Gonçalves Cambui, Mariela Estefany Vera Roa, Vinicius Nunes Cordeiro Leal, Suemy Melim Yamada, Leonardo Antônio Teixeira de Oliveira, Izabel Nazira Nadaf, Cleiton Ribeiro Lelis, Rafaela Cássia da Cunha Pedroso, Rafaela Cardoso do Nascimento Costa, Raquel Maria Neves Amorim, Jefferson Rodrigues do Amaral, Polyana Silva Lemes, Leonardo Amorim Rizzo, Gilmar Ferreira do Espírito Santo, Rosa Maria Elias, Bruno Cogliati, Marcelo Hill, Alessandra Pontillo
Purpose TMEM176B has been recently identified as a novel player in anti-cancer immune responses by negatively modulating the NLRP3 inflammasome activation in colorectal cancer (CRC). Yet, the TMEM176B/NLRP3 axis in CRC needs to be deeply investigated.
{"title":"Inverse correlation between NLRP3 and TMEM176B as a possible tool for colorectal cancer progression","authors":"Raylane Adrielle Gonçalves Cambui, Mariela Estefany Vera Roa, Vinicius Nunes Cordeiro Leal, Suemy Melim Yamada, Leonardo Antônio Teixeira de Oliveira, Izabel Nazira Nadaf, Cleiton Ribeiro Lelis, Rafaela Cássia da Cunha Pedroso, Rafaela Cardoso do Nascimento Costa, Raquel Maria Neves Amorim, Jefferson Rodrigues do Amaral, Polyana Silva Lemes, Leonardo Amorim Rizzo, Gilmar Ferreira do Espírito Santo, Rosa Maria Elias, Bruno Cogliati, Marcelo Hill, Alessandra Pontillo","doi":"10.1101/2024.08.30.24312793","DOIUrl":"https://doi.org/10.1101/2024.08.30.24312793","url":null,"abstract":"<strong>Purpose</strong> TMEM176B has been recently identified as a novel player in anti-cancer immune responses by negatively modulating the NLRP3 inflammasome activation in colorectal cancer (CRC). Yet, the TMEM176B/NLRP3 axis in CRC needs to be deeply investigated.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202871","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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