Gender-Related Survival Differences Associated withEGFRPolymorphisms in Metastatic Colon Cancer

Abstract

Evidence is accumulating supporting gender-related differences in the development of colonic carcinomas. Sex steroid hormone receptors are expressed in the colon and interact with epidermal growth factor receptor (EGFR), a gene widely expressed in colonic tissue. Increased EGFR expression is linked with poor prognosis in colon cancer. Within the EGFR gene there are two functional polymorphisms of interest: a polymorphism located at codon 497 (HER-1 R497K) and a dinucleotide (CA) n repeat polymorphism located within intron 1. These germ-line polymorphisms of EGFR were analyzed in genomic DNA from 318 metastatic colon cancer patients, 177 males and 141 females, collected from 1992 to 2003. Gender-related survival differences were associated with the HER-1 R497K polymorphism (P interaction = 0.003). Females with the HER-1 497 Arg/Arg variant had better overall survival (OS) when compared with the Lys/Lys and/or Lys/Arg variants. In males the opposite was true. The EGFR dinucleotide (CA) n repeat also trended with a gender-related OS difference (P interaction = 0.11). Females with both short <20 (CA) n repeat alleles had better OS than those with any long z20 (CA) n repeats. In males the opposite was true. Combination analysis of the two polymorphisms taken together also revealed the same gender-related survival difference (P interaction = 0.002). These associations were observed using multivariable analysis. The two polymorphisms were not in linkage disequilibrium and are independent of one another. This study supports the role of functional EGFR polymorphisms as independent prognostic markers in metastatic colon cancer. As a prognostic factor, these variants had opposite prognostic implications based on gender. [Cancer Res 2008;68(8):3037-42]

Gender-Related Differences in Repopulation and Early Tumor Response to Preoperative Radiotherapy in Rectal Cancer Patients

“…Recently, clinical studies have been published showing gender difference in rectal cancer patients survival. [4][5][6]28,29 They clearly show better survival rates for younger female patients compared to male patients, 5,6 which suggests the protective effect of estrogen on colorectal cancer and results from hormonal differences between genders.…”

Association of Epidermal Growth Factor Receptor Polymorphism, Skin Toxicity, and Outcome in Patients with Squamous Cell Carcinoma of the Head and Neck Receiving Cetuximab-Docetaxel Treatment

“…DNA content and quality was determined using the Nanodrop 1000 spectrophotometer. The EGFR-R521K polymorphism (rs11543848) was analyzed by RFLP-PCR as described previously (20). Briefly, for amplification of the designated region in exon 13 of the EGFR gene, the forward primer (5′-TGC TGT GAC CCA CTC TGT CT-3′) and reverse primer (5′-CCA GAA GGT TGC ACT TGT CC-3′) were used.…”

Sexual dimorphism in cancer

“…In colon cancer, a polymorphism in the ERβ promoter, possibly influencing its activity levels, has been associated with increased survival 91 . Polymorphisms in the EGFR gene have also been identified that are positively associated with colon cancer survival in women and negatively in males 92 , pointing to a possible interplay between EGFR and ERβ signaling underlying the differences between the two sexes.…”