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Predictive impact of genetic polymorphisms in DNA repair genes on susceptibility and therapeutic outcomes to colorectal cancer patients

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Tumor Biology

Abstract

Several hereditary syndromes characterized by defective DNA repair are associated with high risk of colorectal cancer (CRC). To explore whether common polymorphisms in DNA repair genes affect risk and prognosis of CRC, we evaluated the association between single nucleotide polymorphisms (SNPs) in XPG, XPC, and WRN gene and susceptibility of CRC, and clinical outcomes in a population-based case–control study. A total of 890 CRC cases and 910 controls recruited into the study provided a biologic sample. Individuals with variant genotypes of XPC Ala499Val appeared to be associated with the increased risk of CRC. WRN Cys1367Arg variants carriers showed an increased susceptibility for CRC. More importantly, the risk of CRC increased further in a combined analysis of multiple polymorphisms. Furthermore, stratified analyses revealed that XPG Arg1104His polymorphism was associated with tumor differentiation of CRC patients (P = 0.043). Log-rank test and adjusted multivariate Cox regression analysis verified that XPG Arg1104His variants were associated with a longer disease-free survival (DFS) [CG genotype: adjusted HR (95 % confidence interval (CI)) = 0.163 (0.107–0.248), P < 0.001; CC genotype: adjusted HR (95 % CI) = 0.333 (0.235–0.470), P < 0.001; CG/CC genotype: adjusted HR (95 % CI) = 0.333 (0.235–0.470)] in patients with oxaliplatin-based chemotherapy (N = 718). Moreover, XPC Ala499Val CT genotype showed a significant impact on DFS [CC genotype: adjusted HR (95 % CI) = 0.691 (0.528–0.904), P = 0.007; CT/CC genotype: adjusted HR (95 % CI) = 0.602 (0.389–0.934), P = 0.024]. However, no correlation was found between WRN Cys1367Arg polymorphism and prognosis in CRC patients. Our findings will add to the literature on the impact of genetic variation in DNA repair genes involved in susceptibility for CRC and therapeutic outcomes in response to oxaliplatin-based chemotherapy.

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Abbreviations

XPG :

Xeroderma pigmentosum complementation group G

XPC :

Xeroderma pigmentosum complementation group C

WRN :

Werner syndrome, RecQ helicase-like

OR:

Odds ratio

CI:

Confidence interval

LD:

Linkage disequilibrium

PCR–RFLP:

Polymerase chain reaction-restriction fragment length polymorphism

HWE:

Hardy–Weinberg equilibrium

Folfox:

Oxaliplatin, leucovorin plus 5-FU

Xelox:

Oxaliplatin plus capecitabine

Lv5-Fu2:

Leucovorin plus 5-FU

FUP:

(Fluorouracil plus cisplatin

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Acknowledgment

This work was supported by project L2013340 (2013, Pin Liang) from the Research Foundation of Dalian Technology Bureau in China and 2010E15SF180 (2010, Pin Liang) from the Research Foundation of Liaoning Provincial Education Office in China.

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None

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Authors and Affiliations

  1. Department of Digestive Endoscopy, The First Affiliated Hospital of Dalian Medical University, NO.222 Zhongshan Road, Dalian, 116011, Liaoning Province, People’s Republic of China

    Kang Sun & Aixia Gong

  2. Department of Gastrointestinal Surgery, The First Affiliated Hospital of Dalian Medical University, NO.222 Zhongshan Road, Dalian City, 116011, Liaoning Province, People’s Republic of China

    Pin Liang

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  1. Kang Sun
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  2. Aixia Gong
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  3. Pin Liang
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Correspondence to Pin Liang.

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Sun, K., Gong, A. & Liang, P. Predictive impact of genetic polymorphisms in DNA repair genes on susceptibility and therapeutic outcomes to colorectal cancer patients. Tumor Biol. 36, 1549–1559 (2015). https://doi.org/10.1007/s13277-014-2721-3

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  • DOI: https://doi.org/10.1007/s13277-014-2721-3

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