Cold Spring Harbor Molecular Case Studies最新文献_第8页

Corrigendum: Functional impact and targetability of PI3KCA, GNAS, and PTEN mutations in a spindle cell rhabdomyosarcoma with MYOD1 L122R mutation. 更正:PI3KCA、GNAS和PTEN突变对MYOD1 L122R突变梭形细胞横纹肌肉瘤的功能影响和靶向性。

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-04-01 DOI: 10.1101/mcs.a006216

Florence Choo, I. Odintsov, K. Nusser, K. Nicholson, Lara E Davis, C. Corless, L. Stork, R. Somwar, M. Ladanyi, Jessica L. Davis, M. Davare

引用次数: 0

Prolonged response to checkpoint inhibitor therapy in two metastatic mucoepidermoid salivary gland carcinoma cases: a research report 2例转移性黏液表皮样唾液腺癌对检查点抑制剂治疗的延长反应:一项研究报告

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-04-01 DOI: 10.1101/mcs.a006189

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

{"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}

引用次数: 3

Tuberous sclerosis complex: a complex case 结节性硬化症:一个复杂的病例

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-04-01 DOI: 10.1101/mcs.a006182

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

{"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}

引用次数: 1

The utility of cerebrospinal fluid–derived cell-free DNA in molecular diagnostics for the PIK3CA-related megalencephaly-capillary malformation (MCAP) syndrome: a case report 脑脊液来源的无细胞DNA在pik3ca相关的巨脑-毛细血管畸形(MCAP)综合征分子诊断中的应用:一个病例报告

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-04-01 DOI: 10.1101/mcs.a006188

Wei-Liang Chen, E. Pao, James Owens, I. Glass, C. Pritchard, Brain H Shirts, C. Lockwood, G. Mirzaa

{"title":"The utility of cerebrospinal fluid–derived cell-free DNA in molecular diagnostics for the PIK3CA-related megalencephaly-capillary malformation (MCAP) syndrome: a case report","authors":"Wei-Liang Chen, E. Pao, James Owens, I. Glass, C. Pritchard, Brain H Shirts, C. Lockwood, G. Mirzaa","doi":"10.1101/mcs.a006188","DOIUrl":"https://doi.org/10.1101/mcs.a006188","url":null,"abstract":"The megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth disorder caused by mosaic gain-of-function variants in PIK3CA. It is characterized by megalencephaly or hemimegalencephaly, vascular malformations, somatic overgrowth, among other features. Epilepsy is commonly associated with MCAP, and a subset of individuals have cortical malformations requiring resective epilepsy surgery. Like other mosaic disorders, establishing a molecular diagnosis is largely achieved by screening lesional tissues (such as brain or skin), with a low diagnostic yield from peripheral tissues (such as blood). Therefore, in individuals with MCAP in whom lesional tissues are scarce or unavailable or those ineligible for epilepsy surgery, establishing a molecular diagnosis can be challenging. Here we report on the utility of cerebrospinal fluid (CSF)-derived cfDNA for the molecular diagnosis of an individual with MCAP syndrome harboring a mosaic PIK3CA variant (c.3139C > T, p.His1047Tyr). The proband presented with asymmetric megalencephaly without significant dysgyria. He did not have refractory epilepsy and was therefore not a candidate for epilepsy surgery. However, he developed diffuse large B-cell lymphoma (DLBCL) in late childhood, with four CSF samples obtained via lumbar puncture for cancer staging during which one sample was collected for cfDNA extraction and sequencing. PIK3CA variant allele fractions in CSF cell-free DNA (cfDNA), skin fibroblasts, and peripheral blood were 3.08%, 37.31%, and 2.04%, respectively. This report illustrates the utility of CSF-derived cfDNA in MCAP syndrome. Minimally invasive–based molecular diagnostic approaches utilizing cfDNA not only facilitate accurate genetic diagnosis but also have important therapeutic implications for individuals with refractory epilepsy as repurposed PI3K-AKT-MTOR pathway-inhibitors become more widely available.","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":"120 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77423492","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}

引用次数: 8

Tumor-immune microenvironment revealed by Imaging Mass Cytometry in a metastatic sarcomatoid urothelial carcinoma with a prolonged response to pembrolizumab 对派姆单抗有长期反应的转移性肉瘤样尿路上皮癌的肿瘤免疫微环境成像细胞术显示

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-04-01 DOI: 10.1101/mcs.a006151

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

{"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}

引用次数: 5

Computational and experimental methods for classifying variants of unknown clinical significance 未知临床意义变异分类的计算和实验方法

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-04-01 DOI: 10.1101/mcs.a006196

M. Spielmann, Martin Kircher

{"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}

引用次数: 7

Pathogenic ATM and BAP1 germline mutations in a case of early-onset, familial sarcomatoid renal cancer 早发性家族性肉瘤样肾癌的病原性ATM和BAP1种系突变1例

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-04-01 DOI: 10.1101/mcs.a006203

Hannah N. Bell, Chandan Kumar-Sinha, R. Mannan, D. Zakalik, Yuping Zhang, R. Mehra, Deepak V Jagtap, S. Dhanasekaran, U. Vaishampayan

{"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}

引用次数: 4

Whole-genome and transcriptome analysis of advanced adrenocortical cancer highlights multiple alterations affecting epigenome and DNA repair pathways 晚期肾上腺皮质癌的全基因组和转录组分析强调了影响表观基因组和DNA修复途径的多种改变

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-04-01 DOI: 10.1101/mcs.a006148

J. Lavoie, V. Csizmok, L. Williamson, Luka Culibrk, G. Wang, M. Marra, J. Laskin, Steven J. M. Jones, D. Renouf, C. Kollmannsberger

{"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}

引用次数: 3

A de novo SFMBT1 pathogenic variant identified in a boy with Poland syndrome 在一名波兰综合征男孩中发现一种新的SFMBT1致病变异

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-04-01 DOI: 10.1101/mcs.a006168

Andri Miltiadous, P. Demetriou, M. Kyriakou, P. Gerasimou, George Herodotou, Agathi Elpidoforou, Yiannos Kyprianou, M. Iacovou, J. Chi, P. Costeas, G. Tanteles

引用次数: 0

Neurodevelopmental and neuropsychiatric disorders in cobalamin C disease: a case report and review of the literature. 钴胺素C病的神经发育和神经精神障碍:一例报告和文献回顾。

IF 1.8

Cold Spring Harbor Molecular Case Studies Pub Date : 2022-03-24 Print Date: 2022-02-01 DOI: 10.1101/mcs.a006179

Minh G Nguyen, Lauren Tronick, Faraz Modirian, Rebecca Mardach, Aaron D Besterman

引用次数: 1