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Association of DNA repair and cell cycle gene variations with breast cancer risk in Northeast Indian population: a multiple interaction analysis

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Tumor Biology

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.

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Acknowledgments

This work was supported by funding given by the Indian Council of Medical Research (ICMR), New Delhi, India.

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Authors and Affiliations

  1. National Institute of Pathology, ICMR, Safdarjung Hospital Campus, New Delhi, 110029, India

    Mishi Kaushal Wasson, Pradeep Singh Chauhan, L. C. Singh, Sujala Kapur & Sunita Saxena

  2. National Jalma Institute of Leprosy and other Mycobacterial Diseases, ICMR, Agra, 282001, India

    Dheeraj Katara

  3. Dr. B. Borrooah Cancer Institute, Guwahati, India

    Jagannath Dev Sharma & Amal Kataki

  4. Civil Hospital, Aizwal, India

    Eric Zomawia

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  1. Mishi Kaushal Wasson
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  2. Pradeep Singh Chauhan
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Correspondence to Sunita Saxena.

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Supplementary Table 1

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Supplementary Table 2

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Supplementary Fig. 1

DHPLC analysis showing heteroduplex peaks and homoduplex peaks in Exon27 of BRCA2 gene. The polymorphic variant was identified as 10462A>G: I3412V by sequencing (JPEG 389 kb)

High Resolution Image (TIFF 359 kb)

Supplementary Fig. 2

DHPLC analysis showing heteroduplex homoduplex peaks in Exon18 of BRCA2 gene. The variant was identified as 8415G>T: K2729N in Exon18 of BRCA2 gene (JPEG 427 kb)

High Resolution Image (TIFF 469 kb)

Supplementary Fig. 3

DHPLC analysis of −26G>A polymorphism. Heteroduplex peak shows samples with GA genotype and homoduplex peaks shows samples with AA genotype. Sequencing analysis of samples with Exon 2 variants depicting GA heterozygous and AA homozygous genotype of BRCA2 gene. (JPEG 537 kb)

High Resolution Image (TIFF 518 kb)

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Wasson, M.K., Chauhan, P.S., Singh, L.C. et al. Association of DNA repair and cell cycle gene variations with breast cancer risk in Northeast Indian population: a multiple interaction analysis. Tumor Biol. 35, 5885–5894 (2014). https://doi.org/10.1007/s13277-014-1779-2

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  • DOI: https://doi.org/10.1007/s13277-014-1779-2

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