Marlene Richter Jensen, U. Stoltze, T. V. Hansen, M. Bak, A. Sehested, C. Rechnitzer, R. Mathiasen, D. Scheie, K. B. Larsen, T. Olsen, A. Muhic, J. Skjøth-Rasmussen, M. Rossing, K. Schmiegelow, K. Wadt
Germline pathogenic variants in CDKN2A predispose to various cancers, including melanoma, pancreatic cancer, and neural system tumors, whereas CDKN2B variants are associated with renal cell carcinoma. A few case reports have described heterozygous germline deletions spanning both CDKN2A and CDKN2B associated with a cancer predisposition syndrome (CPS) that constitutes a risk of cancer beyond those associated with haploinsufficiency of each gene individually, indicating an additive effect or a contiguous gene deletion syndrome. We report a young woman with a de novo germline 9p21 microdeletion involving the CDKN2A/CDKN2B genes, who developed six primary cancers since childhood, including a very rare extraskeletal osteosarcoma (eOS) at the age of 8. To our knowledge this is the first report of eOS in a patient with CDKN2A/CDKN2B deletion.
{"title":"9p21.3 Microdeletion involving CDKN2A/2B in a young patient with multiple primary cancers and review of the literature","authors":"Marlene Richter Jensen, U. Stoltze, T. V. Hansen, M. Bak, A. Sehested, C. Rechnitzer, R. Mathiasen, D. Scheie, K. B. Larsen, T. Olsen, A. Muhic, J. Skjøth-Rasmussen, M. Rossing, K. Schmiegelow, K. Wadt","doi":"10.1101/mcs.a006164","DOIUrl":"https://doi.org/10.1101/mcs.a006164","url":null,"abstract":"Germline pathogenic variants in CDKN2A predispose to various cancers, including melanoma, pancreatic cancer, and neural system tumors, whereas CDKN2B variants are associated with renal cell carcinoma. A few case reports have described heterozygous germline deletions spanning both CDKN2A and CDKN2B associated with a cancer predisposition syndrome (CPS) that constitutes a risk of cancer beyond those associated with haploinsufficiency of each gene individually, indicating an additive effect or a contiguous gene deletion syndrome. We report a young woman with a de novo germline 9p21 microdeletion involving the CDKN2A/CDKN2B genes, who developed six primary cancers since childhood, including a very rare extraskeletal osteosarcoma (eOS) at the age of 8. To our knowledge this is the first report of eOS in a patient with CDKN2A/CDKN2B deletion.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"71 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86400327","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}
Florence Choo, I. Odintsov, K. Nusser, K. Nicholson, Lara E Davis, C. Corless, L. Stork, R. Somwar, M. Ladanyi, Jessica L. Davis, M. Davare
{"title":"Corrigendum: Functional impact and targetability of PI3KCA, GNAS, and PTEN mutations in a spindle cell rhabdomyosarcoma with MYOD1 L122R mutation.","authors":"Florence Choo, I. Odintsov, K. Nusser, K. Nicholson, Lara E Davis, C. Corless, L. Stork, R. Somwar, M. Ladanyi, Jessica L. Davis, M. Davare","doi":"10.1101/mcs.a006216","DOIUrl":"https://doi.org/10.1101/mcs.a006216","url":null,"abstract":"","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"18 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82355363","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}
Rebecca R Pharaon, T. Gernon, Sue Chang, N. Vora, V. Villaflor, D. Bell, M. Afkhami, A. Amini, S. Sampath, R. Kang, E. Maghami, E. Massarelli
Salivary gland tumors (SGTs) are heterogeneous tumors that range from benign masses to aggressive high-grade carcinomas with distant metastatic potential and limited response to chemotherapy. Mucoepidermoid carcinoma (MEC) accounts for 10% of SGTs and has a poor prognosis. In this research report, we describe two cases of metastatic high-grade MECs with prolonged response to immune checkpoint inhibitor pembrolizumab. Case 1 presented with a left neck mass, and biopsy of the parotid mass revealed MEC. The patient underwent surgical resection and adjuvant chemoradiation therapy for stage IVB disease. Post-treatment, she was found to have brain and spinal metastases and was placed on pembrolizumab. Case 2 presented with a left neck mass, and biopsy of the right parotid gland revealed MEC. Further staging demonstrated metastatic disease in the lungs, and he was placed on pembrolizumab. Both cases of MEC demonstrated prolonged extracranial responses to pembrolizumab. Although both cases reported little to no PD-L1 expression, these results demonstrate immunotherapy efficacy in advanced/metastatic MEC.
{"title":"Prolonged response to checkpoint inhibitor therapy in two metastatic mucoepidermoid salivary gland carcinoma cases: a research report","authors":"Rebecca R Pharaon, T. Gernon, Sue Chang, N. Vora, V. Villaflor, D. Bell, M. Afkhami, A. Amini, S. Sampath, R. Kang, E. Maghami, E. Massarelli","doi":"10.1101/mcs.a006189","DOIUrl":"https://doi.org/10.1101/mcs.a006189","url":null,"abstract":"Salivary gland tumors (SGTs) are heterogeneous tumors that range from benign masses to aggressive high-grade carcinomas with distant metastatic potential and limited response to chemotherapy. Mucoepidermoid carcinoma (MEC) accounts for 10% of SGTs and has a poor prognosis. In this research report, we describe two cases of metastatic high-grade MECs with prolonged response to immune checkpoint inhibitor pembrolizumab. Case 1 presented with a left neck mass, and biopsy of the parotid mass revealed MEC. The patient underwent surgical resection and adjuvant chemoradiation therapy for stage IVB disease. Post-treatment, she was found to have brain and spinal metastases and was placed on pembrolizumab. Case 2 presented with a left neck mass, and biopsy of the right parotid gland revealed MEC. Further staging demonstrated metastatic disease in the lungs, and he was placed on pembrolizumab. Both cases of MEC demonstrated prolonged extracranial responses to pembrolizumab. Although both cases reported little to no PD-L1 expression, these results demonstrate immunotherapy efficacy in advanced/metastatic MEC.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"61 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84211933","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}
Ryan M Powell, S. Pattison, Jiří C. Moravec, B. Bhat, Nada Guirguis, D. Markie, G. Jones, Jason Copedo, C. Print, I. Morison, A. Gavryushkin, Bronwyn Gray, Lisa J. Wyeth, M. Eccles, E. Macaulay
Tuberous sclerosis complex (TSC) is an inheritable disorder characterized by the formation of benign yet disorganized tumors in multiple organ systems. Germline mutations in the TSC1 (hamartin) or more frequently TSC2 (tuberin) genes are causative for TSC. The malignant manifestations of TSC, pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML), may also occur as independent sporadic perivascular epithelial cell tumor (PEComa) characterized by somatic TSC2 mutations. Thus, discerning TSC from the copresentation of sporadic LAM and sporadic AML may be obscured in TSC patients lacking additional features. In this report, we present a case study on a single patient initially reported to have sporadic LAM and a mucinous duodenal adenocarcinoma deficient in DNA mismatch repair proteins. Moreover, the patient had a history of Wilms’ tumor, which was reclassified as AML following the LAM diagnosis. Therefore, we investigated the origins and relatedness of these tumors. Using germline whole-genome sequencing, we identified a premature truncation in one of the patient's TSC2 alleles. Using immunohistochemistry, loss of tuberin expression was observed in AML and LAM tissue. However, no evidence of a somatic loss of heterozygosity or DNA methylation epimutations was observed at the TSC2 locus, suggesting alternate mechanisms may contribute to loss of the tumor suppressor protein. In the mucinous duodenal adenocarcinoma, no causative mutations were found in the DNA mismatch repair genes MLH1, MSH2, MSH6, or PMS2. Rather, clonal deconvolution analyses were used to identify mutations contributing to pathogenesis. This report highlights both the utility of using multiple sequencing techniques and the complexity of interpreting the data in a clinical context.
{"title":"Tuberous sclerosis complex: a complex case","authors":"Ryan M Powell, S. Pattison, Jiří C. Moravec, B. Bhat, Nada Guirguis, D. Markie, G. Jones, Jason Copedo, C. Print, I. Morison, A. Gavryushkin, Bronwyn Gray, Lisa J. Wyeth, M. Eccles, E. Macaulay","doi":"10.1101/mcs.a006182","DOIUrl":"https://doi.org/10.1101/mcs.a006182","url":null,"abstract":"Tuberous sclerosis complex (TSC) is an inheritable disorder characterized by the formation of benign yet disorganized tumors in multiple organ systems. Germline mutations in the TSC1 (hamartin) or more frequently TSC2 (tuberin) genes are causative for TSC. The malignant manifestations of TSC, pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML), may also occur as independent sporadic perivascular epithelial cell tumor (PEComa) characterized by somatic TSC2 mutations. Thus, discerning TSC from the copresentation of sporadic LAM and sporadic AML may be obscured in TSC patients lacking additional features. In this report, we present a case study on a single patient initially reported to have sporadic LAM and a mucinous duodenal adenocarcinoma deficient in DNA mismatch repair proteins. Moreover, the patient had a history of Wilms’ tumor, which was reclassified as AML following the LAM diagnosis. Therefore, we investigated the origins and relatedness of these tumors. Using germline whole-genome sequencing, we identified a premature truncation in one of the patient's TSC2 alleles. Using immunohistochemistry, loss of tuberin expression was observed in AML and LAM tissue. However, no evidence of a somatic loss of heterozygosity or DNA methylation epimutations was observed at the TSC2 locus, suggesting alternate mechanisms may contribute to loss of the tumor suppressor protein. In the mucinous duodenal adenocarcinoma, no causative mutations were found in the DNA mismatch repair genes MLH1, MSH2, MSH6, or PMS2. Rather, clonal deconvolution analyses were used to identify mutations contributing to pathogenesis. This report highlights both the utility of using multiple sequencing techniques and the complexity of interpreting the data in a clinical context.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"55 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89753306","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}
Hussein Alnajar, H. Ravichandran, André Figueiredo Rendeiro, Kentaro Ohara, Wael Al Zoughbi, J. Manohar, Noah Greco, M. Sigouros, Jesse M. Fox, Emily Muth, Samuel Angiuoli, B. Faltas, M. Shusterman, C. Sternberg, O. Elemento, J. Mosquera
Sarcomatoid urothelial carcinoma (SUC) is a rare subtype of urothelial carcinoma (UC) that typically presents at an advanced stage compared to more common variants of UC. Locally advanced and metastatic UC have a poor long-term survival following progression on first-line platinum-based chemotherapy. Antibodies directed against the programmed cell death 1 protein (PD-1) or its ligand (PD-L1) are now approved to be used in these scenarios. The need for reliable biomarkers for treatment stratification is still under research. Here, we present a novel case report of the first Imaging Mass Cytometry (IMC) analysis done in SUC to investigate the immune cell repertoire and PD-L1 expression in a patient who presented with metastatic SUC and experienced a prolonged response to the anti-PD1 immune checkpoint inhibitor pembrolizumab after progression on first-line chemotherapy. This case report provides an important platform for translating these findings to a larger cohort of UC and UC variants.
{"title":"Tumor-immune microenvironment revealed by Imaging Mass Cytometry in a metastatic sarcomatoid urothelial carcinoma with a prolonged response to pembrolizumab","authors":"Hussein Alnajar, H. Ravichandran, André Figueiredo Rendeiro, Kentaro Ohara, Wael Al Zoughbi, J. Manohar, Noah Greco, M. Sigouros, Jesse M. Fox, Emily Muth, Samuel Angiuoli, B. Faltas, M. Shusterman, C. Sternberg, O. Elemento, J. Mosquera","doi":"10.1101/mcs.a006151","DOIUrl":"https://doi.org/10.1101/mcs.a006151","url":null,"abstract":"Sarcomatoid urothelial carcinoma (SUC) is a rare subtype of urothelial carcinoma (UC) that typically presents at an advanced stage compared to more common variants of UC. Locally advanced and metastatic UC have a poor long-term survival following progression on first-line platinum-based chemotherapy. Antibodies directed against the programmed cell death 1 protein (PD-1) or its ligand (PD-L1) are now approved to be used in these scenarios. The need for reliable biomarkers for treatment stratification is still under research. Here, we present a novel case report of the first Imaging Mass Cytometry (IMC) analysis done in SUC to investigate the immune cell repertoire and PD-L1 expression in a patient who presented with metastatic SUC and experienced a prolonged response to the anti-PD1 immune checkpoint inhibitor pembrolizumab after progression on first-line chemotherapy. This case report provides an important platform for translating these findings to a larger cohort of UC and UC variants.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"25 2 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80383460","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}
The increase in sequencing capacity, reduction in costs, and national and international coordinated efforts have led to the widespread introduction of next-generation sequencing (NGS) technologies in patient care. More generally, human genetics and genomic medicine are gaining importance for more and more patients. Some communities are already discussing the prospect of sequencing each individual's genome at time of birth. Together with digital health records, this shall enable individualized treatments and preventive measures, so-called precision medicine. A central step in this process is the identification of disease causal mutations or variant combinations that make us more susceptible for diseases. Although various technological advances have improved the identification of genetic alterations, the interpretation and ranking of the identified variants remains a major challenge. Based on our knowledge of molecular processes or previously identified disease variants, we can identify potentially functional genetic variants and, using different lines of evidence, we are sometimes able to demonstrate their pathogenicity directly. However, the vast majority of variants are classified as variants of uncertain clinical significance (VUSs) with not enough experimental evidence to determine their pathogenicity. In these cases, computational methods may be used to improve the prioritization and an increasing toolbox of experimental methods is emerging that can be used to assay the molecular effects of VUSs. Here, we discuss how computational and experimental methods can be used to create catalogs of variant effects for a variety of molecular and cellular phenotypes. We discuss the prospects of integrating large-scale functional data with machine learning and clinical knowledge for the development of accurate pathogenicity predictions for clinical applications.
{"title":"Computational and experimental methods for classifying variants of unknown clinical significance","authors":"M. Spielmann, Martin Kircher","doi":"10.1101/mcs.a006196","DOIUrl":"https://doi.org/10.1101/mcs.a006196","url":null,"abstract":"The increase in sequencing capacity, reduction in costs, and national and international coordinated efforts have led to the widespread introduction of next-generation sequencing (NGS) technologies in patient care. More generally, human genetics and genomic medicine are gaining importance for more and more patients. Some communities are already discussing the prospect of sequencing each individual's genome at time of birth. Together with digital health records, this shall enable individualized treatments and preventive measures, so-called precision medicine. A central step in this process is the identification of disease causal mutations or variant combinations that make us more susceptible for diseases. Although various technological advances have improved the identification of genetic alterations, the interpretation and ranking of the identified variants remains a major challenge. Based on our knowledge of molecular processes or previously identified disease variants, we can identify potentially functional genetic variants and, using different lines of evidence, we are sometimes able to demonstrate their pathogenicity directly. However, the vast majority of variants are classified as variants of uncertain clinical significance (VUSs) with not enough experimental evidence to determine their pathogenicity. In these cases, computational methods may be used to improve the prioritization and an increasing toolbox of experimental methods is emerging that can be used to assay the molecular effects of VUSs. Here, we discuss how computational and experimental methods can be used to create catalogs of variant effects for a variety of molecular and cellular phenotypes. We discuss the prospects of integrating large-scale functional data with machine learning and clinical knowledge for the development of accurate pathogenicity predictions for clinical applications.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"14 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91143790","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}
Hannah N. Bell, Chandan Kumar-Sinha, R. Mannan, D. Zakalik, Yuping Zhang, R. Mehra, Deepak V Jagtap, S. Dhanasekaran, U. Vaishampayan
Metastatic renal cell carcinoma (RCC) remains an incurable malignancy, despite recent advances in systemic therapies. Genetic syndromes associated with kidney cancer account for only 5%–8% of all diagnosed kidney malignancies, and genetic predispositions to kidney cancer predisposition are still being studied. Genomic testing for kidney cancer is useful for disease molecular subtyping but provides minimal therapeutic information. Understanding how aberrations drive RCC development and how their contextual influences, such as chromosome loss, genome instability, and DNA methylation changes, may alter therapeutic response is of importance. We report the case of a 36-yr-old female with aggressive, metastatic RCC and a significant family history of cancer, including RCC. This patient harbors a novel, pathogenic, germline ATM mutation along with a rare germline variant of unknown significance in the BAP1 gene. In addition, somatic loss of heterozygosity (LOH) in BAP1 and ATM genes, somatic mutation and LOH in the VHL gene, copy losses in Chromosomes 9p and 14, and genome instability are also noted in the tumor, potentially dictating this patient's aggressive clinical course. Further investigation is warranted to evaluate the association of ATM and BAP1 germline mutations with increased risk of RCC and if these mutations should lead to enhanced and early screening.
{"title":"Pathogenic ATM and BAP1 germline mutations in a case of early-onset, familial sarcomatoid renal cancer","authors":"Hannah N. Bell, Chandan Kumar-Sinha, R. Mannan, D. Zakalik, Yuping Zhang, R. Mehra, Deepak V Jagtap, S. Dhanasekaran, U. Vaishampayan","doi":"10.1101/mcs.a006203","DOIUrl":"https://doi.org/10.1101/mcs.a006203","url":null,"abstract":"Metastatic renal cell carcinoma (RCC) remains an incurable malignancy, despite recent advances in systemic therapies. Genetic syndromes associated with kidney cancer account for only 5%–8% of all diagnosed kidney malignancies, and genetic predispositions to kidney cancer predisposition are still being studied. Genomic testing for kidney cancer is useful for disease molecular subtyping but provides minimal therapeutic information. Understanding how aberrations drive RCC development and how their contextual influences, such as chromosome loss, genome instability, and DNA methylation changes, may alter therapeutic response is of importance. We report the case of a 36-yr-old female with aggressive, metastatic RCC and a significant family history of cancer, including RCC. This patient harbors a novel, pathogenic, germline ATM mutation along with a rare germline variant of unknown significance in the BAP1 gene. In addition, somatic loss of heterozygosity (LOH) in BAP1 and ATM genes, somatic mutation and LOH in the VHL gene, copy losses in Chromosomes 9p and 14, and genome instability are also noted in the tumor, potentially dictating this patient's aggressive clinical course. Further investigation is warranted to evaluate the association of ATM and BAP1 germline mutations with increased risk of RCC and if these mutations should lead to enhanced and early screening.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"125 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73341906","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}
J. Lavoie, V. Csizmok, L. Williamson, Luka Culibrk, G. Wang, M. Marra, J. Laskin, Steven J. M. Jones, D. Renouf, C. Kollmannsberger
Adrenocortical cancer (ACC) is a rare cancer of the adrenal gland. Several driver mutations have been identified in both primary and metastatic ACCs, but the therapeutic options are still limited. We performed whole-genome and transcriptome sequencing on seven patients with metastatic ACC. Integrative analysis of mutations, RNA expression changes, mutation signature, and homologous recombination deficiency (HRD) analysis was performed. Mutations affecting CTNNB1 and TP53 and frequent loss of heterozygosity (LOH) events were observed in our cohort. Alterations affecting genes involved in cell cycle (RB1, CDKN2A, CDKN2B), DNA repair pathways (MUTYH, BRCA2, ATM, RAD52, MLH1, MSH6), and telomere maintenance (TERF2 and TERT) consisting of somatic and germline mutations, structural variants, and expression outliers were also observed. HRDetect, which aggregates six HRD-associated mutation signatures, identified a subset of cases as HRD. Genomic alterations affecting genes involved in epigenetic regulation were also identified, including structural variants (SWI/SNF genes and histone methyltransferases), and copy gains and concurrent high expression of KDM5A, which may contribute to epigenomic deregulation. Findings from this study highlight HRD and epigenomic pathways as potential therapeutic targets and suggest a subgroup of patients may benefit from a diverse array of molecularly targeted therapies in ACC, a rare disease in urgent need of therapeutic strategies.
{"title":"Whole-genome and transcriptome analysis of advanced adrenocortical cancer highlights multiple alterations affecting epigenome and DNA repair pathways","authors":"J. Lavoie, V. Csizmok, L. Williamson, Luka Culibrk, G. Wang, M. Marra, J. Laskin, Steven J. M. Jones, D. Renouf, C. Kollmannsberger","doi":"10.1101/mcs.a006148","DOIUrl":"https://doi.org/10.1101/mcs.a006148","url":null,"abstract":"Adrenocortical cancer (ACC) is a rare cancer of the adrenal gland. Several driver mutations have been identified in both primary and metastatic ACCs, but the therapeutic options are still limited. We performed whole-genome and transcriptome sequencing on seven patients with metastatic ACC. Integrative analysis of mutations, RNA expression changes, mutation signature, and homologous recombination deficiency (HRD) analysis was performed. Mutations affecting CTNNB1 and TP53 and frequent loss of heterozygosity (LOH) events were observed in our cohort. Alterations affecting genes involved in cell cycle (RB1, CDKN2A, CDKN2B), DNA repair pathways (MUTYH, BRCA2, ATM, RAD52, MLH1, MSH6), and telomere maintenance (TERF2 and TERT) consisting of somatic and germline mutations, structural variants, and expression outliers were also observed. HRDetect, which aggregates six HRD-associated mutation signatures, identified a subset of cases as HRD. Genomic alterations affecting genes involved in epigenetic regulation were also identified, including structural variants (SWI/SNF genes and histone methyltransferases), and copy gains and concurrent high expression of KDM5A, which may contribute to epigenomic deregulation. Findings from this study highlight HRD and epigenomic pathways as potential therapeutic targets and suggest a subgroup of patients may benefit from a diverse array of molecularly targeted therapies in ACC, a rare disease in urgent need of therapeutic strategies.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"54 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77490233","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}
Andri Miltiadous, P. Demetriou, M. Kyriakou, P. Gerasimou, George Herodotou, Agathi Elpidoforou, Yiannos Kyprianou, M. Iacovou, J. Chi, P. Costeas, G. Tanteles
Poland syndrome is a rare developmental disorder characterized by unilateral, complete or partial, absence of the pectoralis major (and often minor) muscle, accompanied with ipsilateral hand malformations. To date, no clear genetic cause has been associated with Poland syndrome, although familial cases have been reported. We report the employment of trio exome investigation and the identification of a heterozygous de novo pathogenic variant in the SFMBT1 gene, a transcription factor associated with transcriptional repression during development, in a 14-yr-old boy with Poland syndrome. We further demonstrate by means of cDNA sequencing and western blot analysis that this variant results in SFMBT1 exon 10 skipping and a lower concentration of the SFMBT1 wild-type protein. To our knowledge, the heterozygous pathogenic SFMBT1 variant identified in association with this condition is novel as it has not been elsewhere described in the literature and it can be incorporated to the limited reported cases published.
{"title":"A de novo SFMBT1 pathogenic variant identified in a boy with Poland syndrome","authors":"Andri Miltiadous, P. Demetriou, M. Kyriakou, P. Gerasimou, George Herodotou, Agathi Elpidoforou, Yiannos Kyprianou, M. Iacovou, J. Chi, P. Costeas, G. Tanteles","doi":"10.1101/mcs.a006168","DOIUrl":"https://doi.org/10.1101/mcs.a006168","url":null,"abstract":"Poland syndrome is a rare developmental disorder characterized by unilateral, complete or partial, absence of the pectoralis major (and often minor) muscle, accompanied with ipsilateral hand malformations. To date, no clear genetic cause has been associated with Poland syndrome, although familial cases have been reported. We report the employment of trio exome investigation and the identification of a heterozygous de novo pathogenic variant in the SFMBT1 gene, a transcription factor associated with transcriptional repression during development, in a 14-yr-old boy with Poland syndrome. We further demonstrate by means of cDNA sequencing and western blot analysis that this variant results in SFMBT1 exon 10 skipping and a lower concentration of the SFMBT1 wild-type protein. To our knowledge, the heterozygous pathogenic SFMBT1 variant identified in association with this condition is novel as it has not been elsewhere described in the literature and it can be incorporated to the limited reported cases published.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"7 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84248603","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 : 2022-03-24Print Date: 2022-02-01DOI: 10.1101/mcs.a006179
Minh G Nguyen, Lauren Tronick, Faraz Modirian, Rebecca Mardach, Aaron D Besterman
Cobalamin C disease is the most common complementation class of cobalamin disorders. Here, we present a case of a 14-yr-old male with early-onset cblC disease and autism spectrum disorder (ASD) admitted to our inpatient medical service for behavioral decompensation. We use this case to highlight key aspects of the neurodevelopmental and neuropsychiatric disorders associated with cblC disease. By incorporating a comprehensive review of existing literature, we highlight salient domains of psychological impairment in cblC disease, discuss the full range of neuropsychiatric presentations, and review clinical management implications unique to cblC disease.
{"title":"Neurodevelopmental and neuropsychiatric disorders in cobalamin C disease: a case report and review of the literature.","authors":"Minh G Nguyen, Lauren Tronick, Faraz Modirian, Rebecca Mardach, Aaron D Besterman","doi":"10.1101/mcs.a006179","DOIUrl":"https://doi.org/10.1101/mcs.a006179","url":null,"abstract":"<p><p>Cobalamin C disease is the most common complementation class of cobalamin disorders. Here, we present a case of a 14-yr-old male with early-onset cblC disease and autism spectrum disorder (ASD) admitted to our inpatient medical service for behavioral decompensation. We use this case to highlight key aspects of the neurodevelopmental and neuropsychiatric disorders associated with cblC disease. By incorporating a comprehensive review of existing literature, we highlight salient domains of psychological impairment in cblC disease, discuss the full range of neuropsychiatric presentations, and review clinical management implications unique to cblC disease.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/69/26/MCS006179Ngu.PMC8958916.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39741449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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