- 學位論文
Genetic Polymorphisms Associated with Colorectal Cancer in Patients with Lynch Syndrome in Taiwan
Genetic Polymorphisms Associated with Colorectal Cancer in Patients with Lynch Syndrome in Taiwan
摘要
ABSTRACT Background Lynch syndrome is an autosomal dominant disorder caused by germline mutation in mismatch repair (MMR) genes. Patients with Lynch syndrome have an increased risk of developing colorectal cancer (CRC) and other Lynch syndrome-related cancers including cancer of the endometrium, ovary, brain, bladder, prostate, renal pelvis, small bowel, hepatobiliary tract, and stomach. Study objectives The overall aim of this study was to determine genetic polymorphisms that are associated with CRC in patients with Lynch syndrome in Taiwan, and we have three specific objectives to achieve our aim. 1. To estimate the age-and sex-specific cumulative risk of developing CRC in patients with Lynch syndrome in Taiwan. 2. To investigate whether polymorphisms of xenobiotic-metabolizing genes, DNA repair genes, TP53 gene, and TGFB pathway genes are associated with CRC. 3. To investigate whether xenobiotic-metabolizing genes interact with environmental factors to modify CRC risk in patients with Lynch syndrome. Material and methods Patients suspected of having hereditary non-polyposis colorectal cancer where recruited into the Amsterdam criteria family registry using the Amsterdam II criteria. Probands and family members who met the criteria were screened for germline mutation in MLH1 and MSH2. Genotyping of xenobiotic-metabolizing genes, DNA repair genes, TP53 gene, and TGFB pathways genes were performed using Sequenom iPLEX MassARRAY. Age-and sex-specific cumulative risk of CRC in patients with Lynch syndrome were calculated using Mendel version 16. A weighted Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for association between genetic polymorphisms and CRC. Multiplicative interactions between xenobiotic-metabolizing genes and environmental factors were assessed by likelihood ratio test. Results Age-specific cumulative risk of CRC in patients with Lynch syndrome at age 70 were estimated to be 29.3% (95% CI, 23.6%–36.5%) for MLH1 or MH2, 27.5% (95% CI, 22.0%–34.0%) for MLH1, and 36.8% (95% CI, 28.4%–46.7%) for MSH2 germline mutation. Variant TT and CC genotypes of xenobiotic-metabolizing genes GSTA1 rs3957356 (HR = 5.36, 95% CI = 2.39–12.0) and CYP1B1 rs1056836 (HR = 7.24, 95% CI = 3.51–14.9) significantly increased the risk of CRC compared with the wild-type CC and GG genotypes, respectively. For DNA repair genes, the heterozygous variants of rs1799832 in NUDT1 (HR = 2.97, 95% CI = 1.51–5.83) and rs13181 in ERCC2 (HR = 2.69, 95% CI = 1.10–6.55) also significantly increased the risk of CRC compared with wild-type homozygous CC and TT genotypes, respectively. Patients carrying the AA genotype of EGFR rs2227983 had a higher risk of CRC (HR = 2.55, 95% CI = 1.25–5.17) than those carrying the G allele. Moreover, the dominant model of SMAD7 rs12953717 significantly increased CRC risk (HR = 2.17, 95% CI = 1.12–4.16) compared with the wild-type CC genotype. However, CYP1A1 rs4646903 CC genotype was associated with a decrease risk of CRC (HR = 0.33, 95% CI = 0.12–0.89) compared with the TT genotype. The GC+GG genotype in MUTYH rs3219489 of DNA repair exerted a protective effect (HR = 0.49, 95% CI = 0.26–0.91) compared with the CC genotype. The variant C allele of TP53 rs1042522 were associated with a decreased CRC risk (HR = 0.35, 95% CI = 0.14–0.86 and HR = 0.28, 95% CI = 0.13–0.57 for GC and CC genotypes, respectively). Similarly, the CT (HR = 0.20, 95% CI = 0.08–0.46) and the TT (HR = 0.25, 95% CI = 0.09–0.65) genotypes of the TP53 rs12947788 also significantly decreased CRC risk. Moreover, we found significant interaction between polymorphisms in xenobiotic-metabolizing genes and intake of meat. Conclusion Age-specific cumulative risk of CRC in Chinese patients with Lynch syndrome were estimated to be 27.5% for MLH1 and 36.8% for MSH2 mutation carriers after adjusted for ascertainment bias. Polymorphisms in GSTA1 rs3957356, CYP1B1 rs1056836, NUDT1 rs1799832, ERCC2 rs13181, EGFR rs2227983, and SMAD7 rs12953717 were significantly associated with an increased risk of CRC, whereas polymorphisms in CYP1A1 rs4646903, MUTYH rs3219489, TP53 rs1042522, and rs12947788 were associated with a decreased CRC risk.
並列摘要
ABSTRACT Background Lynch syndrome is an autosomal dominant disorder caused by germline mutation in mismatch repair (MMR) genes. Patients with Lynch syndrome have an increased risk of developing colorectal cancer (CRC) and other Lynch syndrome-related cancers including cancer of the endometrium, ovary, brain, bladder, prostate, renal pelvis, small bowel, hepatobiliary tract, and stomach. Study objectives The overall aim of this study was to determine genetic polymorphisms that are associated with CRC in patients with Lynch syndrome in Taiwan, and we have three specific objectives to achieve our aim. 1. To estimate the age-and sex-specific cumulative risk of developing CRC in patients with Lynch syndrome in Taiwan. 2. To investigate whether polymorphisms of xenobiotic-metabolizing genes, DNA repair genes, TP53 gene, and TGFB pathway genes are associated with CRC. 3. To investigate whether xenobiotic-metabolizing genes interact with environmental factors to modify CRC risk in patients with Lynch syndrome. Material and methods Patients suspected of having hereditary non-polyposis colorectal cancer where recruited into the Amsterdam criteria family registry using the Amsterdam II criteria. Probands and family members who met the criteria were screened for germline mutation in MLH1 and MSH2. Genotyping of xenobiotic-metabolizing genes, DNA repair genes, TP53 gene, and TGFB pathways genes were performed using Sequenom iPLEX MassARRAY. Age-and sex-specific cumulative risk of CRC in patients with Lynch syndrome were calculated using Mendel version 16. A weighted Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for association between genetic polymorphisms and CRC. Multiplicative interactions between xenobiotic-metabolizing genes and environmental factors were assessed by likelihood ratio test. Results Age-specific cumulative risk of CRC in patients with Lynch syndrome at age 70 were estimated to be 29.3% (95% CI, 23.6%–36.5%) for MLH1 or MH2, 27.5% (95% CI, 22.0%–34.0%) for MLH1, and 36.8% (95% CI, 28.4%–46.7%) for MSH2 germline mutation. Variant TT and CC genotypes of xenobiotic-metabolizing genes GSTA1 rs3957356 (HR = 5.36, 95% CI = 2.39–12.0) and CYP1B1 rs1056836 (HR = 7.24, 95% CI = 3.51–14.9) significantly increased the risk of CRC compared with the wild-type CC and GG genotypes, respectively. For DNA repair genes, the heterozygous variants of rs1799832 in NUDT1 (HR = 2.97, 95% CI = 1.51–5.83) and rs13181 in ERCC2 (HR = 2.69, 95% CI = 1.10–6.55) also significantly increased the risk of CRC compared with wild-type homozygous CC and TT genotypes, respectively. Patients carrying the AA genotype of EGFR rs2227983 had a higher risk of CRC (HR = 2.55, 95% CI = 1.25–5.17) than those carrying the G allele. Moreover, the dominant model of SMAD7 rs12953717 significantly increased CRC risk (HR = 2.17, 95% CI = 1.12–4.16) compared with the wild-type CC genotype. However, CYP1A1 rs4646903 CC genotype was associated with a decrease risk of CRC (HR = 0.33, 95% CI = 0.12–0.89) compared with the TT genotype. The GC+GG genotype in MUTYH rs3219489 of DNA repair exerted a protective effect (HR = 0.49, 95% CI = 0.26–0.91) compared with the CC genotype. The variant C allele of TP53 rs1042522 were associated with a decreased CRC risk (HR = 0.35, 95% CI = 0.14–0.86 and HR = 0.28, 95% CI = 0.13–0.57 for GC and CC genotypes, respectively). Similarly, the CT (HR = 0.20, 95% CI = 0.08–0.46) and the TT (HR = 0.25, 95% CI = 0.09–0.65) genotypes of the TP53 rs12947788 also significantly decreased CRC risk. Moreover, we found significant interaction between polymorphisms in xenobiotic-metabolizing genes and intake of meat. Conclusion Age-specific cumulative risk of CRC in Chinese patients with Lynch syndrome were estimated to be 27.5% for MLH1 and 36.8% for MSH2 mutation carriers after adjusted for ascertainment bias. Polymorphisms in GSTA1 rs3957356, CYP1B1 rs1056836, NUDT1 rs1799832, ERCC2 rs13181, EGFR rs2227983, and SMAD7 rs12953717 were significantly associated with an increased risk of CRC, whereas polymorphisms in CYP1A1 rs4646903, MUTYH rs3219489, TP53 rs1042522, and rs12947788 were associated with a decreased CRC risk.