The Influence of HER2 Genotypes as Molecular Markers on Breast Cancer Outcome

Abstract

Alterations of the human epidermal growth factor receptor 2 (HER2) protooncogene have been implicated in the carcinogenesis and prognosis of breast cancer. A polymorphism has been identified at codon 655 (ATC/isoleucine to GTC/valine [I655V]) in the transmembrane domain-coding region of this gene, which may be associated with the risk of breast cancer. In this study we aimed to determine whether the risk of breast cancer is associated with the I655V polymorphism of HER2 transmembrane domain-coding region at codon 655. The genomic DNA from breast cancer patients and control subjects underwent analysis by the polymerase chain reaction-fragment length polymorphism. We observed no overall association between HER2 genotype and breast cancer (p = 0.53). However, an elevated positive association was observed for Ile/Val+Val/Val versus Ile/Ile genotypes in women >age 60 years (p = 0.02). Further, other risk factors--namely, the body mass index and family history--were found to be risk factors for developing breast cancer (p = 0.006 and p = 0.00, respectively). In conclusion, results of this study suggest that polymorphisms of the HER2 gene may be important susceptibility biomarkers for breast cancer risk among older women.

HER2 Ile655Val polymorphism contributes to breast cancer risk: evidence from 27 case–control studies

“…The results of many subsequent case-control studies [15,18,24,26,27,29,31] supported the association. Two studies by Millikan et al [15] and Mutluhan et al [30] showed no overall association between HER2 Ile655Val polymorphism and breast cancer, but an positive association was observed in women under 45 with a family history of breast cancer and in women older than 60, respectively. The more interesting finding revealed by Cox et al [22] showed an inverse association which indicated that the polymorphism may be associated with a modest decrease, rather than an increase in risk of breast cancer.…”

Polymorphisms of ERBB2 and breast cancer risk: A meta-analysis of 26 studies involving 35,088 subjects

“…Twenty‐six studies with a total number of 15,940 case and 19,148 controls were included in this analysis . Among these studies, 26 and 3 studies were considered for meta‐analysis concerning ERBB2 Ile655Val and Ala1170Pro polymorphisms, respectively.…”

Lack of association between HER2 codon 655 polymorphism and breast cancer susceptibility was not credible: appraisal of a recent meta-analysis

“…Importantly, four sizeable eligible studies [2][3][4][5] (1,745 cases and 1,921 controls) have not been included in this meta-analysis, even though they satisfied the search criteria. Specifically, the study by Millikan et al [2] has provided separate data on African (754 cases and 676 controls) and Caucasian (1,261 cases and 1,132 controls) subpopulations.…”

“…Under the light of the above, we put all studies into a new meta-analysis, including the four sizeable eligible studies [2][3][4][5], and we observed that the HER2 codon 655 polymorphism was significantly correlated with breast cancer risk in the Val versus Ile allele contrast model (OR 1.10, 95% CI 1.02-1.19, random effects model) and the dominant model (OR 1.10, 95% CI 1.01-1.19, random effects model). However, we did not find any associations in additive genetic model (the homozygote codominant: OR 1.15, 95% CI 0.93-1.43; the heterozygote codominant: OR 1.07, 95% CI 0.99-1.16; the recessive model: OR 1.11, 95% CI 0.90-1.35, random effects model).…”

“…But the eligible studies [2][3][4][5] were also not been included in the sub-analysis on Asian and Caucasian subjects. Moreover, the study by Ma et al [1] has sorted the researches by Nelson et al [6] and Kallel et al [7] to mixed ethnicities.…”