TP53 Polymorphisms and Colorectal Cancer Risk in Patients with Lynch Syndrome in Taiwan: A Retrospective Cohort Study.

Abram Bunya Kamiza,Jeng-Fu You,Li-Ling Chiu,Chao A Hsiung,Kuan-Yi Hung,Tsai-Ping Lo,Chih-Ching Yeh,Ling-Ling Hsieh,Huei-Tzu Chien,Chih-Hsiung Lai,Wen-Chang Wang,Reiping Tang,Kanaga Sabapathy

doi:10.1371/journal.pone.0167354

Abstract

Background and AimTP53 encodes p53, which has a crucial role in modulating genes that regulate defense against cancer development. This study investigated whether TP53 polymorphisms are associated with colorectal cancer (CRC) in patients with Lynch syndrome and whether TP53 interacts with lifestyle factors to modify CRC risk.MethodsWe identified 260 MLH1 and MSH2 germline mutation carriers from the Taiwan Hereditary Nonpolyposis Colorectal Cancer Consortium. A weighted Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to determine the association of TP53 polymorphisms with CRC development.ResultsThe carriers of the variant C allele of rs1042522 were associated with a decreased CRC risk (GC genotype: HR = 0.35, 95% CI = 0.14–0.86; CC genotype: HR = 0.28, 95% CI = 0.13–0.57). In addition, the dominant model of rs1042522 was associated with a decreased CRC risk (HR = 0.32, 95% CI = 0.15–0.67). The CRC risk was decreased in carriers with the CT and TT genotypes of rs12947788 (HR = 0.20, 95% CI = 0.08–0.46 and HR = 0.25, 95% CI = 0.09–0.65, respectively). Moreover, the dominant model of rs12947788 was significantly associated with a decreased CRC risk (HR = 0.21, 95% CI = 0.09–0.46). A haplotype analysis indicated that compared with the most common GC haplotype, the CT haplotype was associated with a decreased CRC risk (HR = 0.26, 95% CI = 0.11–0.59). However, no significant interaction was observed between TP53 polymorphisms and lifestyle factors.ConclusionThe study results revealed that the rs1042522 genotype with the C allele and the rs12947788 genotype with the T allele in TP53 were associated with a decreased CRC risk in patients with Lynch syndrome in Taiwan.

Highlights

Lynch syndrome is a hereditary disorder caused by mutations in mismatch repair (MMR) genes, in MLH1 and MSH2 and less commonly in MSH6 and PMS2 [1, 2]
The carriers of the variant C allele of rs1042522 were associated with a decreased colorectal cancer (CRC) risk (GC genotype: hazard ratios (HRs) = 0.35, 95% confidence intervals (CIs) = 0.14–0.86; CC genotype: HR = 0.28, 95% CI = 0.13– 0.57)
The dominant model of rs1042522 was associated with a decreased CRC risk (HR = 0.32, 95% CI = 0.15–0.67)

Summary

Introduction

Lynch syndrome is a hereditary disorder caused by mutations in mismatch repair (MMR) genes, in MLH1 and MSH2 and less commonly in MSH6 and PMS2 [1, 2]. TP53, one of the most crucial tumor suppressor genes, has a critical role of modulating genes that regulate defense against cancer development through inhibiting the cell cycle, angiogenesis, and cellular senescence and causing apoptosis [8]. When DNA in a cell is damaged, p53 plays a critical role in determining whether the damaged DNA will undergo the repair or apoptosis mechanism [9, 10]. This process prevents further division of cells with mutated or damaged DNA, which facilitates the prevention of tumorigenesis [7]. This study investigated whether TP53 polymorphisms are associated with colorectal cancer (CRC) in patients with Lynch syndrome and whether TP53 interacts with lifestyle factors to modify CRC risk

Methods

Results

Conclusion