Search

Fig. S6. Examples of the genes that remain significant after adjusting for the Risk-Of-Recurrence for LIBCSP participants.

Table S2 (Excel file). Full list of the genes included in the panel (not showed 6 reference genes: CLTC, GAPDH, GUSB, HPRT1, PGK1 and TUBB). Columns are as follows: 1) HUGO gene symbol; 2) shows association with miR-500a activity by ActMiR algorithm in TCGA dataset; 3) presence in PAM50 panel; 4) differentially expressed in MCF7 cells after modulation of miR-500a (overexpression of mimic or antagonist).

Purpose: Breast cancer is among the leading causes of cancer-related death; discovery of novel prognostic markers is needed to improve outcomes. Combining systems biology and epidemiology, we investigated miRNA-associated genes and breast cancer survival in a well-characterized population-based study.Experimental Design: A recently developed algorithm, ActMiR, was used to identify key miRNA “activities” corresponding to target gene degradation, which were predictive of breast cancer mortality in published databases. We profiled miRNA-associated genes in tumors from our well-characterized population-based cohort of 606 women with first primary breast cancer. Cox proportional hazards models were used to estimate HRs and 95% confidence intervals (CI), after 15+ years of follow-up with 119 breast cancer–specific deaths.Results: miR-500a activity was identified as a key miRNA for estrogen receptor–positive breast cancer mortality using public databases. From a panel of 161 miR-500a–associated genes profiled, 73 were significantly associated with breast cancer–specific mortality (FDR < 0.05) in our population, among which two clusters were observed to have opposing directions of association. For example, high level of SUSD3 was associated with reduced breast cancer–specific mortality (HR = 0.3; 95% CI, 0.2–0.4), whereas the opposite was observed for TPX2 (HR = 2.7; 95% CI, 1.8–3.9). Most importantly, we identified set of genes for which associations with breast cancer–specific mortality were independent of known prognostic factors, including hormone receptor status and PAM50–derived risk-of-recurrence scores. These results are validated in independent datasets.Conclusions: We identified novel markers that may improve prognostic efficiency while shedding light on molecular mechanisms of breast cancer progression. Clin Cancer Res; 24(3); 581–91. ©2017 AACR.

Legends for Supplemental Tables

Purpose: To explore the etiologic role of genetic variants in telomere pathway genes and breast cancer risk.Methods: A population-based case-control study, the Long Island Breast Cancer Study Project, was conducted, and 1,067 cases and 1,110 controls were included in the present study. Fifty-two genetic variants of nine telomere-related genes were genotyped.Results: Seven single nucleotide polymorphisms (SNP) showed significant case-control differences at the level of P < 0.05. The top three statistically significant SNPs under a dominant model were TERT-07 (rs2736109), TERT-54 (rs3816659), and POT1-03 (rs33964002). The odds ratios (OR) were 1.56 [95% confidence interval (95% CI), 1.22-1.99] for the TERT-07 G-allele, 1.27 (95% CI, 1.05-1.52) for the TERT-54 T-allele, and 0.79 (95% CI, 0.67-0.95) for the POT1-03 A-allele. TERT-67 (rs2853669) was statistically significant under a recessive model; the OR of the CC genotype was 0.69 (95% CI, 0.69-0.93) compared with the T-allele. However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P < 0.001 (0.05/52) except for TERT-07. When restricted to Caucasians (94% of the study subjects), a stronger association for the TERT-07 G-allele was observed with an OR of 1.60 (95% CI, 1.24-2.05; P = 0.0002). No effect modifications were found for variant alleles and menopausal status, telomere length, cigarette smoking, body mass index status, and family history of breast cancer risk.Conclusions: Four SNPs in the TERT and POT1 genes were significantly related with overall breast cancer risk. This initial analysis provides valuable clues for further exploration of the biological role of telomere pathway genes in breast cancer. Cancer Epidemiol Biomarkers Prev; 19(1); 219–28

Fig. S8. Survival curves for SUSD3 gene expression. A) current LIBCSP study, B) METABRIC population, C) KMplot combined dataset. From left to right: global population, HR-positive (i.e. positive for ER or/and PR) patients, HR-negative (i.e. negative for both ER and PR) patients.

Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10−8) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10−4) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10−6. In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 658–69. ©2014 AACR.

Fig. S4. Principal component analysis of gene expression levels.

Table S1 (pdf file). Full demographic and clinical characteristics of profiled patients and the LIBCSP parent subset.

Association between 387 SNPs and risk of EA, BE, or EA/BE combined

Fig. S1. Correlation between IHC-defined status and gene expression levels for estrogen receptor (ER, left panel) and progesterone receptor (PR, right panel). Each panel shows, left to right, distribution of gene expression values (vertical axis) for IHC-negative, IHC-positive and IHC-unknown groups. Red lines indicate the cut-off chosen (see below).

Legends for Supplemental Figures

Fig. S2. Function of false-positives (red line), false-negatives (green line) and sum of false-positives and false-negatives (blue line), depending on the cut-off value of gene expression levels. Horizontal line indicates the cut-off chosen as giving the minimal sum of false-positives and false-negatives.

Background: Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus.Methods: We examined the associations between risks of EA and Barrett's esophagus and 387 SNPs that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 Barrett's esophagus) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn.Results: After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or Barrett's esophagus. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed.Conclusions: Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or Barrett's esophagus.Impact: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and Barrett's esophagus. Cancer Epidemiol Biomarkers Prev; 24(11); 1801–3. ©2015 AACR.

Supplementary Tables 1-3, Supplementary Figures 1-2 from Multiple Genetic Variants in Telomere Pathway Genes and Breast Cancer Risk

Fig. S7. Validation of the associations found in the current study, by the METABRIC dataset, keeping the cutoff selected by LIBCSP dataset. Horizontal axis displays hazards ratio for given gene in the LIBCSP dataset, vertical axis shows HR for METABRIC dataset. Size of the dot indicates p-value for METABRIC dataset. Pink colors marks the genes of PAM50 panel.

Table S3 (Excel file). Association of profiled genes with breast cancer mortality among participants in the LIBCSP, in different subsets or adjustments. For all analyses, age and tumor stage were included as cofactors; "ERPR_all" - included all patients; "ERPR_pos" - ER|PR+ patients; "ERPR_neg" - ER-/PR- patients; "ERPR_adj" - all patients, with ER/PR status as additional cofactor; "ROR_adj" - all patients, with ROR group as additional cofactor; "ROR_high" - patients assigned to high ROR group; "ROR_low+med" - patients assigned to low and medium ROR groups. For each analysis, columns are as follows: HR - hazard ratio; HR.CI - 95% confidence interval for HR; p - unadjusted p-value; p.BH - Benjamini-Hochberg-adjusted p-value; q - decile threshold for high/low expression level stratification; N.hi - number of patients in "high expression" group.

Supplemental Methods

Fig. S3. Distribution of expression levels among genes and samples. Each dot represents a gene, with horizontal axis showing the percent of samples expressing this gene and vertical axis showing median log2 expression level of this gene.

PDF file - 197K, Table S1. Discovery set study populations. Table S2. Distribution of discovery set subjects by site, case-control status and chip. Table S3. Discovery set quality control summary. Table S4. SNPs with score-based P-values < 4 X 10-8 among 58016 SNPs for which Plink aborted the logistic regressions. Table S5. Replication set study populations. Table S6. Distribution of replication set subjects by site, case-control status and

Fig. S5. Survival curves among the LIBCSP patients, stratified by ROR group (left panel) and molecular subtype (right panel).

Supplementary Methods and Materials from Replication and Functional Genomic Analyses of the Breast Cancer Susceptibility Locus at 6q25.1 Generalize Its Importance in Women of Chinese, Japanese, and European Ancestry

We evaluated the generalizability of a single nucleotide polymorphism (SNP), rs2046210 (A/G allele), associated with breast cancer risk that was initially identified at 6q25.1 in a genome-wide association study conducted among Chinese women. In a pooled analysis of more than 31,000 women of East-Asian, European, and African ancestry, we found a positive association for rs2046210 and breast cancer risk in Chinese women [ORs (95% CI) = 1.30 (1.22–1.38) and 1.64 (1.50–1.80) for the AG and AA genotypes, respectively, P for trend = 1.54 × 10−30], Japanese women [ORs (95% CI) = 1.31 (1.13–1.52) and 1.37 (1.06–1.76), P for trend = 2.51 × 10−4], and European-ancestry American women [ORs (95% CI) = 1.07 (0.99–1.16) and 1.18 (1.04–1.34), P for trend = 0.0069]. No association with this SNP, however, was observed in African American women [ORs (95% CI) = 0.81 (0.63–1.06) and 0.85 (0.65–1.11) for the AG and AA genotypes, respectively, P for trend = 0.4027]. In vitro functional genomic studies identified a putative functional variant, rs6913578. This SNP is 1,440 bp downstream of rs2046210 and is in high linkage disequilibrium with rs2046210 in Chinese (r2 = 0.91) and European-ancestry (r2 = 0.83) populations, but not in Africans (r2 = 0.57). SNP rs6913578 was found to be associated with breast cancer risk in Chinese and European-ancestry American women. After adjusting for rs2046210, the association of rs6913578 with breast cancer risk in African Americans approached borderline significance. Results from this large consortium study confirmed the association of rs2046210 with breast cancer risk among women of Chinese, Japanese, and European ancestry. This association may be explained in part by a putatively functional variant (rs6913578) identified in the region. Cancer Res; 71(4); 1344–55. ©2011 AACR.