Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers.

Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

Prostate cancer in young men represents a distinct clinical phenotype: gene expression signature to predict early metastases.

AIM: Several genomic signatures are available to predict Prostate Cancer (CaP) outcomes based on gene expression in prostate tissue. However, no signature was tailored to predict aggressive CaP in younger men. We attempted to develop a gene signature to predict the development of metastatic CaP in young men. METHODS: We measured genome-wide gene expression for 119 tumor and matched benign tissues from prostatectomies of men diagnosed at ≤ 50 years and > 70 years and identified age-related differentially expressed genes (DEGs) for tissue type and Gleason score. Age-related DEGs were selected using the improved Prediction Analysis of Microarray method (iPAM) to construct and validate a classifier to predict metastasis using gene expression data from 1,232 prostatectomies. Accuracy in predicting early metastasis was quantified by the area under the curve (AUC) of receiver operating characteristic (ROC), and abundance of immune cells in the tissue microenvironment was estimated using gene expression data. RESULTS: Thirty-six age-related DEGs were selected for the iPAM classifier. The AUC of five-year survival ROC for the iPAM classifier was 0.87 (95%CI: 0.78-0.94) in young (≤ 55 years), 0.82 (95%CI: 0.76-0.88) in middle-aged (56-70 years), and 0.69 (95%CI: 0.55-0.69) in old (> 70 years) patients. Metastasis-associated immune responses in the tumor microenvironment were more pronounced in young and middle-aged patients than in old ones, potentially explaining the difference in accuracy of prediction among the groups. CONCLUSION: We developed a genomic classifier with high precision to predict early metastasis for younger CaP patients and identified age-related differences in immune response to metastasis development.

Genetic variation in IGFBP2 and IGFBP5 is associated with breast cancer in populations of African descent.

The insulin-like growth factor (IGF) signaling pathway is thought to play a major role in the etiology of breast cancer. Although incidence rates of breast cancer overall are lower in African Americans than in Caucasians, African-American women have a higher incidence under age 40 years, are diagnosed with more advanced disease, and have poorer prognosis. We investigated the association of breast cancer and genetic variants in genes in the IGF signaling pathway in a population-based case-control study of African-American women. We found significant associations at a locus encompassing parts of the IGFBP2 and IGFBP5 genes on chromosome 2q35, which we then replicated in a case-control study of Nigerian women. Based on those initial findings, we genotyped a total of 34 single nucleotide polymorphisms (SNPs) across the region in both study populations. Statistically significant associations with breast cancer were observed across approximately 50 kb of DNA sequence encompassing three exons in the 3' end of IGFBP2 and three exons in the 3' end of IGFBP5. SNPs were associated with breast cancer risk with P values as low as P = 0.0038 and P = 0.01 in African-Americans and Nigerians, respectively. This study is the first to report associations between genetic variants in IGFBP2 and IGFBP5 and breast cancer risk.

A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers.

BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. IMPACT: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.

Prostate cancer risk and IRS1, IRS2, IGF1, and INS polymorphisms: strong association of IRS1 G972R variant and cancer risk.

BACKGROUND: As cellular proliferation is central to the carcinogenic process, pathways that regulate proliferation may be important. Therefore, genes in the insulin and the insulin-like growth factor signaling pathways are plausible candidates for susceptibility genes for prostate cancer. We hypothesized that functional polymorphisms in INS, IRS1, IRS2, and IGF1 may be associated with prostate cancer. METHODS: We studied 199 incident prostate cancer cases and 267 age-matched controls. Genotyping was performed for the INS +1127 Ins-PstI, IRS1 G972R, IRS2 G1079D, and the IGF1 CA-repeat polymorphisms. Outcomes were prostate cancer, Gleason score, and AJCC stage. RESULTS: The IRS1 G972R GR/RR genotypes were associated with a significant 2.8-fold increased risk for prostate cancer (95% CI 1.5-5.1, P = 0.0007). The other variants were not significantly associated with prostate cancer. The IRS1 G972R GR/RR genotypes were also significantly associated with more advanced Gleason score (P = 0.001) and AJCC stage (P = 0.004). CONCLUSIONS: These results support a role of the insulin and/or insulin-like growth factor pathways in the etiology of prostate cancer.