Associations Between Genetic Polymorphisms of Epidermal Growth Factor Receptor (EGFR) and Survival of Colorectal Cancer (CRC) Patients Treated with 5-Fluorouracil-Based Chemotherapy

Lai, Ching Yu; Sung, Fung Chang; Hsieh, Ling Ling; Tang, Reiping; Chiou, Hung Yi; Wu, Fang; Yeh, Chih Ching

doi:10.1245/s10434-013-3069-4

Cited by 10 publications

(2 citation statements)

References 29 publications

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“…In contrast, another study reported that the wildtype GG genotype of rs2227983 is associated with CRC risk (31). Moreover, patients carrying wild-type genotype have been reported to have a poorer prognosis than those carrying the variant genotype (18,32). The rs2227983 polymorphism, an arginine-to-lysine amino acid substitution at codon 521 of the EGFR, has been shown to decrease ligand binding affinity, thus attenuating growth stimulation, tyrosine kinase activation and the induction of proto-oncogenes (33).…”

Section: Discussionmentioning

confidence: 96%

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EGFR, SMAD7, and TGFBR2 Polymorphisms Are Associated with Colorectal Cancer in Patients with Lynch Syndrome

et al. 2018

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Background/Aim: Epidermal growth factor receptor (EGFR), mothers against decapentaplegic homolog 7 (SMAD7) and transforming growth factor betta (TGFB) are crucial for colorectal cancer (CRC) tumorigenesis. This study investigated whether polymorphisms in EGFR, SMAD7, and TGFB are associated with CRC risk in patients with Lynch syndrome. Materials and Methods: Genotyping was performed using Sequenom iPLEX MassArray. Association between genetic polymorphisms and CRC was assessed using a weighted Cox proportional hazard model. Results: Patients carrying the AA genotype of EGFR rs2227983 had a significantly higher CRC risk than those carrying the G allele (HR=2.55,). The dominant model of SMAD7 rs12953717 (CT + TT genotypes) significantly increased CRC risk (HR=2.17, 95% CI=1.12-4.16) when compared to the wild-type CC genotype. Similarly, the GG genotype of TGFBR2 rs6785358 significantly increased the risk of CRC (HR=21.1, 95% CI=5.06-88.1) compared to the AA genotype. Conclusion: EGFR, SMAD7, and TGFBR2 are associated with CRC risk in patients with Lynch syndrome.Lynch syndrome is a cancer predisposition disorder caused by a germline mutation in one of the mismatch repair (MMR) genes (1). MMR genes encode proteins that prevent both mutation and cancer development (2). Loss of function in MMR proteins usually results in error-prone DNA replication and microsatellite instability (MSI) (3). Approximately 1 in 3,140 individuals harbors a germline mutation in MLH1 or MSH2 and are at a higher risk of colorectal cancer (CRC) and other cancers than the general population (4, 5). Moreover, these patients exhibit an earlier onset of CRC and other cancers compared to the general population (6, 7).Lichtenstein et al. estimated that 35% of inherited genetic factors are associated with CRC susceptibility (8). One of these genetic factors is the transforming growth factor beta (TGFB), whose mutations have been identified in colorectal tumors with MSI (9), a feature of Lynch syndrome. The TGFB signaling pathway is mediated via the TGFB receptor (TGFBR) or mothers against decapentaplegic homolog 7 (SMAD7) (9). Epidermal growth factor receptor (EGFR) inhibits TGFB signaling pathway through SMAD7 (10). Studies have reported that single nucleotide polymorphisms (SNPs) in EGFR, SMAD7, and TGFB are associated with cancer predisposition (11-13). More specifically, EGFR is involved in angiogenesis, metastasis, tumor invasion, and survival; TGFB plays a crucial role in cell proliferation, differentiation, and apoptosis, whereas SMAD7 is an 5983

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Section: Discussionmentioning

confidence: 96%

“…Disruption of TGFB signaling pathways by SMAD7 leads to various forms of tumorigenesis (34), thus increasing cancer risk. Moreover, other polymorphisms of the EGFR, including rs712829 and rs712830, have also been reported to be associated with CRC susceptibility (32).…”

Section: Discussionmentioning

confidence: 99%

EGFR, SMAD7, and TGFBR2 Polymorphisms Are Associated with Colorectal Cancer in Patients with Lynch Syndrome

et al. 2018

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Polymorphisms of MTHFR C677T and A1298C associated with survival in patients with colorectal cancer treated with 5-fluorouracil-based chemotherapy

et al. 2017

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A synonymous EGFR polymorphism predicting responsiveness to anti-EGFR therapy in metastatic colorectal cancer patients

et al. 2015

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Genetic factors are known to affect the efficiency of therapy with monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) in patients with metastatic colorectal cancer (mCRC). At present, the only accepted molecular marker predictive of the response to anti-EGFR mAbs is the somatic mutation of KRAS and NRAS as a marker of resistance to anti-EGFR. However, only a fraction of KRAS wild-type patients benefit from that treatment. In this study, we show that the EGFR gene polymorphism rs1050171 defines, independently of RAS mutational status, a sub-population of 11 % of patients with a better clinical outcome after anti-EGFR treatment. Median PFS for patients with the GG genotype was 10.17 months compared to 5.37 of those with AG + AA genotypes. Taken together, our findings could be used to better define CRC populations responding to anti-EGFR therapy. Further studies in larger independent cohorts are necessary to validate the present observation that a synonymous polymorphism in EGFR gene impacts on clinical responsiveness.

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Associations Between Genetic Polymorphisms of Epidermal Growth Factor Receptor (EGFR) and Survival of Colorectal Cancer (CRC) Patients Treated with 5-Fluorouracil-Based Chemotherapy

Abstract: EGFR polymorphisms can serve as prognostic predictors for CRC patients receiving 5-FU-based chemotherapy.

Cited by 10 publications

References 29 publications

EGFR, SMAD7, and TGFBR2 Polymorphisms Are Associated with Colorectal Cancer in Patients with Lynch Syndrome

EGFR, SMAD7, and TGFBR2 Polymorphisms Are Associated with Colorectal Cancer in Patients with Lynch Syndrome

Polymorphisms of MTHFR C677T and A1298C associated with survival in patients with colorectal cancer treated with 5-fluorouracil-based chemotherapy

A synonymous EGFR polymorphism predicting responsiveness to anti-EGFR therapy in metastatic colorectal cancer patients

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