Browsing by Subject "Somatic mutation"

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    Hypoplastic Left Heart Syndrome Sequencing Reveals a Novel NOTCH1 Mutation in a Family with Single Ventricle Defects
    (Springer Nature, 2017-08) Durbin, Matthew D.; Cadar, Adrian G.; Williams, Charles H.; Guo, Yan; Bichell, David P.; Su, Yan Ru; Hong, Charles C.; Pediatrics, School of Medicine
    Hypoplastic left heart syndrome (HLHS) has been associated with germline mutations in 12 candidate genes and a recurrent somatic mutation in HAND1 gene. Using targeted and whole exome sequencing (WES) of heart tissue samples from HLHS patients, we sought to estimate the prevalence of somatic and germline mutations associated with HLHS. We performed Sanger sequencing of the HAND1 gene on 14 ventricular (9 LV and 5 RV) samples obtained from HLHS patients, and WES of 4 LV, 2 aortic, and 4 matched PBMC samples, analyzing for sequence discrepancy. We also screened for mutations in the 12 candidate genes implicated in HLHS. We found no somatic mutations in our HLHS cohort. However, we detected a novel germline frameshift/stop-gain mutation in NOTCH1 in a HLHS patient with a family history of both HLHS and hypoplastic right heart syndrome (HRHS). Our study, involving one of the first familial cases of single ventricle defects linked to a specific mutation, strengthens the association of NOTCH1 mutations with HLHS and suggests that the two morphologically distinct single ventricle conditions, HLHS and HRHS, may share a common molecular and cellular etiology. Finally, somatic mutations in the LV are an unlikely contributor to HLHS.
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    Multi-region Whole Exome Sequencing of Intraductal Papillary Mucinous Neoplasms Reveals Frequent Somatic KLF4 Mutations Predominantly in Low-Grade Regions
    (BMJ, 2021) Fujikura, Kohei; Hosoda, Waki; Felsenstein, Matthäus; Song, Qianqian; Reiter, Johannes G.; Zheng, Lily; Guthrie, Violeta Beleva; Rincon, Natalia; Molin, Marco Dal; Dudley, Jonathan; Cohen, Joshua D.; Wang, Pei; Fischer, Catherine G.; Braxton, Alicia M.; Noë, Michaël; Jongepier, Martine; Castillo, Carlos Fernández-del; Mino-Kenudson, Mari; Schmidt, C. Max; Yip-Schneider, Michele T.; Lawlor, Rita T.; Salvia, Roberto; Roberts, Nicholas J.; Thompson, Elizabeth D.; Karchin, Rachel; Lennon, Anne Marie; Jiao, Yuchen; Wood, Laura D.; Surgery, School of Medicine
    Objective: Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression. Design: We performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples. Results: Our multiregion whole exome sequencing identified KLF4, a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in KLF4 were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in KLF4 were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs. Conclusion: Hotspot mutations in KLF4 occur at high prevalence in IPMNs. Unique among pancreatic driver genes, KLF4 mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway.