ABSTRACT
Background@#The genetic landscape of intestinal (INT) and pancreatobiliary (PB) type ampullary cancer (AC) has been evolving with distinct as well as overlapping molecular profiles. @*Methods@#We performed whole-exome sequencing in 37 cases of AC to identify the targetable molecular profiles of INT and PB tumors. Paired tumor-normal sequencing was performed on the HiSeq 2500 Illumina platform. @*Results@#There were 22 INT, 13 PB, and two cases of mixed differentiation of AC that exhibited a total of 1,263 somatic variants in 112 genes (2–257 variants/case) with 183 somatic deleterious variants. INT showed variations in 78 genes (1–31/case), while PB showed variations in 51 genes (1–29/case). Targetable mutations involving one or more major pathways were found in 86.5% of all ACs. Mutations in APC, CTNNB1, SMAD4, KMT2, EPHA, ERBB, and Notch genes were more frequent in INT tumors, while chromatin remodeling complex mutations were frequent in PB tumors. In the major signaling pathways, the phosphoinositide 3-kinase (PI3)/AKT and RAS/mitogen-activated protein kinase (MAPK) pathways were significantly mutated in 70% of cases (82% INT, 46% PB, p = .023), with PI3/AKT mutation being more frequent in INT and RAS/MAPK in PB tumors. Tumor mutation burden was low in both differentiation types, with 1.6/Mb in INT and 0.8/Mb in PB types (p =.217). @*Conclusions@#The exome data suggest that INT types are genetically more unstable than PB and involve mutations in tumor suppressors, oncogenes, transcription factors, and chromatin remodeling genes. The spectra of the genetic profiles of INT and PB types suggested primary targeting of PI3/AKT in INT and RAS/RAF and PI3/AKT pathways in PB carcinomas.
ABSTRACT
Background@#The genetic landscape of intestinal (INT) and pancreatobiliary (PB) type ampullary cancer (AC) has been evolving with distinct as well as overlapping molecular profiles. @*Methods@#We performed whole-exome sequencing in 37 cases of AC to identify the targetable molecular profiles of INT and PB tumors. Paired tumor-normal sequencing was performed on the HiSeq 2500 Illumina platform. @*Results@#There were 22 INT, 13 PB, and two cases of mixed differentiation of AC that exhibited a total of 1,263 somatic variants in 112 genes (2–257 variants/case) with 183 somatic deleterious variants. INT showed variations in 78 genes (1–31/case), while PB showed variations in 51 genes (1–29/case). Targetable mutations involving one or more major pathways were found in 86.5% of all ACs. Mutations in APC, CTNNB1, SMAD4, KMT2, EPHA, ERBB, and Notch genes were more frequent in INT tumors, while chromatin remodeling complex mutations were frequent in PB tumors. In the major signaling pathways, the phosphoinositide 3-kinase (PI3)/AKT and RAS/mitogen-activated protein kinase (MAPK) pathways were significantly mutated in 70% of cases (82% INT, 46% PB, p = .023), with PI3/AKT mutation being more frequent in INT and RAS/MAPK in PB tumors. Tumor mutation burden was low in both differentiation types, with 1.6/Mb in INT and 0.8/Mb in PB types (p =.217). @*Conclusions@#The exome data suggest that INT types are genetically more unstable than PB and involve mutations in tumor suppressors, oncogenes, transcription factors, and chromatin remodeling genes. The spectra of the genetic profiles of INT and PB types suggested primary targeting of PI3/AKT in INT and RAS/RAF and PI3/AKT pathways in PB carcinomas.
ABSTRACT
The present report is a review article on various aspects of Hepatitis C virus (HCV) genotypes and their subtypes. HCV has six genotypes and several subtypes showing important epidemiological and clinical implications. The information based on previous studies and presented through this article highlight the origin, classification and causes of genetic diversity, global status, detection assays, pathogenicity and response to treatment of HCV-genotypes. The six genotypes differ in 30-35% of nucleotide sites over the complete genome. The difference in genomic composition of sub-types of genotype is usually found to be 20-25%. The variability remains more frequent in structural genes as compared to non-structural or untranslated genes. Both genotypes and their sub-types show a varied prevalence globally and raise several issues related to their transmission and treatment of HCV-infection. All this information has a great significance while planning future strategies for eradication and therapeutic management of HCV. In addition, these reports produce a further scope for more studies to unravel the mystery behind HCV-genotypes and formulate guidelines to resolve this public health problem noted worldwide.
