FGFR2 Rs2981582 Research Articles

Fibroblast growth factor receptor 2 gene (FGFR2) rs2981582T/C polymorphism and susceptibility to breast cancer in Saudi women

Fibroblast growth factor receptor 2 is a protein encoded by FGFR2 gene and plays an important role in cellular growth. This study was conducted to investigate a potential association of FGFR2 rs2981582 with breast cancer. DNA was obtained from 137 Formalin-fixed, paraffin-embedded tumors and 98 normal breast tissue samples. Genotypes were carried out with PCR-RFLP. The odds ratio and 95% confidence interval (CI) were used to evaluate the power of the associations. A significant association between FGFR2 rs2981582 C allele and susceptibility to breast cancer was found (p-value < 0.0001, Odds Ratio = 2.3, %95 CI (1.5–3.0). No significant differences in FGFR2 rs2981582 genotypes and alleles distribution among breast patients with different hormonal receptor status (p > 0.05) were detected. However, a significant difference was found in genotypes and alleles distribution in ER+, PR- and HER2 between breast cancer cases and controls. This study showed an association of FGFR2 rs2981582T/C with breast cancer in Saudi women, further large study is required to validate the results.

Genetic polymorphism of fibroblast growth factor receptor 2 and trinucleotide repeat-containing 9 influence the susceptibility to HCV-induced hepatocellular carcinoma

BackgroundFibroblast growth factor receptor 2 (FGFR2) and trinucleotide repeat-containing 9 (TNRC9) gene polymorphisms have been associated with some cancers. We aimed to assess the association of FGFR2 rs2981582 and TNRC9 rs12443621 polymorphisms with hepatocellular cancer risk. MethodsOne hundred patients with HCV-induced HCC, 100 patients with chronic HCV infection, and 100 controls were genotyped for FGFR2 rs2981582 and TNRC9 rs12443621 using allele-specific Real-Time PCR analysis. ResultsFGFR2 rs2981582 genotype TT was associated with increased risk of HCC when compared to controls (OR = 3.09, 95% CI = 1.24–7.68). However, it was significantly associated with a lower risk of HCC when using HCV patients as controls (OR = 0.21, 95% CI = 0.09–0.5), and T-allele of FGFR2 appears to be a protective allele against HCC in HCV patients (OR = 0.42, 95% CI = 0.21−0.85). While AG and GG genotypes of TNRC9 rs12443621 were linked with significantly increased risk of HCC (OR = 3.91, 95% CI = 2.02–7.6 and OR = 9.26, 95% CI = 3.21–26.7 respectively) and HCV patients carrying G allele were at increased risk of HCC by 2.7-fold. A significant high frequency of small tumor size and early-stage of HCC were observed in patients carrying FGFR2 rs2981582 genotype CT and TT (P = 0.029 and <0.001 respectively), while, TNRC9 rs12443621 genotype AG and GG were associated large tumor size and late-stage of HCC (P < 0.001 and 0.015 respectively). ConclusionsSNPs in rs2981582 for FGFR2 and rs12443621 for TNRC9 gene were associated with HCC susceptibility, suggesting their implication in hepatocarcinogenesis in chronically HCV-infected patients.

Low-penetrance susceptibility variants and postmenopausal oestrogen receptor positive breast cancer

The risk of breast cancer (BC) in women is high and many factors including genetic factors increase the risk for the disease. It is revealed that the variations of low-penetrance susceptibility genes are important for carcinogenesis as they interact with the environmental and hereditary factors. Recently, the list of BC-associated common single nucleotide polymorphisms (SNPs) and chromosomal loci in low-penetrance susceptibility genes have been expanded in genomewide association studies. FGFR2, LSP1, MAP3K1, TGFB1, TOX3, 2q35 and 8q loci variations are some examples for these common SNPs. These SNPs and their association with BC risk was investigated in many different populations. Therefore in this study, we aimed to evaluate low-penetrance susceptibility SNPs; namely FGFR2 rs1219648, rs2981579, rs2981582; MAP3K1 rs889312; TOX3 rs3803662; LSP1 rs909116, rs3817198 and SLC4A7 rs4973768 together, for the firsttime in Turkish postmenopausal oestrogen receptor positive BC cases. Following the DNA isolation, multiplex PCR and matrix-assisted laser desorption/ionization mass spectrometry with time of flight measurement (MALDI-TOF) based SNP analysis were performed. MAP3K1 rs889312 SNP demonstrated the strongest association with BC risk among the other low penetrant SNPs, it was also associated with BC risk in a dominant model. Only in a ressesive model, TOX3 rs3803662 was associated with BC risk. In addition, rs4973768 CC and rs909116 CC genotypes are correlated with higher tumour size which is not reported in the literature as yet; on the other hand there are no associations between any of the other SNP genotypes and clinopathological parameters. In our opinion, MAP3K1 rs889312 may be a good BC susceptibility biomarker candidate for Turkish population.

Determination of SIRT1 rs12778366, FGFR2 rs2981582, STAT3 rs744166, and RAGE rs1800625 Single Gene Polymorphisms in Patients with Laryngeal Squamous Cell Carcinoma.

Purpose To determine the frequency of the genotype of signal transducer and activator of transcription protein 3 (STAT3) rs744166, sirtuin (SIRT1) rs12778366, fibroblast growth factor (FGFR2) rs2981582, and advanced glycosylation end product-specific receptor (RAGE) rs1800625 gene polymorphisms in patients with laryngeal squamous cell carcinoma (LSCC). Methods A total of 944 subjects were evaluated, which includes 144 patients with LSCC and 800 healthy controls. The genotyping of STAT3 rs744166, SIRT1 rs12778366, FGFR2 rs2981582, and RAGE rs1800625 was carried out using the RT-PCR. Results The analysis of STAT3 rs744166, SIRT1 rs12778366, and FGFR2 rs2981582 gene polymorphisms did not reveal any differences in genotype distribution between the patients with LSCC and the control subjects. However, statistical analysis revealed that genotypes (AA, AG, and GG) of rs1800625 in RAGE gene were distributed statistically significantly differently between patients and controls (61.1%, 30.6%, and 23.6% vs. 72.5%, 25.8%, and 1.8%, respectively; p < 0.001). Additionally, statistical significance was observed in allele distribution between these two groups, i.e., allele G at rs1800625 was more frequently observed in the patient group than in controls (23.6% vs. 14.6%; p < 0.001). Conclusion RAGE rs1800625 gene polymorphism may play a significant role in laryngeal squamous cell carcinoma development.

P21 Ser31Arg and FGFR2 rs2981582 Polymorphisms as Risk Factors for Early Onset of Breast Cancer in Yogyakarta, Indonesia.

Objectives:Breast cancer tend to be more progressive with poorer prognosis in younger patients than those at an older age. Single Nucleotide Polymorphisms (SNPs) of P53 Pro72Arg, MDM2 SNP309, P21 Ser31Arg, ER SNP594, HER2 Ile655Val, and FGFR2 rs2981582 have drawn attention as genetic factors associated with cancer risk. However, there were contradictory results involving different races and their association is still unknown in Indonesian populations. This study was performed to examine the proportion of these six genes polymorphisms and their associations with age of onset of breast cancer patients in Yogyakarta, Indonesia. Methods:Biorepository DNA from 199 patients registered at Dr. Sardjito Hospital Yogyakarta from 2006-2013 were tested for polymorphisms using the PCR-RFLP method. Samples were taken from two age groups; early-onset (<40 years) and late-onset of breast cancer (>55 years). Chi-square tests with odds ratio were used for data analysis. Results:The mean age of the early-onset group was 36±4.2 years, while the late-onset group was 62±6.9 years. AA genotype and A allele of P21 and TT genotypes and T allele of FGFR2 were significantly more frequent and were associated with an increased risk of early-onset of breast cancer (95%CI: 2.54 and 1.59; 2.63 and 1.64, respectively). Conclusions:Our study indicates that the A allele of P21 and the allele T of FGFR2 may be associated with an increased risk of early-onset of breast cancer in Yogyakarta, Indonesia. Further analysis is needed to confirm the findings.

FGFR2 gene polymorphism rs2981582 is associated with non-functioning pituitary adenomas in Chinese Han population: a case-control study.

The association of the fibroblast growth factor receptor 2 gene (FGFR2) polymorphism rs2981582 with breast cancer has been extensively studied, whereas the role of this polymorphism in non-functioning pituitary adenoma (NFPA) has not been elucidated. We thus investigated a potential association of rs2981582 with NFPA. A total of 79 patients and 142 healthy control participants were enrolled in our study. DNA of the participants was extracted from peripheral blood samples and genotyped by using the MassARRAY method. We found that the AA genotype was associated with a higher risk of developing NFPA (OR = 1.743, 95%CI: 1.151–2.64, P=0.008). After adjusting for risk factors, significant difference was still observed between the two groups (OR = 1.862, 95%CI: 1.172–2.957, P=0.008). Moreover, under the assumptions of the recessive model (OR = 3.051, 95%CI: 1.403–6.635, P=0.005) and the additive model (AG: OR = 0.329, 95%CI: 0.144–0.755, P=0.009; AA: OR = 0.326, 95%CI: 0.141–0.757, P=0.009), rs2981582 was associated with an increased risk of NFPA. Our results proved that FGFR2 rs2981582 AA genotype was associated with a higher risk of NFPA. The recessive model and additive model also showed increased the risk of NFPA.

SIRT1 rs12778366, FGFR2 rs2981582, STAT3 rs744166, LIPC rs10468017, rs493258 and LPL rs12678919 genotypes and haplotype evaluation in patients with age-related macular degeneration

ObjectiveAge-related macular degeneration (AMD) is the leading cause of blindness in elderly individuals in the developed countries. The etiology of AMD is thought to be multifactorial, including environmental and genetic factors. Our purpose was to determine the genotype frequencies of six different SNPs in genes that encode proteins involved in AMD-related molecular changes (SIRT1 rs12778366, FGFR2 rs2981582, STAT3 rs744166, LIPC rs10468017, rs493258 and LPL rs12678919) for evaluation of haplotype risk in patients with AMD. MethodsThe study cohort consisted of 652 AMD patients and 829 healthy controls. The genotyping was carried out using the RT-PCR. ResultsTT genotype of the LIPC rs493258 polymorphism was associated with decreased odds of early AMD development under the codominant and recessive models (OR = 0.446; 95% CI: 0.258–0.772; p = 0.004 and OR = 0.455; 95% CI: 0.274–0.756; p = 0.002, respectively) after Bonferroni correction, (p > 0.05/6, since we analyzed 6 different SNPs). The haplotype containing the two minor alleles T-T in rs10468017-rs493258 were significantly (p = 0.034) associated with early AMD development decreasing. There were no associations found with atrophic AMD development. ConclusionThe study showed that LIPC rs493258 gene and haplotype containing the two minor alleles T-T in rs10468017-rs493258 may decrease AMD development.

Association of FGFR2 and PI3KCA genetic variants with the risk of breast cancer in a Chinese population.

PurposeGenome-wide association studies have found plenty of single nucleotide polymorphisms (SNPs) which are associated with breast cancer risk. SNPs in FGFR2 are mostly identified. However, the association between PI3KCA SNP and breast cancer risk remains largely unknown. The aim of this study was to investigate the significance of FGFR2 and PI3KCA genetic variants in breast cancer and their association with prognosis.MethodsWe performed genotyping of 328 breast cancer patients and 389 healthy controls. Then, we evaluated the associations of FGFR2 rs1219648 and PI3KCA rs6443624 with the susceptibility and clinicopathological features of breast cancer. Kaplan-Meier curve with log-rank test was performed to determine the prognostic values of FGFR2 rs1219648 and PI3KCA rs6443624.ResultsThe results indicated that genotype frequencies of rs1219648 and rs6443624 were significantly different between breast cancer patients and healthy controls. Furthermore, PI3KCA rs6443624 A carriers and FGFR2 rs1219648 G carriers more frequently had advanced stages and shorter survival times.ConclusionThe SNPs of FGFR2 rs1219648 and PI3KCA rs6443624 may contribute to the identification of breast cancer patients at risk of more aggressive disease and may be potential prognostic factors in breast cancer in a Chinese population.

Frequency of 14 genetic variants associated with breast cancer risk and treatment in a Colombian population

Introducción: las variaciones genéticas se han relacionado con el riesgo y la eficacia del tratamiento. Es sabido que muchos polimorfismos en cáncer de mama influyen en la susceptibilidad, el riesgo de cáncer y el resultado del tratamiento. Los polimorfismos varían entre las poblaciones, y por tanto, es necesario realizar estudios locales.Objetivo: establecer la frecuencia de polimorfismos asociados al riesgo de cáncer de mama y la farmacogenómica del tratamiento en un grupo de individuos colombianos.Métodos: los datos de los perfiles de microarreglos, incluidos los polimorfismos genéticos asociados con el tratamiento del cáncer de mama, se obtuvieron de forma retrospectiva (Pathway Genomics®). Se estudiaron la frecuencia del marcador CYP2D6 rs3892097 y un panel de cáncer de mama (CAS8 rs1045485, CHEK21100delC, ESR1 rs2046210, FGFR2 rs1219648, intergenic_2q35rs13387042, intergenic_8q24 rs13281615, MSRP30 rs10941679, TNRC9 rs3803662, AKAP9 rs6964587, LSP1 rs3817198, MAP3K1rs889312, PALBS1592 delT, ESR1 rs3020314).Resultados: se analizaron los datos de microarreglos de 68 hombres y 92 mujeres. Todos los polimorfismos siguieron el equilibrio Hardy-Weinberg. Las frecuencias fenotípicas de CYP2D6 rs3892097 C/T, CAS8 rs1045485 G/C, y aquellas de los genes incluidos en un panel de cáncer de mama (CAS8 rs1045485, CHEK21100delC, FGFR2rs1219648, intergenic_2q35rs13387042, intergenic_8q24 rs13281615, MSRP30 rs10941679, TNRC9 rs3803662, LSP1 rs3817198, MAP3K1rs889312, PALBS1592 del T, ESR1rs3020314) no difirieron significativamente de los datos publicados previamente. ESR1 rs2046210, con frecuencias alélicas de C = 0,04 y T = 0,02, y AKAP9 rs6964587, con una frecuencia de A = 0,005, se determinaron como raras.

Smoking and FGFR2 rs2981582 variant independently modulate male breast cancer survival: A population-based study in Tuscany, Italy

AimMale breast cancer (MBC) is a rare disease and recommendations for its clinical management are often extrapolated from those for female breast cancer, even if breast cancer (BC) has different characteristics in the two sexes. The purpose of this study was to assess the influence of several individual characteristics including clinico-pathological, lifestyle and genetic factors on overall survival (OS) of a relatively large and well characterized population-based series of 166 MBCs enrolled in Tuscany. MethodsWe genotyped MBC cases at BRCA1/2 genes and at 9 candidate BC susceptibility SNPs. Kaplan-Meier method and multivariate Cox regression, adjusted for several individual characteristics were used. To reduce a possible selection bias related to the interval between diagnosis and enrolment of MBC cases into the study, we used the date of blood donation as the date of the start of observation for survival analysis. ResultsOnly smoking habits had a significant effect on OS at 10 years (for current smokers, HR: 3.34; 95% CI 1.45–7.68; p = 0.004), while lymph node status fell short of reaching statistical significance (for pN positive, HR: 2.07; 95% CI 0.93–4.55; p = 0.07). In the same multivariate analysis we found a significantly higher OS in cases with FGFR2 rs2981582 variant in the dominant transmission model (HR: 0.29; 95% CI: 0.13–0.62; p = 0.028). A sensitivity analysis with left truncation showed similar results. ConclusionsOur results may contribute to shed light on factors influencing MBC survival suggesting an important role for cigarette smoking and FGFR2 rs2981582 variant, and provide clues for better patient management.

A polygenic risk score for breast cancer risk in a Taiwanese population.

Multiple common variants identified by genome-wide association studies showed limited evidence of the risk of breast cancer in Taiwan. In this study, we analyzed the breast cancer risk in relation to 13 individual single-nucleotide polymorphisms (SNPs) identified by a GWAS in an Asian population. In total, 446 breast cancer patients and 514 healthy controls were recruited for this case-control study. In addition, we developed a polygenic risk score (PRS) including those variants significantly associated with breast cancer risk, and also evaluated the contribution of PRS and clinical risk factors to breast cancer using receiver operating characteristic curve (AUC). Logistic regression results showed that nine individual SNPs were significantly associated with breast cancer risk after multiple testing. Among all SNPs, six variants, namely FGFR2 (rs2981582), HCN1 (rs981782), MAP3K1 (rs889312), TOX3 (rs3803662), ZNF365 (rs10822013), and RAD51B (rs3784099), were selected to create PRS model. A dose-response association was observed between breast cancer risk and the PRS. Women in the highest quartile of PRS had a significantly increased risk compared to women in the lowest quartile (odds ratio 2.26; 95% confidence interval 1.51-3.38). The AUC for a model which contained the PRS in addition to clinical risk factors was 66.52%, whereas that for a model which with established risk factors only was 63.38%. Our data identified a genetic risk predictor of breast cancer in Taiwanese population and suggest that risk models including PRS and clinical risk factors are useful in discriminating women at high risk of breast cancer from those at low risk.

Association of single nucleotide polymorphisms in FGF-RAS/MAP signalling cascade with breast cancer susceptibility.

The fibroblast growth factor receptors (FGFRs) and Ras/mitogen activated protein (RAS/MAP) signalling cascades are the main molecular pathways involved in breast carcinogenesis. This study aims to determine the association between FGF10 (rs4415084 C>T), FGFR2 (rs2981582 C>T) and MAP3K1 (rs889312 A>C) gene polymorphisms and breast cancer, to analyse the discriminative ability of each SNP and to test the accuracy of the predictive breast cancer risk model which includes all SNPs. We conducted a case-control study of 170 women (57.06 ± 11.60 years) with histologically confirmed breast cancer and 146 controls (50.24 ± 10.69 years). High resolution melting (HRM) method with Sanger sequencing validation was used in analyses. We have revealed significant association of FGFR2 and MAP3K1 polymorphisms with breast cancer. The odds ratio of FGFR2 T allele was 1.897 (95% CI 1.231-2.936, p = 0.004) and MAP3K1 C allele 1.804 (95% CI 1.151-2.845, p = 0.012). FGFR2 polymorphism achieved the best discriminative ability (41.95%). The Random Forest algorithm selected FGFR2, MAP3K1 and age as important breast cancer predictors. The accuracy of this prediction model approached moderate accuracy (70%), with 35.9% sensitivity and 88.6% specificity.

Association of discovered novel SNPs of FGFR2 and MAP3K1 genes from next-generation sequencing with the prognosis of hormone receptor-positive early breast cancer patients.

e12054Background: We and other investigators have demonstrated that CYP19TTTA repeat polymorphism, MAP3K1 rs889312, FGFR2 rs2981582, ABCB1 rs2032582, and TOX3 rs3803662 are associated with the prognosis of hormone receptor (HR)-positive early breast cancer patients. In this study, we assessed whether undiscovered single nucleotide polymorphisms (SNPs) of CYP19A1, MAP3K1, FGFR2, ABCB1, and TOX3are associated with clinical outcome of these patients. Methods: Using next-generation sequencing (NGS), we performed target region re-sequencing to analyze unidentified SNPs located in the candidate genes of CYP19A1, MAP3K1, FGFR2, ABCB1, and TOX3 in 84 HR+ early breast cancer patients with negative or 1 to 3 lymph nodal (LN) metastases. Among them, 74 (88.1%) with grade 1-2, 15 (17.9%) with HER2, and 16 (19.0%) with positive LN. The multivariate-adjusted hazard ratio of overall survival (OS) associated with the individual genotypes was assessed after adjusting for age, tumor size, tumor grade, HER2 status, and chem...

Genetic and Computational Analysis of Tgfb1 &amp; Fgfr2 Polymorphism in Correlation to Breast Cancer Susceptibility in Pakistani Women

Worldwide genome-wide association studies have proven very helpful in analyzing the association of susceptible breast cancer genes. In the study presenting here association of susceptible genes FGFR2 and TGFB1 to breast cancer development was explored in Pakistani population which will be helpful in determining the choice of therapy and genetic counseling for ultimately cure of the disease and better treatment. The outcome is that we analyzed 100 samples including follow up patients and found that T-C base substitution of FGFR2 rs1219648 and rs2981582 was strongly associated with the risk of breast cancer whereas the T-C base substitution of TGFB1 rs1800470 was found in some cases though not in all patients suggesting its association within specific caste Awan and Rajput belonging to Mianwali and Khushab district area and thereby elucidating weak association with breast cancer risk. In follow ups we have analyzed that patient with T nucleotide at base position 88 had showed no therapeutic response to chemotherapy i.e. taxanestamoxifen, whereas individuals with C nucleotide chemotherapy was effective. In Silico analysis revealed that mutations of FGFR2 are in intronic region. We subsequently scanned its intronic region. We subsequently scanned its intronic region and mutant structure comparison of TGFB1 with native showed drastic change in its structure having stemmed –loop which blocks the receptor site. Detailed medical history of patients revealed that in our population breast cancer is strongly associated with risk factors such as post menopause, high tea consumption and same caste of spouse and previous breast biopsy. Statistical analysis showed that the frequency of breast cancer at age greater than 40 is higher. It has also been seen that women who had children after age 30 were more susceptible to breast cancer. P value was greater than 0.1 which is not significant showing its high prevalence in our society similar to western population. Phylogenetic analysis has also been done on both genes. In FGFR2 mouse and humans are in same clusters showing close relation whereas in TGFB1 horse and chimpanzee show convergence to human. This analysis will help in choice of economical organism for pharmacogenomics to check drug response.

Abstract P3-06-02: Genetic polymorphisms from genome-wide association study associated with the metabolic and cell proliferation pathways affect the time to distant metastases of hormone receptor-positive and Her2-negative early breast cancer

Abstract Background: Single nucleotide polymorphisms (SNPs) identified from genome-wide association study (GWAS) have been found to be associated with breast cancer risk. We hypothesized that candidate genes and genes derived from GWAS involving in the Estrone/Estradiol (E2)/Tamoxifen biosynthesis may influence the adjuvant hormonal therapy effect and the survival. In this study, we sought to investigate whether these SNPs are associated with prognosis of hormone receptor (HR)-positive breast cancer patients, especially in HER2-negative patients. Patients and methods: We selected breast cancer susceptibility SNPs identified by GWAS, SNPs in tamoxifen metabolizing related genes, and SNPs in estrogen receptor genes and estrogen metabolism genes, and genotyped for variations of above genes, including ALDH3A1, CYP2C19, COMT, CYP19, MAP3K1, FGFR2, TNRC9, HCN1, ERCC4, CYP3A5, UGT1A1, ER, ABCG2, CYP2B6, CYP2D6, 5p12 in 171 hormone receptor-positive, and Her2-negative early breast cancer patients (127 with negative lymph node [LN], and 44 with 1–3 positive LN). All patients received adjuvant hormonal therapy. The associations were examined between SNPs and distance disease-free survival (DDFS), and overall survival (OS) by using the log-rank test and Cox's proportional hazard model. Furthermore, we combined clinicopathologic features and SNPs into the risk score analysis to further validate above identified genetic markers. Results: We found that SNPs of CYP2B6 (rs3211371), FGFR2 (rs2981582), and MAP3K1 (rs889312) were significantly associated with DDFS and OS. Furthermore, in lymph node-negative patients, CYP2B6 (rs3211371), FGFR2 (rs2981582), MAP3K1 (rs889312) and 5p12 (rs10941679 and rs4415084) were significantly associated with DDFS and OS, while CYP3A5 (rs776746) was significantly associated with OS but not DDFS. We further assessed the associations of disease prognosis with the number of high-risk genotypes in CYP3A5, FGFR2, and MAP3K1, and showed significant dose-response relationships between the number of high-risk alleles at these 3 loci and DDFS (P = 0.005 for trend) and OS (P = 0.0008 for trend). When combining the clinicopathologic features and SNPs into the risk score analysis, patients were divided into 3 subgroups (subgroup 1, risk score&amp;lt;-1.438, n=43 [LN-positive, n=7]; subgroup 2, risk score between −1.438 and 1.708, n=85 [LN-positive, n=26]; subgroup 3, risk score&amp;gt;1.708, n=43 [LN-positive, n=11]). We found that around 20 % of subgroup 3 patients had early development of distant metastases (DM) in the upfront 3 years (the trend of DM appeared to persist at least 10 years), and subgroup 2 patients had higher risk of DM after 5 years, whereas subgroup 1 patients had no development of DM even after 12 years. Conclusion: Our results indicate that in addition to drug metabolic genes, genes related to cell proliferation, anti-apoptosis, and signaling transduction, for example, CYP3A5, CYP2B6, FGFR2, and MAP3K1 genes were associated with DDFS and OS in HR-positive/Her2-negative breast cancer patients. These findings provide additional insight that the genetic variants, or host factors, may affect the prognosis of breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-02.

Genetic variants in FGFR2 and MAP3K1 are associated with the risk of familial and early-onset breast cancer in a South-American population

Genome-Wide Association Studies have identified several loci associated with breast cancer (BC) in populations of different ethnic origins. One of the strongest associations was found in the FGFR2 gene, and MAP3K1 has been proposed as a low-penetrance BC risk factor. In this study, we evaluated the associations among FGFR2 SNPs rs2981582, rs2420946, and rs1219648; and MAP3K1 rs889312, with BC risk in 351 BRCA1/2-negative Chilean BC cases and 802 controls. All the SNPs studied were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC, in a dose-dependent manner. Subjects with 3 risk alleles were at a significantly increased risk of BC compared with subjects with 0-2 risk alleles, in both familial BC and early-onset non-familial BC (OR = 1.47, 95 % CI 1.04-2.07, P = 0.026 and OR = 2.04 95 % CI 1.32-3.24, P < 0.001, respectively). In the haplotype analysis, the FGFR2 rs2981582 T / rs2420946 T / rs1219648 G haplotype (ht2) was associated with a significantly increased BC risk compared with the rs2981582 C / rs2420946 C / rs1219648 A haplotype in familial BC and in non-familial early-onset BC (OR = 1.32, 95 % CI 1.06-1.65, P = 0.012; OR = 1.46, 95 % CI 1.11-1.91, P = 0.004, respectively). When the FGFR2 ht2 and MAP3K1 rs889312 were evaluated as risk alleles, the risk of BC increased in a dose-dependent manner as the number of risk alleles increased (P trend <0.0001), indicating an additive effect. Nevertheless, there is no evidence of an interaction between FGFR2 ht2 and the MAP3K1 rs889312 C allele. These findings suggest that genetic variants in the FGFR2 and MAP3K1 genes may contribute to genetic susceptibility to BC.

Replication of five GWAS-identified loci and breast cancer risk among Hispanic and non-Hispanic white women living in the Southwestern United States

Genome-wide association studies (GWAS) have identified several loci as being associated with breast cancer in mostly European populations. We focus on TNRC9 rs3803662, FGFR2 rs1219648 and rs2981582, MAP3K1 rs889312, and 2q35 rs13387042, to replicate in the 4-Corner's Breast Cancer Study of Hispanic (N=565 cases and 714 controls) and non-Hispanic white (NHW) women (N=1177 cases and 1330 controls). We evaluate associations by ethnicity, menopausal status, and tumor ER/PR status after adjusting for genetic admixture. TNRC9 AA genotype was associated with significant increased risk among NHW women (OR 1.54, 95% CI 1.14, 2.08; P trend 0.003). Both polymorphisms of FGFR2 were associated with statistically significant increased risk for NHW and Hispanic women; MAP3K1 was not associated with risk among either ethnic group. The polymorphism on 2q35 was associated with a statistically significant increased risk among Hispanic women (OR 1.53, 95% CI 1.08, 2.15 for the AA genotype; P trend=0.004). Associations were significantly different among pre/peri-menopausal women for TNRC9 (P heterogeneity 0.008) and for 2q35 (P heterogeneity 0.08) for NHW and Hispanic women. Both FGFR2 polymorphisms reduced risk of ER-/PR- tumors in the presence of the minor allele among NHW women. Among Hispanic women, polymorphisms of the FGFR2 gene were associated with almost a twofold increase risk of an ER+/PR+ tumor, while non-significantly inversely associated with ER-/PR- tumors. Our data replicated some of the previously reported GWAS findings. Differences in associations were detected for NHW and Hispanic women by menopausal status and by ER/PR status of tumors.

Genetic polymorphisms and breast cancer risk: evidence from meta-analyses, pooled analyses, and genome-wide association studies

To address the association between variants and breast cancer, an increasing number of articles on genetic association studies, genome-wide association studies (GWASs), and related meta- and pooled analyses have been published. Such studies have prompted an updated assessment of the associations between gene variants and breast cancer risk. We searched PubMed, Medline, and Web of Science and retrieved a total of 87 meta- and pooled analyses, which addressed the associations between 145 gene variants and breast cancer. Analyses met the following criteria: (1) breast cancer was the outcome, (2) the articles were all published in English, and (3) in the recent published meta- and pooled analyses, the analyses with more subjects were selected. Among the 145 variants, 46 were significantly associated with breast cancer and the other 99 (in 62 genes) were not significantly associated with breast cancer. The summary ORs for the 46 significant associations (P<0.05) were further assessed by the method of false-positive report probability (FPRP). Our results demonstrated that 10 associations were noteworthy: CASP8 (D302H), CHEK2 (*1100delC), CTLA4 (+49G>A), FGFR2 (rs2981582, rs1219648, and rs2420946), HRAS (rare alleles), IL1B (rs1143627), LSP1 (rs3817198), and MAP3K1 (rs889312). In addition, eight GWASs were identified, in which 25 loci were obtained (14 in nine genes, six near a gene or genes, and five intergenic loci). Of the 25 SNPs, 20 were noteworthy: C6orf97 (rs2046210 and rs3757318), FGFR2 (rs2981579, rs1219648, and rs2981582), LSP1 (rs909116), RNF146 (rs2180341), SLC4A7 (rs4973768), MRPS30 (rs7716600), TOX3 (rs3803662 and rs4784227), ZNF365 (rs10995190), rs889312, rs614367, rs13281615, rs13387042, rs11249433, rs1011970, rs614367, and rs1562430. In summary, in this review of genetic association studies, 31.7% of the gene-variant breast cancer associations were significant, and 21.7% of these significant associations were noteworthy. However, in GWASs, 80% of the significant associations were noteworthy.

Evaluating cancer epidemiologic risk factors using multiple primary malignancies.

Several authors have proposed the use of patients with double primary malignancies affecting the same or contralateral organ as a genetically enriched resource of cases for epidemiologic case-control studies in cancer. Such an approach is based on the assumption that the factors that increase the risk of a second primary are the same ones which influence the risk of a first primary. The advantages for statistical power are premised on the assumption that relative risks in survivors of a first primary cancer are similar to relative risks in the unaffected population. We explore these assumptions theoretically and empirically using published data from breast cancer studies involving bilateral breast cancer. We conducted a literature review to identify case-control studies of variants in 4 genes known to affect breast cancer risk: CHEK2*1100delC; multiple variants in BRCA1 and BRCA2; and FGFR2 rs2981582. Summary odds ratios were obtained for each of 3 study designs: a conventional case-control design, the design comparing bilateral cases with unilateral controls, and the design comparing bilateral cases with population controls. The data show strong patterns of steadily increasing prevalence of risk factors from healthy controls to primary cases to bilateral cases, as expected. Relative risks in survivors of unilateral breast cancer are either the same as in the general population, or modestly attenuated. Patients with double primary malignancies are a very important underused resource for cancer epidemiologic investigation. Such patients are especially useful for broad genome-wide discovery studies, and for studies of rare, strong risk factors such as high penetrance genes.

Association of FGFR2 gene polymorphisms with the risk of breast cancer in population of West Siberia

Polymorphisms within intron 2 of the FGFR2 gene have been associated with increased risk of breast cancer (BC) in European and Asian populations. The study by Easton et al reported two FGFR2 SNPs, rs2981582 and rs7895676, to be among those most strongly associated with BC risk. Statistical modeling suggested that rs7895676 was the variant responsible for the association observed in the region. In this work, we studied the association between seven FGFR2 SNPs, including rs2981582 and rs7895676, and BC risk in the Russian population of 766 case and 665 control women from Siberia, Russian Federation. In our population, allelic frequencies and the magnitude of linkage disequilibrium (LD) were different from those observed in European and Asian populations. The following three SNPs were significantly associated with BC in our study: rs7895676[C] (odds ratio (OR)=1.28 (1.12-1.43), P=1.7 x 10(-3)), rs2981582[T] (OR=1.46 (1.30-1.62), P=2 x 10(-6)) and rs3135718[G] (OR=1.43 (1.27-1.58), P=6 x 10(-6)). The latter two SNPs were in strong (r(2)=0.95) LD in our sample. Maximum likelihood analysis showed that the model, including rs7895676, only explains that the association is significantly (P<0.001) worse than any of the models, including either rs2981582 or rs3135718. Thus, in addition to the confirmation of association of FGFR2 with the BC risk in this new population, our study has suggested that rs7895676 is not likely to represent the causative variant.