Saurabh Yadav1,2, Navonil DE Sarkar3, Niraj Kumari4, Narendra Krishnani4, Ashok Kumar2, Balraj Mittal5,6. 1. Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India. 2. Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India. 3. Human Biology Division, Fred Hutchinson Cancer Research Centre, Seattle, WA, U.S.A. 4. Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India. 5. Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India balrajmittal@gmail.com. 6. Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, India.
Abstract
BACKGROUND: Gallbladder carcinoma (GBC) is a subtype of biliary tract malignancy with poor prognosis and high fatality rate. The present study was designed to uncover somatic and rare germline mutations in GBC to reveal the disease biology and understand the clinical importance of mutation profile in terms of prognostics and actionability. MATERIALS AND METHODS: We performed ultra-deep sequencing across 409 cancer-related genes in 11 GBC patients of North-Indian descent. NGS data analysis was performed using Ion Reporter and several other publicly available resources and databases. RESULTS: We identified 184 nonsynonymous somatic and 60 rare germline mutations in bona-fide cancer drivers such as SMAD family member 4 (SMAD4), lysine methyltransferase 2C (KMT2C), and tumor protein p53 (TP53). All the early-onset cases or hypermutated cases harbored mutation(s) in critical DNA-repair genes. Additionally, we detected 9 novel genes with high-impact somatic mutations in GBC. CONCLUSION: Our results indicated the significance of inherited rare germline mutations in DNA-repair pathway genes in addition to acquired somatic mutations in GB carcinogenesis. Copyright
BACKGROUND: Gallbladder carcinoma (GBC) is a subtype of biliary tract malignancy with poor prognosis and high fatality rate. The present study was designed to uncover somatic and rare germline mutations in GBC to reveal the disease biology and understand the clinical importance of mutation profile in terms of prognostics and actionability. MATERIALS AND METHODS: We performed ultra-deep sequencing across 409 cancer-related genes in 11 GBC patients of North-Indian descent. NGS data analysis was performed using Ion Reporter and several other publicly available resources and databases. RESULTS: We identified 184 nonsynonymous somatic and 60 rare germline mutations in bona-fide cancer drivers such as SMAD family member 4 (SMAD4), lysine methyltransferase 2C (KMT2C), and tumor protein p53 (TP53). All the early-onset cases or hypermutated cases harbored mutation(s) in critical DNA-repair genes. Additionally, we detected 9 novel genes with high-impact somatic mutations in GBC. CONCLUSION: Our results indicated the significance of inherited rare germline mutations in DNA-repair pathway genes in addition to acquired somatic mutations in GB carcinogenesis. Copyright
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