title: Sequence and expression variations in 23 genes involved in mitochondrial and non-mitochondrial apoptotic pathways and risk of oral leukoplakia and cancer.
abstract: Oral cancer is usually preceded by pre-cancerous lesion and related to tobacco abuse. Tobacco carcinogens damage DNA and cells harboring such damaged DNA normally undergo apoptotic death, but cancer cells are exceptionally resistant to apoptosis. Here we studied association between sequence and expression variations in apoptotic pathway genes and risk of oral cancer and precancer. Ninety nine tag SNPs in 23 genes, involved in mitochondrial and non-mitochondrial apoptotic pathways, were genotyped in 525 cancer and 253 leukoplakia patients and 538 healthy controls using Illumina Golden Gate assay. Six SNPs (rs1473418 at BCL2; rs1950252 at BCL2L2; rs8190315 at BID; rs511044 at CASP1; rs2227310 at CASP7 and rs13010627 at CASP10) significantly modified risk of oral cancer but SNPs only at BCL2, CASP1and CASP10 modulated risk of leukoplakia. Combination of SNPs showed a steep increase in risk of cancer with increase in "effective" number of risk alleles. In silico analysis of published data set and our unpublished RNAseq data suggest that change in expression of BID and CASP7 may have affected risk of cancer. In conclusion, three SNPs, rs1473418 in BCL2, rs1950252 in BCL2L2 and rs511044 in CASP1, are being implicated for the first time in oral cancer. Since SNPs at BCL2, CASP1 and CASP10 modulated risk of both leukoplakia and cancer, so, they should be studied in more details for possible biomarkers in transition of leukoplakia to cancer. This study also implies importance of mitochondrial apoptotic pathway gene (such as BCL2) in progression of leukoplakia to oral cancer.
authors.affiliation: Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
authors.forename: Sayantan
authors.initials: S
authors.lastname: Datta
authors.affiliation: Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
authors.forename: Anindita
authors.initials: A
authors.lastname: Ray
authors.affiliation: Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
authors.forename: Richa
authors.initials: R
authors.lastname: Singh
authors.affiliation: Molecular and Human Genetics Division, Indian Institute of Chemical Biology, CSIR, Kolkata, India.
authors.forename: Pinaki
authors.initials: P
authors.lastname: Mondal
authors.affiliation: National Institute of Biomedical Genomics, Kalyani, West Bengal, India.
authors.forename: Analabha
authors.initials: A
authors.lastname: Basu
authors.affiliation: Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
authors.forename: Navonil
authors.initials: N
authors.lastname: De Sarkar
authors.affiliation: Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
authors.forename: Mousumi
authors.initials: M
authors.lastname: Majumder
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, India.
authors.forename: Guruparasad
authors.initials: G
authors.lastname: Maiti
authors.affiliation: Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, CSIR, Delhi, India.
authors.forename: Aradhita
authors.initials: A
authors.lastname: Baral
authors.affiliation: Department of Anthropology, Vinoba Bhave University, Hazaribagh, Jharkhand, India.
authors.forename: Ganga Nath
authors.initials: GN
authors.lastname: Jha
authors.affiliation: Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
authors.forename: Indranil
authors.initials: I
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, India.
authors.forename: Chinmay
authors.initials: C
authors.lastname: Panda
authors.affiliation: Proteomics and Structural Biology Unit, Institute of Genomics and Integrative Biology, CSIR, Delhi, India.
authors.forename: Shantanu
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Molecular and Human Genetics Division, Indian Institute of Chemical Biology, CSIR, Kolkata, India.
authors.forename: Susanta
authors.initials: S
authors.lastname: Roychoudhury
authors.affiliation: Human Genetics Unit, Indian Statistical Institute, Kolkata, India. Electronic address: broy@isical.ac.in.
authors.forename: Bidyut
authors.initials: B
authors.lastname: Roy
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D007972:Leukoplakia, Oral / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011230:Precancerous Conditions / Q000235:genetics*; D018570:Risk Assessment; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*
keywords: Apoptotic pathway genes; Expression; Leukoplakia; Oral cancer; Risk; SNPs