title: Association of DNA repair and cell cycle gene variations with breast cancer risk in Northeast Indian population: a multiple interaction analysis.
abstract: Polymorphisms in DNA repair and cell cycle genes contribute to increased breast cancer (BC) risk. Their association and interaction in relation to betel quid and tobacco chewing habits need exhaustive multi-analytical investigation to explain BC predisposition due to DNA damage. Polymorphism in TP53-72Arg>Pro, RAD51-135G>C, BRCA2, and CCND1-G870A were examined in 204 BC cases and 217 controls from Northeast Indian population. Multifaceted analytic approaches were used to explore relationships between polymorphisms, tobacco history, and BC susceptibility. Betel quid chewing was identified as the predominant risk factor. CCND-AA and dominant model showed protection towards BC in betel quid chewer (BQC) [(0.28 (0.10-0.77), 0.01 and 0.32 (0.12-0.81), 0.01)] and non-betel quid chewers (NBQC) [(0.26 (0.09-0.78), 0.01 and 0.37 (0.16-0.87), 0.02)]. TP53-Pro/Pro genotype showed protection towards BC in NBQC (0.29 (0.10-0.81), p=0.01) and (0.51 (0.32-0.80), p=0.003, respectively). RAD51-C allele was associated with BC risk (2.03 (1.26-3.30) 0.002) in BQC. Two BQC cases had BRCA2 8415G>T:K2729N mutation in Exon18. MDR analysis showed best four locus model with TBA 0.6765 (0.005) and CVC of 10/10 in NBQC. Interaction diagram concurred the interactions between TP53 and RAD51 (1.32 %) with independent effect (1.89 %) of CCND1in NBQC. In CART analysis, BQC with CCND1 GG genotype were at risk (OR=33.0; 95 % CI=6.08-179.07), p<0.001) followed by combination of BQC, CCND1, No-Smk, and Alc (OR=42.00; 95 % CI=5.11-345.11, p<0.001). Risk was also observed in BQC, CCND1, No-Smk, Non-Alc, and TP53 combination (OR=14.84; 95 % CI=3.13-70.34, p<0.001) and BQC, CCND1, No-Smk, Non-Alc, TP53 (OR=9.40; 95 % CI=1.99-44.34, p<0.001). NBQC group showed risk with combination of NBQC and TP53 (OR=5.54; 95 % CI=1.11-27.42, p=0.03). Genetic variants in DNA repair and cell cycle genes contribute to BC risk through gene-gene and gene-environmental interactions.
authors.affiliation: National Institute of Pathology, ICMR, Safdarjung Hospital Campus, New Delhi, 110029, India.
authors.forename: Mishi Kaushal
authors.initials: MK
authors.lastname: Wasson
authors.forename: Pradeep Singh
authors.initials: PS
authors.lastname: Chauhan
authors.forename: L C
authors.initials: LC
authors.lastname: Singh
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Katara
authors.forename: Jagannath
authors.initials: J
authors.lastname: Dev Sharma
authors.forename: Eric
authors.initials: E
authors.lastname: Zomawia
authors.forename: Amal
authors.initials: A
authors.lastname: Kataki
authors.forename: Sujala
authors.initials: S
authors.lastname: Kapur
authors.forename: Sunita
authors.initials: S
authors.lastname: Saxena
mesh_terms: D000328:Adult; D000368:Aged; D001114:Areca / Q000009:adverse effects; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D019277:Entropy; D005260:Female; D024522:Genes, BRCA2; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051135:Rad51 Recombinase / Q000235:genetics; D012306:Risk
chemical_list: C530104:CCND1 protein, human; D019938:Cyclin D1; D051135:Rad51 Recombinase