TMC-SNPdb: an Indian germline variant database derived from whole exome sequences

Abstract

Cancer is predominantly a somatic disease. A mutant allele present in a cancer cell genome is considered somatic when it’s absent in the paired normal genome along with public SNP databases. The current build of dbSNP, the most comprehensive public SNP database, however inadequately represents several non-European Caucasian populations, posing a limitation in cancer genomic analyses of data from these populations. We present the Tata Memorial Centre-SNP database (TMC-SNPdb), as the first open source, flexible, upgradable, and freely available SNP database (accessible through dbSNP build 149 and ANNOVAR)—representing 114 309 unique germline variants—generated from whole exome data of 62 normal samples derived from cancer patients of Indian origin. The TMC-SNPdb is presented with a companion subtraction tool that can be executed with command line option or using an easy-to-use graphical user interface with the ability to deplete additional Indian population specific SNPs over and above dbSNP and 1000 Genomes databases. Using an institutional generated whole exome data set of 132 samples of Indian origin, we demonstrate that TMC-SNPdb could deplete 42, 33 and 28% false positive somatic events post dbSNP depletion in Indian origin tongue, gallbladder, and cervical cancer samples, respectively. Beyond cancer somatic analyses, we anticipate utility of the TMC-SNPdb in several Mendelian germline diseases. In addition to dbSNP build 149 and ANNOVAR, the TMC-SNPdb along with the subtraction tool is available for download in the public domain at the following:Database URL: http://www.actrec.gov.in/pi-webpages/AmitDutt/TMCSNP/TMCSNPdp.html

ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer

“…The variant analysis was performed as described previously. 26,27 MutSigCV v2.0 28 and IntOgen 29 were used for identification of the significantly mutated gene and p value ≤0.05 was considered as the threshold for significance. The variants were excluded if they were present in exclusively in dbSNP, TMC-SNPdb or both.…”

“…Also, we removed variants that were identified in all three databases -COSMIC (v68), 30 dbSNP (v142) 31 and TMC-SNPdb database. 27 The annotated cancer-associated variants were annotated using Oncotator (v1.1.6.0) 32 and restricted our further analysis to only coding variants. Intogen (https://www.intogen.org/ search) was used to calculate the significance of frequently mutated gene in our cohort.…”

ERBB2andKRASAlterations Mediate Response to EGFR Inhibitors in early stage Gallbladder Cancer

“…The variant analysis was performed as described previously (Chandrani et al, 2017;Upadhyay et al, 2016a). MutSigCV v2.0 (Lawrence et al, 2013) and IntOgen (Gonzalez-Perez et al, 2013) were used for identification of the significantly mutated gene and p value ≤0.05 was considered as the threshold for significance.…”

“…The variants were excluded if they were present in exclusively in dbSNP, TMC-SNPdb or both. Also, we removed variants that were identified in all three databases -COSMIC (v68) (Forbes et al, 2008), dbSNP (v142) (Sherry et al, 2001) and TMC-SNPdb database (Upadhyay et al, 2016a).…”

INDEX-db: The Indian Exome Reference database (Phase-I)

“…A comprehensive reference variation map, established from a clinically normal cohort that is representative of this population, will be of great benefit. There have been several reports of cataloging genetic variation from the Indian population which have suggested presence of distinct genome level sub-structuring, and its probable impact on disease Biology (Narang et al, 2010;Rustagi et al, 2017;The HUGO Pan-Asian SNP Consortium, 2011;The Indian Genome Variation Consortium, 2005;Upadhyay et al, 2016). However, there are a few limitations to these studies -a) these predominantly catalogue germline variants; b) are designed to capture high frequency common variations, which is sufficient for deciphering population structure, but lack information on rare mutations, CNVs and disallow haplotype analysis; and, importantly c) are not available as open access reference map.…”