Lack of replication for the association between HER2 I655V polymorphism and breast cancer risk: A systematic review and meta-analysis

doi:10.1016/j.canep.2011.01.007

Cancer Epidemiology

Volume 35, Issue 6, December 2011, Pages 503-509

https://doi.org/10.1016/j.canep.2011.01.007 Get rights and content

Abstract

Background: Multiple epidemiological studies have investigated rs1136201, a non-synonymous polymorphism of the human epidermal growth factor receptor-2 gene (HER2) resulting in the substitution of valine for isoleucine at codon 655 (Ile655Val) of the HER2 protein, as a risk factor for breast cancer. Methods: We searched multiple databases to identify genetic association studies investigating the effect of rs1136201 on breast cancer risk. For each study we calculated unadjusted odds ratios (ORs) with their variance under additive, dominant, recessive and allele-frequency genetic models. Summary ORs with their corresponding confidence interval (CI) were calculated using random effects models. Results: Based on the 33 case–control studies reporting data for the additive genetic model (20,461 cases/23,832 controls) we did not find evidence of an association between rs1136201 and breast cancer, OR = 1.05 (95% CI, 0.99–1.11), with significant between-study heterogeneity (p_Q < 0.001; I² = 49%). Smaller studies produced more extreme results compared to larger studies (p = 0.001). Studies in which genotyping was not blind to case–control status (p = 0.01), studies not reporting the use of genotyping quality control (p = 0.01), and studies using RFLP-based methods (p = 0.01) produced significant associations. Meta-regression results confirmed that there was a significant interaction between lack of quality control (p = 0.04) and lack of blinding (p = 0.04) and the genetic effect of rs1136201 on breast cancer risk. Conclusions: It is unlikely that HER2 rs1136201 is a risk factor for breast cancer. Laboratory artifacts, lack of genotyping quality control or blinding and publication bias appear to have influenced the results published to date and need to be addressed in the design of future studies.

Introduction

Breast cancer is a major public health concern with an estimated 190,000 new cases diagnosed annually and a lifetime risk of 12% for women in the USA [1]. Family-based and twin-concordance studies suggest that breast cancer has a substantial hereditary component [2], [3]. However, high penetrance genetic variants, such as BRCA1 and BRCA2 mutations, only account for a small proportion of all breast cancer cases and it has been hypothesized that multiple, high-frequency low-penetrance genetic variants may account for a proportion of the unexplained breast cancer heritability [4], [5], [6]. The expected low magnitude of the genetic effects of such variants and the risk for false positive findings necessitate large-scale evidence synthesis for validating candidate genetic risk factors for breast cancer [7], [8].

A polymorphism of the human epidermal growth factor receptor-2 gene (HER2, located at 17q21.1) that results in the substitution of valine for isoleucine at codon 655 of the HER2 protein (Ile655Val, GTC > ATC; refSNP number, rs1136201) has been extensively investigated as risk factor for breast cancer [9]. This extensive body of evidence has been driven by an initial positive study that reported a strong association of the valine-encoding allele with breast cancer in an East Asian population from Shanghai, China [10]. Several subsequently published epidemiological studies have provided conflicting results and an update from the original Shanghai cohort failed to replicate their initial findings [11]. Additionally, it has been suggested that the proximity of rs1136201 to rs1801201, another HER2 polymorphism affecting codon 654 of the HER2 gene, may influence the results of allelic discrimination assays, such as Taqman assays, by interfering with primer binding [12], [13]. This potential source of genotyping error may be of particular concern for genetic association studies using a single genotyping method and not employing quality control procedures. One approach to evaluating the potential effect of different genotyping methods on the reported effect sizes lies in synthesizing evidence across multiple studies [8], [14].

To assess the cumulative evidence regarding the association of rs1136201 with female breast cancer, and to investigate potential sources of bias and heterogeneity, we conducted a systematic review and meta-analysis of epidemiological studies investigating this association.

Section snippets

Search strategy, inclusion and exclusion criteria

We searched Medline (through PubMed, from inception to February 9th, 2010) to identify genetic association studies investigating the association between the HER2 Ile655Val polymorphism and breast cancer risk using combinations of the following keywords and their synonyms: “HER2”; “ERBB2”; “polymorphism”; “variant”; “rs1136201”; “rs1801200” (refSNP number which has been merged with rs1136201); “breast cancer”; “breast neoplasms”. No language restriction was imposed. We also searched the Human

Results

The Medline search identified 348 citations and the HuGE Net Literature Finder search identified 55 citations. Fig. 1 presents the flow of the literature search. Perusal of the reference lists of retrieved articles identified two additional citations. In total, 58 unique citations were considered potentially eligible and were retrieved in full text. Twenty-two of those were excluded (14 were case-only or genotype prevalence studies; 3 did not investigate the polymorphism of interest; 3 provided

Discussion

This systematic review and meta-analysis of case–control studies investigating the association between the rs1136201 and breast cancer risk failed to find any association between the G-allele and breast cancer. This finding is in contrast with a recently published meta-analysis that concluded that rs1136201 is a significant risk factor for breast cancer [37]. Our literature search identified 14 additional studies, reporting on approximately 10,000 additional cases and 12,500 controls, including

Conflict of interest statement

The authors declare no conflict of interest.

Acknowledgments

We would like to thank Drs. Dong-Young Noh and Wonshik Han [31] (Seoul National University College of Medicine, Seoul, Korea); Dr. KristjanaEinarsdottir [32] (School of Population Health, University of Western Australia, Crawley, Australia); and Dr. Asahi Hishida [35] (Aichi Cancer Center, Nagoya, Japan) for providing access to unpublished data from their case–control studies.

IJD is supported by a research scholarship from the “Maria P. Lemos” Foundation.

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Cited by (28)

Human Epidermal Growth Factor Receptor-2 gene polymorphism and breast cancer risk in women from the Northeastern region of Brazil
2020, Clinics
Citation Excerpt :
Thus, some authors hypothesized that the HER2 Ile655Val polymorphism may be considered a genetic biomarker of susceptibility to breast cancer risk, although it is not reliable for the estimation of tumor aggressiveness. However, the association between the HER2 Ile655Val (rs1136201) SNP and breast cancer risk has still not been fully elucidated (27). Furrer et al. (28) studied the association between this polymorphism and non-metastatic HER2-positive breast cancer; they theorized that the HER2 Ile655Val SNP may play a significant role in breast carcinogenesis in Caucasian women.
In the Human Epidermal Growth Factor Receptor-2 (HER2) rs1136201 variant, the presence of the G allele may promote cellular alterations and increase breast cancer risk, in addition to enhanced cellular proliferation, tumor aggressiveness, and metastases. The aim of this study was to investigate the presence of the single-nucleotide polymorphism (SNP) variant, rs1136201, within the HER2 gene in women from the Northeastern region of Brazil and breast cancer risk.
The study included 140 women who were divided into two groups, case (breast cancer) and control (without breast cancer), with 70 women in each group. Peripheral blood of each woman was drawn for the study of genomic Deoxyribonucleic acid (DNA) extracted from leukocytes using the genotyping technique by real-time polymerase chain reaction.
The GG genotype occurred in 1 woman in both groups (1.4%) (p=0.32), while the AG genotype occurred in 19 (27.2%) and 13 (18.6%) women in the case and control (p=1.00) groups, respectively. No statistically significant difference in GG and AG genotypes was observed between the case and control groups in premenopausal women (p=1.00). Furthermore, no significant difference in genotypes was observed between the groups, among postmenopausal women (p=0.14).
In this study, the HER2 rs1136201 polymorphism did not show any statistically significant association with breast cancer, both in premenopausal and postmenopausal women. Nevertheless, further studies with a larger sample size should be performed to assess the association of HER2 polymorphism with breast cancer risk in women from the Northeastern region of Brazil.
Afatinib in patients with metastatic or recurrent HER2-mutant lung cancers: a retrospective international multicentre study
2019, European Journal of Cancer
Citation Excerpt :
One patient treated with afatinib was found to have an SNP in HER2, which resulted in the substitution of valine for isoleucine at codon 655 (Ile655Val) of the HER2 protein. The role of Ile655Val in driving oncogenesis has been explored in prior studies in patients with breast cancer with conflicting results, and this SNP has not been well characterised in HER2-mutant lung adenocarcinomas [21]. While RECIST data were unavailable for this patient, the patient experienced clinical benefit while on treatment with afatinib for 4 months.
HER2 mutations occur in 1–3% of lung adenocarcinomas. With increasing use of next-generation sequencing at diagnosis, more patients with HER2-mutant tumours present for treatment. Few data are available to describe the clinical course and outcomes of these patients when treated with afatinib, a pan-HER inhibitor.
We identified patients with metastatic or recurrent HER2-mutant lung adenocarcinomas treated with afatinib among seven institutions across Europe, Australia, and North America between 2009 and 2017. We determined the partial response rate to afatinib, types of HER2 mutations, duration of response, time on treatment, and survival.
We collected information on 27 patients with stage IV or recurrent HER2-mutant lung adenocarcinomas treated with afatinib. Of 23 patients evaluable for response, three partial responses were noted (13%, 95% confidence interval [CI] 4–33%). In addition, 57% of patients (13/23) had stable disease, and 30% (7/23) had progressive disease. We documented partial responses in patients with HER2 exon 20 insertions, including two with YVMA insertion and one with VAG insertion. Two patients with partial responses were previously treated with trastuzumab and pertuzumab. Median duration of response to afatinib was 6 months (range 5–10); median time on treatment was 3 months (range 1–30) and median overall survival from the date of diagnosis of metastatic or recurrent disease was 23 months (95% CI 18–53 months).
Afatinib is modestly active in patients with HER2-mutant lung adenocarcinomas, including responses after progression on prior HER2-targeted therapies. However, investigations into the biology of HER2-mutant lung adenocarcinomas and development of better HER2-directed therapies are warranted.
Evaluation of human epidermal growth factor receptor 2 (HER2) single nucleotide polymorphisms (SNPs) in normal and breast tumor tissues and their link with breast cancer prognostic factors
2016, Breast
Citation Excerpt :
The Ala1170Pro polymorphism, which has been identified in the coding region of the carboxyl-terminal regulatory domain at codon 1170, leads to the substitution of Alanine (Ala:GCC) for Proline (Pro:CCC) [9]. The role of both polymorphisms as prognostic factors and as markers of breast cancer risk is still controversial [9–14]. To date, only a few studies have investigated the clinical and biological relevance of these polymorphisms in breast cancer [9,10,12].
Amplification of the human epidermal growth factor receptor 2 (HER2) gene is associated with worse prognosis and decreased overall survival in breast cancer patients. The HER2 gene contains several polymorphisms; two of the best-characterized HER2 polymorphisms are Ile655Val and Ala1170Pro. The aim of this study was to evaluate the association between these two HER2 polymorphisms in normal breast and breast cancer tissues and known breast cancer prognostic factors in a retrospective cohort study of 73 women with non-metastatic HER2-positive breast cancer. HER2 polymorphisms were assessed in breast cancer tissue and normal breast tissue using TaqMan assay. Ala1170Pro polymorphism in normal breast tissue was associated with age at diagnosis (p = 0.007), tumor size (p = 0.004) and lymphovascular invasion (p = 0.06). Similar significant associations in cancer tissues were observed. No association between the Ile655Val polymorphism and prognostic factors were observed. However, we found significant differences in the distribution of Ile655Val (p = 0.03) and Ala1170Pro (p = 0.01) genotypes between normal breast and breast tumor tissues. This study demonstrates that only the Ala1170Pro polymorphism is associated with prognostic factors in HER2-positive breast cancer patients. Moreover, our results suggest that both HER2 polymorphisms could play a significant role in carcinogenesis in non-metastatic HER2-positive breast cancer women.
Genetic variants in the HER2 gene: Influence on HER2 overexpression and loss of heterozygosity in breast cancer
2016, European Journal of Cancer
Citation Excerpt :
In our own study population, there was a relatively low proportion of HR-negative advanced patients. However, the distribution of genotypes for the Ile655Val SNP was comparable with published data in the NCBI database and with the literature in Caucasian populations [14,17,18]. For the Ala1170Pro SNP, more limited data are available [20,22,37], but the published genotype frequencies are similar to those in our population.
Human epidermal growth factor receptor 2 (HER2) overexpression in breast cancer is an indicator of poor prognosis and is the pre-requisite for treatment with the agents targeting this member of the epidermal growth factor receptor family. In order to determine the influence of these common single-nucleotide polymorphisms (SNPs) in the HER2 gene, genomic DNA was obtained from 361 patients with breast cancer, aged between 29 and 82 years. Samples of tumour tissue were obtained from 241 (66%) patients and material for extraction of DNA is isolated from surrounding normal tissue by laser capture microdissection. Genotyping was performed using the Taqman fluorogenic 5′ nuclease assay. Of the 360 patients with definitive determination of HER2 status, 49% were positive. The Ile655Val SNP had no influence on the frequency of HER2 expression. However, the proline allele of the Ala1170Pro SNP was associated with a higher frequency of HER2 overexpression (56% versus 43%, p = 0.015). Where the germline genotype was homozygous, the tumour genotype was identical in every case and for both SNPs. In HER2-positive tumours, heterozygosity was maintained in only 15% and 18% of the Ile655Val and Ala1170Pro SNPs, respectively. This was lower than in the HER2-negative tumours (46% and 43%, respectively). Normal breast tissue (n = 23) retained the germline genotype in all but one case. The underlying link between the Ala1170Pro SNP and HER2 positivity is not known, nor is the significance of HER2 overexpression and loss of heterozygosity in breast cancer. However, these results illustrate the complexity of HER2 genotype and overexpression in this disease.
Effects of HER2 genetic polymorphisms on its protein expression in breast cancer
2015, Cancer Epidemiology
Citation Excerpt :
Somatic mutations and germinal polymorphism of the HER2 gene may have some effects on its biological function. Relevant studies of germinal polymorphisms in the HER2 gene, including rs1136201 (also known as Ile655Val), rs1058808 (Pro1170Ala) and rs2517956 have mainly focused on the context of breast cancer risk [8–14]. These SNPs reside in a functionally relevant region of the gene that might influence gene function and protein expression; however, there have been limited studies on the association between HER2 genetic polymorphisms and its protein expression.
HER2 protein expression has been considered to be an important prognostic factor in breast cancer patients. Although the molecular mechanism of HER2 protein expression is currently unknown, single nucleotide polymorphisms (SNPs) of the HER2 gene may have some effects on its own expression. Here, we performed a trial to study the association between HER2 genetic polymorphisms and its protein expression in breast cancer.
Three SNPs in the HER2 gene were genotyped in 303 breast cancer patients using the Sequenom Mass ARRAY system. HER2 protein expression, ER, PR, P53, and Ki67 status was detected by immunohistochemistry. A Pearson’s chi-square test was used to analyze the associations of the polymorphisms with its protein expression, corresponding with clinicopathological characteristics of breast cancer.
Under the codominant model, rs1058808 and rs2517956 polymorphisms were associated with HER2 protein expression in breast cancer (p = 0.007; p = 0.008, respectively). For SNP rs1058808, patients with genotypes CG and GG were more likely to have high HER2 protein expression than patients with genotype CC (p = 0.007). No significant associations could be found between the three SNPs and breast cancer patients’ clinical stage, tumor size, histological grade, lymph node metastasis, ER, PR, Ki67 and P53 status (p > 0.05).
HER2 rs1058808 and rs2517956 polymorphisms are associated with its protein expression in breast cancer. Our study might provide new insights into the mechanisms of HER2 protein expression.
Pharmacogenomics for Prediction of Cardiovascular Toxicity: Landscape of Emerging Data in Breast Cancer Therapies
2022, Cancers

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Lack of replication for the association between HER2 I655V polymorphism and breast cancer risk: A systematic review and meta-analysis

Abstract

Introduction

Section snippets

Search strategy, inclusion and exclusion criteria

Results

Discussion

Conflict of interest statement

Acknowledgments

Mol Oncol

Control Clin Trials

Cancer Lett

J Clin Epidemiol

Lancet Oncol

Ann Oncol

J Clin Epidemiol

Cancer statistics, 2009

CA Cancer J Clin

Environmental and heritable factors in the causation of cancer – analyses of cohorts of twins from Sweden, Denmark, and Finland

N Engl J Med

High constant incidence in twins and other relatives of women with breast cancer

Nat Genet

Polygenic susceptibility to breast cancer and implications for prevention

Nat Genet

Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study

Genet Epidemiol

Polygenes, risk prediction, and targeted prevention of breast cancer

N Engl J Med

A systematic review of genetic polymorphisms and breast cancer risk

Cancer Epidemiol Biomarkers Prev

Replication validity of genetic association studies

Nat Genet

HER2 codon 655 polymorphism and breast cancer: results from kin-cohort and case–control analyses

Breast Cancer Res Treat

Population-based, case–control study of HER2 genetic polymorphism and breast cancer risk

J Natl Cancer Inst

ERBB2 genetic polymorphism and breast cancer risk in Chinese women: a population-based case–control study

Breast Cancer Res Treat

A bias in genotyping the ERBB2 (HER2) Ile655Val variant

Carcinogenesis

Reply: a bias in genotyping of the ERBB2 (HER2) Ile655Val variant

Carcinogenesis

Common genetic variants for breast cancer: 32 largely refuted candidates and larger prospects

J Natl Cancer Inst

Tracking the epidemiology of human genes in the literature: the HuGE Published Literature database

Am J Epidemiol

The genetic association database

Nat Genet