HER2 Polymorphism Research Articles

Assessment of HER1 (rs11543848) and HER2 (rs1136201) polymorphism and their association with colorectal cancer susceptibility in Khyber Pakhtunkhwa, Pakistan.

Colorectal cancer (CRC) is a widespread malignancy characterized by uncontrolled growth in the colon or rectum and remains a leading cause of cancer-related mortality globally. Various genes polymorphisms have been linked with the risk of CRC, but our study aimed to investigate the association between HER1 (rs11543848) and HER2 (rs1136201) polymorphisms with the risk of CRC in the Khyber Pakhtunkhwa (KPK) population of Pakistan. The association of the selected polymorphisms (rs11543848 and rs1136201) with CRC risk has been investigated in various ethnic groups, but their impact remains unexplored in Pakistan, particularly within the KPK population, highlighting the need of the study in this region. In this study 120 CRC patients and 120 healthy controls were enrolled. The DNA was extracted from the blood by salting-out method and genotyping was done using ARMS-PCR. Our investigations provided convincing evidence of a strong association between HER1 (rs11543848) and the risk of CRC. Both the genotypes heterozygous GA (OR = 2.07, CI = 1.18 to 3.64, P = 0.01) and homozygous AA (OR = 6.22, CI = 2.56 to 15.08, P = 0.0001) showed higher risk and significant association with the CRC risk. Similarly, heterozygous genotype AG of HER2 (rs1136201) was significantly associated (OR = 3.16, 95% CI = 1.78 to 5.58, P = 0.0001) while mutant genotype GG showed higher risk but non-significant association (OR = 3.23, 95% CI = 0.84 to 12.43, P = 0.08) with CRC patients. HER1 (rs11543848) demonstrated a significant association (P = 0.003) with the age at diagnosis in CRC patients, while HER2 (rs1136201) showed a non-significant association (P = 0.434). Both the SNPs were non-significantly associated with gender (P = 0.793 and 0.117), metastasis (P = 0.582 and 0.129), location of the tumor (P = 0.555 and 0.993), tumor grade (P = 0.290 and 0.920), tumor size (P = 0.535 and 0.289) and stages of cancer (P = 0.892 and 0.352). In conclusion, both the polymorphisms rs11543848 and rs1136201 displayed susceptibility with CRC in the KPK population. However, further investigations are recommended while using whole exome sequencing on a larger sample size for more precise results.

HER2 and BARD1 Polymorphisms in Early HER2-Positive Breast Cancer Patients: Relationship with Response to Neoadjuvant Anti-HER2 Treatment.

The addition to chemotherapy of anti-HER2 drugs such as trastuzumab or pertuzumab has improved outcomes in HER2-positive breast cancer patients. However, resistance to these drugs in some patients remains a major concern. This study examines the possible association between the response to neoadjuvant anti-HER2 treatment in breast cancer patients and the presence of 28 SNPs in 17 genes involved in different cell processes (PON1, CAT, GSTP1, FCGR3, ATM, PIK3CA, HER3, BARD1, LDB2, BRINP1, chr6 intergenic region, RAB22A, TRPC6, LINC01060, EGFR, ABCB1, and HER2). Tumor samples from 50 women with early breast cancer were genotyped using the iPlex®Gold chemistry and MassARRAY platform, and patients were classified as good responders (Miller-Payne tumor grades 4-5) and poor responders (Miller-Payne tumor grades 1-3), as assessed upon surgery after 6 months of treatment. Proportions of patients with the HER2Ala1170Pro (rs1058808) SNP double mutation were higher in good (58.62%) than poor (20%) responders (p = 0.025). Similarly, proportions of patients carrying the synonymous SNP rs2070096 (BARD1Thr351=) (wv + vv) were higher in patients showing a pathological complete response (46.67%) than in those not showing this response (15.15%) (p = 0.031). The SNPs rs1058808 (HER2Ala1170Pro) and rs2070096 (BARD1Thr351=) were identified here as potential biomarkers of a good response to anti-HER2 treatment.

Pharmacogenomics for Prediction of Cardiovascular Toxicity: Landscape of Emerging Data in Breast Cancer Therapies.

Simple SummaryWith the increasing number of breast cancer survivors and with the progress in survival of patients with metastatic breast cancer, consideration of survivorship issues becomes vital. Cardiotoxicity has been an important aspect in the management of early or metastatic breast cancer, not least due to the wide use of anthracyclines and, in HER2-positive breast cancer, anti-HER2 agents. Current baseline assessment includes clinical, such as history of cardiovascular comorbidities and lifestyle factors, and biochemical markers. Further biomarkers for tailored risk assessment and management remain an unmet need. Pharmacogenomics, an emerging field investigating how individual genetic variations, alone or in combination with polygenic risk scores, can impact drug metabolism and efficacy, and could be a complement. We hereby present a comprehensive review of the literature and the current landscape on the role of pharmacogenomics in cardiotoxicity prediction and its potential to become an additional biomarker in personalized risk assessment algorithms.Pharmacogenomics is an emerging field in oncology, one that could provide valuable input on identifying patients with inherent risk of toxicity, thus allowing for treatment tailoring and personalization on the basis of the clinical and genetic characteristics of a patient. Cardiotoxicity is a well-known side effect of anthracyclines and anti-HER2 agents, although at a much lower incidence for the latter. Data on single-nucleotide polymorphisms related to cardiotoxicity are emerging but are still scarce, mostly being of retrospective character and heterogeneous. A literature review was performed, aiming to describe current knowledge in pharmacogenomics and prediction of cardiotoxicity related to breast cancer systemic therapies and radiotherapies. Most available data regard genes encoding various enzymes related to anthracycline metabolism and HER2 polymorphisms. The available data are presented, together with the challenges and open questions in the field.

Analysis of polymorphisms in EGF, EGFR and HER2 genes in pancreatic neuroendocrine tumors (PNETs)

ObjectivesPancreatic neuroendocrine tumors (NETs) are rare and account for about 7% of all cancers occurring in the pancreas. The epidermal growth factor family of receptors and their ligands play an important role in the growth and progression of tumors but their role in PNET development remains unknown. We hypothesized that functional single nucleotide polymorphisms (SNPs) in the EGF, EGFR, and HER2 genes might affect individual susceptibility to PNETs development and invasion like it was shown for various other tumors. MethodsWe genotyped 68 patients with unresectable PNETs and 300 controls to evaluate the association between EGF, EGFR, and HER2 polymorphisms and susceptibility to PNETs and presence of metastases. ResultsGenotype analysis of three SNPs EGF +61A/G (rs4444903), EGFR +1562 G/A (rs11543848), and HER2 +1963 A/G (rs1136201) showed that carriers of EGFR +1562 AG genotype and AA/AG EGF +61/HER2 +1963 genotype combination are at risk of developing PNET. Furthermore, EGFR +1562 AA genotype could be associated with the susceptibility to insulinoma development. ConclusionsOur results suggest involvement of EGFR signaling pathway in etiology of PNET development.

Design and characterization of a SYBR Green I-based melting curve method for investigation of HER2I655V polymorphism in breast cancer

BackgroundBreast cancer is a disease in which cell grows rapidly forming a mass in the breast. HER2 polymorphisms Ile655Val have been studied as biomarkers for breast cancer and may comprise a risk factor of cardiac toxicity for breast cancer-consuming trastuzumab. Aim of work: In this study, we developed a simple, low cost, and rapid test to detect polymorphism at HER2 gene using SYBR Green I-based melting curve method. Subjects and methodsIn this report, we performed allelic discrimination with real-time temperature melting (Tm) Shift SYBR Green I-based melting curve method. The melting profiles of amplified DNA HER-2 Ile655Val and its characteristics were analyzed. ResultTm value of HER2 GG and AA alleles were 85 ± 0.14 °C and 82.5 ± 0.23 °C, respectively, while cycle threshold (Ct) value of GG, AG, and AA alleles were 19.6 ± 0.27, 22.5 ± 0.23, 18.6 ± 0.22 correspondingly; furthermore, no template control has shown consisting Ct value at 31.18 ± 0.27. The developed methods’ characteristics were optimum annealing at 62 °C and Kappa coefficient value 1 with the mean almost consistent with PCR-sequencing. The coefficient of variability for intra-assay of GG, AG, and AA was in the range of 0.2–1%, while the coefficient of variability for inter-assay for each were in the range 0.7–1%. Further, based on PCR, shelf-life assay has shown stability for 3 months of storage observation. ConclusionThis approach may be considered as simple, rapid, and low cost supporting the rapid study of HER2 epidemiology. Furthermore, the developed methods potentially facilitate clinicians in dealing with breast cancer patients, especially in considering about the cardiotoxicity effect of trastuzumab.

Association between HER2 and IL-6 genes polymorphisms and clinicopathological characteristics of breast cancer: significant role of genetic variability in specific breast cancer subtype.

Clinical implications of single nucleotide polymorphisms (SNPs) in breast cancer have been explored to determine the impact of SNP in modulating the pathogenesis of breast cancer. This study aimed to evaluate the association between HER2 (rs2517956) and (IL-6) (rs1800795 and rs2069837) and clinicopathological characteristics in HER2-positive and HER2-negative breast cancer in Tunisian women. A retrospective cohort study included 273 patients. Genomic DNA was extracted from peripheral blood samples, and genotyping of selected SNP was performed by PCR-RFLP assays. Statistical analysis was then carried out to assess genotypic frequencies and genetic association in relation to breast cancer subtypes. SHEsis software was applied to IL-6 haplotypic structure analysis. The distribution of genotype frequencies of rs2517956, rs1800795 and rs2069837 showed no statistically difference between HER2-positive and HER2-negative breast cancer. HER2 (rs2517956) was associated with tumor size (p = 0.01) and age at diagnosis (p = 0.02) in HER2-negative breast cancers, but no significant association was observed in HER2-positive breast cancer. For IL-6 gene, none of the clinicopathological parameters were associated with rs1800795 and rs2069837 in both breast cancer subtypes (p > 0.05). SHEsis analysis revealed a high linkage disequilibrium between rs1800795 and rs2069837; differences in the distribution of IL-6 two loci haplotypes were statistically negative between HER2-positive and HER2-negative breast cancer (p = 0.20) which confirmed no association with HER2 overexpression. This study demonstrates that rs2517956 is associated with clinicopathological characteristics in HER2-negative breast cancer, which could have a differential prognostic role compared to HER2-positive breast cancer.

Association between ESR1, ESR2, HER2, UGT1A4, and UGT2B7 polymorphisms and breast Cancer in Jordan: a case-control study

BackgroundBreast cancer risk, development, and treatment are influenced by genetic variation in certain genes, namely those involved in cell proliferation, tumor suppression, and drug metabolism. In turn, the relevance of the aforementioned genetic variation to cancer depends on the ethnic group in question, highlighting the need for population-specific association studies. Therefore, the objective of the present study was to investigate the association between certain ESR1, ESR2, HER2, UGT1A4, and UGT2B7 single nucleotide polymorphisms and breast cancer.MethodsBlood samples were collected from 437 Jordanian-Arab breast cancer patients and healthy volunteers and subject to genotyping using the Sequenom MassARRAY® system (iPLEX GOLD).ResultsOur findings show a significant association between breast cancer and the allelic (P = 0.02486879) and genotypic (P = 0.04793066) frequencies of the ESR1 polymorphism rs3798577, a result which was confirmed in different genetic models. No other investigated polymorphism showed a significant association with breast cancer itself in Jordanian Arabs, but the Rare Hz (GG) vs Het (AG) genetic model revealed an association of the disease with the ESR1 polymorphism rs3798577. However, several associations were found between certain polymorphisms and breast cancer’s prognostic factors.ConclusionThis study suggests that certain polymorphisms may increase the risk of breast cancer in the Jordanian-Arab population. Future research and clinical translation could incorporate the current results in preventative breast cancer approaches tailored for Jordanian-Arab patients.

The Effect of HER2 Single Nucleotide Polymorphisms on Cervical Cancer Susceptibility and Survival in a Chinese Population.

Background: Cervical cancer (CCa) is a multifactorial gynecologic disease worldwide. Effects of HER2 polymorphisms, especially those in exonic region, have been investigated in many gynecologic diseases. In this study, we evaluated the influence of functional HER2 polymorphisms on susceptibility and survival of CCa in a Chinese population.Methods: We genotyped the HER2 exonic polymorphisms by TaqMan in both case-control study (413 CCa patients vs. 396 controls) and survival study (413 CCa patients). Logistic regression and Cox regression were adopted to evaluate the genetic association with the risk and outcomes of CCa, respectively.Results: In the case-control study, there was no significant difference between patients and controls in either HER2 rs1136201 or rs1058808. However, when combined, these two polymorphisms demonstrated a significant hazardous effect for CCa (P = 0.012). Besides, number of variants was also influential (P trend =0.002). In survival analysis, dominant model of rs1136201 and co-dominant modelof rs1058808 were significantly associated with the survival (P = 0.037 and P =0.028). The combination of rs1136201 and rs1058808 also negatively impacted CCa survival (P = 0.009). Cox regression further revealed the significance of the polymorphism combination (β = 0.38, P = 0.025, HR= 1.47, 95%CI = 1.05-2.05). Functional assay of these polymorphisms demonstrated that rs1058808 G allele was associated with stronger expression of HER2 gene.Conclusions: Our results suggested that the combination of HER2 rs1136201and rs1058808 was significantly associated with the susceptibility of CCa. Besides, this combination of polymorphism s also substantially impacted the survival of CCa patients.

Frequency of I655V SNP of HER-2/neu in colorectal cancer: a study from India.

The present study was conducted to determine the prognostic significance of I655V SNP (rs1136201) is a genetic one in HER-2 oncoprotein in cases of colorectal cancer (CRC). We conducted a case-control study analysing 83 subjects (naïve primary CRC cases) who underwent CRC biopsy/colectomy and included 57 healthy control subjects. Analysis of HER-2 polymorphism was done by PCR-RFLP technique. The mean age was found to be 55.9 years; median age was 56years and mode age was 54years with a range of 43 (30-73). Males constitute 63 (75.9%) and females constitute 20 (24.1%) of patient population. According to gradewise distribution, 12 (14.45%) patients were of Grade I, 53 (63.85%) of Grade II, and 18 (21.68%) were of Grade III. We found out that out of 83 patients, 52 (62.65%) were of homozygous wild type (A/A; Ile/Ile); 27 (32.53%) were of heterozygous type (A/G; Ile/Val) and 4 (4.81%) were of homozygous mutant type (G/G; Val/Val). Allelic frequency of Ile (A) was found out to be 0.79 and that of Val (G) is 0.21 and were not significantly different from the healthy control population. Fischer's exact p value obtained was 0.86.

Genetic association between HER2 and ESR2 polymorphisms and ovarian cancer: a meta-analysis.

ObjectiveThe estrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER2) each play an important role in female cancers. This study aimed to investigate the genetic association between three common single nucleotide polymorphisms (SNPs) and the risk of ovarian cancer. The SNPs investigated in this study were ESR2 rs1271572 and rs3020450 and HER2 rs1801200.MethodsIn this study, databases were electronically searched in a meta-analysis. Databases used were PubMed, Embase, China National Knowledge Infrastructure (CNKI), Wanfang and Cochrane library. Case–control studies on the association between ESR2 and HER2 polymorphisms were selected according to inclusion and exclusion standard. Articles were evaluated for quality, and data were extracted.ResultsA total of 13 articles with 5,461 cases and 7,603 controls were included in this meta-analysis. The recessive model of ESR2 rs1271572 was shown to be significantly associated with the risk of ovarian cancer (p = 0.008, odds ratio [OR] [95% confidence interval {CI}] = 1.13 [1.03, 1.24]), and this significant association still existed in a subgroup analysis stratified by ethnicity (Asian: p = 0.04, OR [95% CI] = 1.92 [1.04, 3.56]; Caucasian: p = 0.02, OR [95% CI] = 1.12 [1.02, 1.23]). In addition, the distribution of the dominant model of ESR2 rs3020450 was significantly different in the total group (p = 0.02, OR [95% CI] = 0.71 [0.53, 0.95]) and the Caucasian subgroup (p = 0.02, OR [95% CI] = 0.67 [0.48, 0.94]). Furthermore, no significant association between allelic, dominant, codominant and recessive models of HER2 rs1801200 (V655I) and ovarian cancer was found (p > 0.05).ConclusionThe recessive model of ESR2 rs1271572 and the dominant model of ESR2 rs3020450 might be susceptible factors for ovarian cancer.

<i>ILE655VAL</i> Genotyping Study of HER2 - Positive Breast Cancer of Patients from Padang - Indonesia With High Resolution Melting Technique

Transtuzumab has proven to be a great improvement in the treatment of HER2 + of breast cancer patients, but it is associated with relevant adverse cardiac events and with significantly elevated cost of treatment. One of the risk factors for cardiotoxicity due to transtuzumab is the I655V HER2 polymorphism (GTC> ATC mutation) in which the allele mutant (Ile val or val / val) has a higher risk than the wild type (Ile/Ile). The detection of specific alleles is very important for therapeutic decision-making. In this study, our group have developed a HRM with EvaGreen dye method to discriminate specific allele of I655V HER2 (wild type, heterozygote mutant or homozygote mutant) in 66 frozen section samples of HER2+ of breast cancer patients. Our group reported the wild type is the most prevalent allele (77,27%), whereas heterozygous mutation is significantly present in this research (21,21%) and only 1,52% of sample detected as minor allele. It showed that only one sample detected as a minor allele (val/val) and may have relatively low abundance in the population. This method has been compared with sanger sequencing and giving 100% of validity.

ILE655VAL Genotyping Study of HER2 - Positive Breast Cancer of Patients from Padang - Indonesia With High Resolution Melting Technique

Transtuzumab has proven to be a great improvement in the treatment of HER2 + of breast cancer patients, but it is associated with relevant adverse cardiac events and with significantly elevated cost of treatment. One of the risk factors for cardiotoxicity due to transtuzumab is the I655V HER2 polymorphism (GTC> ATC mutation) in which the allele mutant (Ile val or val / val) has a higher risk than the wild type (Ile/Ile). The detection of specific alleles is very important for therapeutic decision-making. In this study, our group have developed a HRM with EvaGreen dye method to discriminate specific allele of I655V HER2 (wild type, heterozygote mutant or homozygote mutant) in 66 frozen section samples of HER2+ of breast cancer patients. Our group reported the wild type is the most prevalent allele (77,27%), whereas heterozygous mutation is significantly present in this research (21,21%) and only 1,52% of sample detected as minor allele. It showed that only one sample detected as a minor allele (val/val) and may have relatively low abundance in the population. This method has been compared with sanger sequencing and giving 100% of validity.

Association of Tobacco Use, Alcohol Consumption and HER2 Polymorphisms With Response to Trastuzumab in HER2-Positive Breast Cancer Patients

PurposeAlthough the administration of trastuzumab has improved the survival of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, resistance remains a major clinical obstacle. We retrospectively evaluated the association of HER2 polymorphisms, tobacco use and alcohol consumption with disease-free survival (DFS) in HER2-positive breast cancer patients. Patients and MethodsClinicopathologic and survival data (median follow-up, 7.4 years) were collected from medical records for 236 nonmetastatic trastuzumab-treated HER2-positive breast cancer patients. Tobacco and alcohol consumption were assessed using validated questionnaires, and HER2 polymorphisms (Ile655Val and Ala1170Pro) were determined by TaqMan assay. Multivariate Cox proportional hazard models were used to analyze DFS. ResultsCompared to nonsmokers, patients who smoked before breast cancer diagnosis showed a worse DFS (hazard ratio [HR], 2.63, P = .001), and this association was stronger among patients who smoked > 20 cigarettes per day or who spent more than 2 decades smoking before their diagnosis (HR, 3.65, P = .01, and HR, 3.19, P = .002, respectively). Smoking during trastuzumab treatment was associated with DFS, but only among patients with estrogen receptor–negative tumors (HR, 4.49, P = .02). Compared to nondrinkers, patients who consumed alcohol before breast cancer diagnosis had a significantly better DFS (HR, 0.56, P = .03). No association was observed between alcohol consumption during trastuzumab treatment and DFS. Concerning HER2 polymorphisms, patients with Ile/Val or Val/Val genotype had a significantly worse DFS than those with the Ile/Ile genotype (HR, 4.96, P = .01). ConclusionTobacco and alcohol consumption as well as HER2 Ile655Val polymorphism could influence trastuzumab response. These results need to be confirmed in a larger cohort study.

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

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.

Detection of HER2 polymorphism and expression using circulating DNA and RNA as a tool in lung adenocarcinoma patients: a case control study.

Circulating DNA and RNA is an important prognostic tool for noninvasive malignant disease detection and in disease prognosis. Study aimed to evaluate the possible prognostic role of HER2 (-3444C/T) promoter polymorphism and its mRNA expression in Lung adenocarcinoma patients using circulating DNA and RNA. One hundred newly diagnosed lung adenocarcinoma patients and 100 age and sex matched healthy controls were included and allele specific (AS) polymerase chain reaction (PCR) was used for genotyping and expression was analyzed by quantitative real time PCR. Overall survival of patients was analyzed by Kaplan-Meier method. We observed a statistically significant difference in the frequency of HER2 CC, CT, and CT genotype among lung adenocarcinoma cases vs. healthy controls (P=0.001). Compared to the CC genotype, OR 2.51 (1.4-4.51), 5.97 (1.17-30.41) and RR 1.56 (1.17-2.07), 2.83 (0.82-9.73) for heterozygous CT and homozygous TT genotypes suggesting possible dominant effect on risk of lung adenocarcinoma. Cases with CC genotype showed 9.29 fold increased mRNA expression while cases with heterozygous CT and homozygous TT genotype showed 16.26, 16.72 fold increased mRNA expression (P<0.0001). We observed 13.92 fold increased HER2mRNA expression Lung adenocarcinoma patients. Patients in different TNM stages showed significant difference in HER2 mRNA expression which was found to be significantly associated (P<0.0001). Patients with distant metastases and without distant metastases had 17.44 and 11.16 fold increased HER2 mRNA expression was also found to be significantly associated (P<0.0001). It was also observed that patients with pleural effusion and without pleural effusion showed significant difference in HER2 mRNA expression (P=0.03). We also analysed patients with CC, TT, CT (P=0.02) and CT + TT (P=0.008) genotype showed 15.8, 7.9, 9.5 and 7.9 months of overall median survival time and found to be significantly associated, respectively. Patients with >13 and ≤13 fold increased HER mRNA expression also showed 7.9 and 11.5 months of overall median survival time was also found to be significantly associated (P=0.01). Our work provides evidence that circulating DNA and RNA may be a potential prognostic tool in Lung adenocarcinoma patients. Promoter polymorphism of HER2 (-3444C/T) gene had significant impact on higher HER2 mRNA expression could be a predictive factor for patients' worse overall survival and metastatic behaviour.

Role of HER-2 Ile655Val Polymorphism as Universal Cancer Susceptibility Marker among Different Cancers.

Genetic and expression anomaly of HER-2 have been frequently observed in different cancers. However, an overall association of HER-2 polymorphism (Ile655Val) with available cancer studies has not yet been explored. In the present study, a probable correlation of HER-2 Ile655Val polymorphism with 6 major types of cancers including breast, lung, gastric, ovarian, thyroid and uterine has been collectively assessed. Extensive data mining was performed using online available medical research databanks including Pubmed, Ovid, Medline and Embase. Research articles were retrieved based on common keywords "HER-2, polymorphism, (SNP) and cancer (including breast, gastric, lung, ovarian, thyroid and uterine). A database was maintained and updated for case control studies of HER-2 genotype Ile655Val (rs1136201) information until February 2015. Based on selection criteria, a total of 41 studies containing 37,111 subjects (17845 patients, 19266 controls) were selected for thorough insight about HER-2. A significant risk association of HER-2 Ile655Val polymorphism was observed in different types of cancer using various genetic models (co-dominant heterogeneous Ile/Val vs Ile/Ile; OR=1.1, 95% CI = 1.01-1.16, P = 0.01 and dominant; OR = 1.12, 95% CI = 1.03-1.20, P = 0.0003). Interestingly, a strong correlation of Ile655Val heterogeneity was seen in the stratified subgroup of different population including African-American (co-dominant homogenous Val/Val vs Ile/Ile; OR = 8.7, 95% CI = 2.5-30.4, P = 0.0001, dominant; OR = 1.3, 95% CI = 1.03-1.7, P = 0.003; recessive; OR = 8.3, 95% CI = 2.4-28, P = 0.0002), Caucasians (co-dominant heterogeneous Ile/Val vs Ile/Ile; OR = 1.1, 95% CI = 1.0 - 1.2, P = 0.03, dominant; OR = 1.12, 95% CI = 1.0-1.2, P = 0.01). However, in Asian ethnic group, Ile655Val polymorphism lacked a significant association with cancer. This may be attributed to limited studies explored so far. In summary, the current study reveals a significant association between cancer susceptibility and the HER-2 Ile655Val polymorphism in all genetic models.

Abstract P6-03-09: Genetic polymorphism and correlation with treatment induced cardiotoxicity and prognosis in HER2 amplified early breast cancer patients

Abstract Introduction: Small studies have indicated a possible correlation between a HER2 gene polymorphism at codon 655 and trastuzumab-associated cardiotoxicity. Association between a synonymous coding variant rs7853758 within the SLC28A3 gene and anthracycline induced cardiotoxicity has also been reported. This study aimed to validate these correlations and assess for any relationship with prognosis. Methods: Genomic DNA was isolated from 666 patients enrolled in a large trial of adjuvant chemotherapy in HER2 amplified early breast cancer (BCIRG 006). Genotyping was conducted using Sequenom MassARRAY System for HER2 G-&amp;gt;A polymorphism at amino acid codon 655 (rs1136201) and variant rs7853758 (L461L) within the SLC28A3 gene. Results: Of the 666 patients analyzed, 216 patients were treated with anthracycline based therapy, 226 with trastuzumab based therapy, and 224 with regimens containing both an anthracycline and trastuzumab. Compared with the overall results of the BCIRG006 study (N=3,222), in the subset of patients genotyped in this analysis, a less robust improvement in disease free survival (DFS) was observed for the trastuzumab arms than control arm (HR, 0.821). When stratified for prognostic features, the hazard ratio in favor of trastuzumab was consistent with that of the overall study (HR, 0.674). Samples from 662 patients were successfully genotyped for rs1136201. Of these, 424 (64%) were AA, 30 (4.5%) were GG, 208 (31%) were AG genotype. Samples from 665 patients were successfully genotyped for rs7853758. Of these, 19 (3%) were AA, 475 (71%) were GG, and 171 (26%) were AG genotype. There was no correlation seen between mean left ventricular ejection fraction (LVEF) and HER2 genotype at codon 655 in patients treated with trastuzumab. Of patients tested for the HER2 polymorphism, cardiac dysfunction [defined as &amp;gt; 10% decline in LVEF or clinical congestive heart failure (CHF)] developed in 16% of patients with AA, 17% of patients with GG and 20% of patients with AG. There was also no correlation between mean LVEF and variant rs7853758 in patients treated with anthracyclines. The percentage of patients who developed cardiac dysfunction was 13%, 17% and 21% in AA, GG, and AG genotypes respectively. No correlation between disease free survival and any of the genotypes was seen. Conclusion: In the largest analysis to date to evaluate for relationship between cardiac toxicity and HER2 polymorphism, we did not find a correlation with rs1136201 HER2 polymorphism and trastuzumab induced cardiac toxicity. Our study also did not show a correlation between variant rs7853758 (L461L) and anthracycline induced cardiotoxicity. Neither polymorphism correlated with prognosis. Citation Format: Peddi PF, Hurvitz SA, Fasching PA, Wang L, Cunningham J, Weinshilboum RM, Liu D, Quinaux E, Fourmanoir H, Robert NJ, Valero V, Crown J, Falkson C, Brufsky A, Pienkowski T, Eiermann W, Martin M, Bee V, Slamon DJ. Genetic polymorphism and correlation with treatment induced cardiotoxicity and prognosis in HER2 amplified early breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-09.

A110: −238(G/A) TNF polymorphism impairs outcome of breast cancer patients

Tumor necrosis factor alpha (TNF) is a multifunctional cytokine, which possesses various biologic functions depending on the type of the cells and the physiological context. TNF is synthesized by immune cells as well as malignant cells. Accordingly, TNF plays an important role in the tumor and microenvironment communication as well as systemic response to the disease. TNF gene is located at HLA class III gene locus (6p21.3) and contains several sites of single nucleotide polymorphisms in promoter, which modify TNF gene expression. G to A substitution at position −238 (rs361525) decreases TNF gene expression whereas the G to A substitution at position −308 (rs1800629) increases the expression. Studies on the possible association of these polymorphisms with various malignancies risk yielded contradictory results depending on ethnicity. Breast cancer (BC) is a multifactorial disease with clinicomorphological heterogeneity. Pathways of the main BC associated molecules (ER, PR, Her2) have crossroads with TNF signaling. The goal of the study was to identify possible TNF polymorphism effects on BC predisposition and prognosis in Russian patients. Materials and methods DNA from 413 women with newly diagnosed BC and 226 women without oncological, autoimmune or inflammatory diseases (control group) was examined. Allelic variants of −238(G/A) TNF were determined by a RFLP-PCR, the −308(G/A) TNF polymorphism was analyzed by allele-specific PCR. Additionally Ile655Val HER2 polymorphism was tested by RFLP-PCR in142 BC patients. The comparison of genotypes frequencies was performed using the Fisher’s exact test. Overall survival (OS) rate of BC patients was the criterion for estimation of polymorphism prognostic significance and was analyzed by the Kaplan–Meier method. The Log-rank test was used for the comparison of different groups of patients. The difference was considered as statistically significant at p Results A minor allele −238(A) was found in 10% BC patients and in 7% women from control group. In the same way allele −308(A) was found with a close frequency in BC patients and controls (25% and 22%). It worth to note that allele A was found in two position simultaneously in Conclusions This study found out the opposite effect of polymorphisms at −238 and −308 positions in TNF promoter on the outcome of BC patients. Carriers of low expressed allele −238(A) have poor outcome because of low response to standard hormone therapy which presumably connected with the activation of Her2 pathway. The obtained results allow supposing that a special approach to the treatment of this group of BC patients should be used.

Updated meta-analysis on HER2 polymorphisms and risk of breast cancer: evidence from 32 studies.

Several studies have been performed to investigate the association of the HER2 Ile655Val polymorphism and breast cancer risk. However, the results were inconsistent. To understand the precise relationship, a meta-analysis was here conducted. A search of PubMed conducted to investigate links between the HER2 Ile655Val polymorphism and breast cancer, identified a total of 32 studies, of which 29, including 14,926 cases and 15,768 controls, with odds ratios (ORs) with 95% confidence intervals were used to assess any association. In the overall analysis, the HER2 Ile655Val polymorphism was associated with breast cancer in an additive genetic model (OR=1.136, 95% CI 1.043-1.239, p=0.004) and in a dominant genetic (OR=1.118, 95% CI 1.020-1.227, p=0.018), while no association was found in a recessive genetic model. On subgroup analysis, an association with breast cancer was noted in the additive genetic model (OR=1.111, 95% CI: 1.004-1.230, p=0.042) for the Caucasian subgroup. No significant associations were observed in Asians and Africans in any of the genetic models. In summary, our meta-analysis findings suggest that the HER2 Ile655Val polymorphism is marginally associated with breast cancer susceptibility in worldwide populations with additive and dominant models, but not a recessive model.

Retraction: The effect of HER-2 polymorphism according to age on the risk and pathologic feature of endometrial cancer.

Lee JM, Lee JH, Tong SY, Ki KD, Lee SK, Huh CY. The effect of HER-2 polymorphism according to age on the risk and pathologic feature of endometrial cancer. Korean J Obstet Gynecol 2009;52:529-537. The above article from Korean J Obstet Gynecol, published on May 2009, has been retracted by agreement between the authors, the journal Editor-in-Chief, professor Pil Ryang Lee, and publication office of Korean J Obstet Gynecol. The authors' statement follows below In 2009, we published two articles associated with the effect of HER-2 polymorphism on endometrial cancer. One article appeared in Korean J Obstet Gynecol and the other appeared in BJOG [1]. Specifically, the opening to the readers (including the opening in the online publication) of the two articles are similar. Although the article published in BJOG was designed, written, submitted and accepted earlier, we did not cite the article from BJOG because it had not yet been printed at that time. Thus, in order to make clearance for referencing issue between Korean J Obstet Gynecol and BJOG, we decided to retract the paper published in Korean J Obstet Gynecol. We regret the inadvertent omission of the appropriate referencing and offer sincere apologies to readers for any inconvenience caused by this retraction.