Faculty Bibliography
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109
Genetic variation in immunomodulatory genes as markers of melanoma recurrence-free and overall survival [Meeting Abstract]
Background: Small reported studies have provided some evidence implicating immune related genes in melanoma susceptibility and prognosis; however candidate selection of these prior efforts has been limited. In this study, we performed an analysis of germline variants in immuno-modulatory genes for their association with melanoma survival in a well characterized cohort of prospectively accrued melanoma patients. Methods: Germline DNA isolated from blood samples of 817 melanoma patients was genotyped for 94 SNPs tagging 55 immuno-modulatory genes using Sequenom iPLEX. Cox models were used to test associations between each SNP and recurrence-free and overall survival (RFS and OS), with adjustments for age, gender, subtype, thickness, ulceration, and anatomic site. ROC curves were constructed from different SNP/clinical covariate combinations and the area under the curve (AUC) was used to assess their utility in the classification of 3-year recurrence. Results: The SNP rs2796817 in TGFB2 had strong associations with both RFS (HR=3.8, CI 95%: 1.3-11, p=0.02) and OS (HR=5.5, CI 95%: 1.6-19, p=0.029). Other interesting associations with OS came from IRF8 (rs4843861, HR=0.62, CI 95%: 0.39-0.99, p=0.017), CCL5 (rs4796120, HR=7.6, CI 95%: 2.3-25, p=0.035), and CD8A (rs3810831, HR=2.4, CI 95%: 0.91-6.2, p=0.048). A multivariate model including stage, subtype, and one of the SNPs (rs3810831 from CD8A), was shown to improve the AUC when compared to a model including only stage and subtype (0.77 vs. 0.79). Conclusions: We identified several immune-related loci associated with melanoma RFS and OS. The strongest association, rs2796817, maps in TGFB2, which among other functions suppresses IL-2 dependent T-cell growth. In addition to other associations found in the study these findings provide evidence for the involvement of immuno-modulatory genes in melanoma prognosis and suggest further investigations of immune related genes in disease progression. This is currently underway in the second stage validation an!
EMBASE:71099871
ISSN: 0732-183x
CID: 451922
Breast cancer risk prediction using the novel germ-line signatures in epigenome regulatory pathways [Meeting Abstract]
Background: Epigenetic regulatory pathways are intensely studied for their involvement in breast tumorigenesis, however little is currently known about the genetic variation in epigenome components contributing to the risk and/or prognosis of breast cancer. In this study we have tested how the novel germline genetic signatures identified in epigenetic regulatory genes (ERGs) may potentially contribute to clinical prediction of breast cancer risk. Methods: We have genotyped 711 SNPs tagging 87 ERGs in 1985 breast cancer cases and 1609 controls, using Sequenom i-Plex. The samples were of white European origin with the fraction of Ashkenazi Jewish (AJ) ancestry (n=1642). The association of SNPs with breast cancer risk was assessed using logistic regression, adjusted by age, AJ status and estrogen-receptor (ER) status. The predictive ability of SNP signatures was tested by ROC curves using logistic regression fitting the SNP/clinical covariate models, and the area under the curve (AUC) was used to assess their utility in the classification of breast cancer risk. Results: We have identified the signature of 20 SNPs tagging 13 ERGs, significantly associated with breast cancer risk. The strongest association has been observed for RUNX1 (rs7280097, OR=0.83, CI 95%: 0.71-0.94, p=0.006) and PRDM16 (rs12135987, OR=1.22, CI 95%: 1.06-1.42, p=0.007). The inclusion of predictor variables (age, AJ status, ER status) and 20 associated SNPs in logistic regression ROC curve analysis yielded in best fitting model involving 10 SNPs tagging 8 ERGs with AUC of 0.723, compared to 0.660 with predictor variables alone (p=0.003). Conclusions: We have identified a signature of 20 SNPs in epigenetic regulatory genes (20-SNP-ERG) significantly associated with breast cancer risk. In addition, the incorporation of 10 SNPs from 20-SNP-ERG into risk prediction model increases the ability to classify breast cancer risk in addition to other clinical and demographic covariates. The results suggest the promising clinical potential!
EMBASE:71098184
ISSN: 0732-183x
CID: 452002
Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk
Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 x 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
PMCID:3609647
PMID: 23544012
ISSN: 1553-7390
CID: 335212
Extended replication of a GWAS for breast cancer in BRCA2 mutation carriers [Meeting Abstract]
Population-based genome-wide association studies have identified several common genetic variants that also contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers. To search systematically for genetic modifiers of breast cancer risk in BRCA2 mutation carriers, a GWAS has been carried out that led to the identification of an additional susceptibility locus. Based on the results of stage 1 of the GWAS we selected 19,029 SNPs for inclusion on a custom genotyping array which we genotyped in female BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. Associations with breast cancer risk were evaluated within a survival framework using a score test statistic based on modelling the retrospective likelihood of the observed genotypes given the disease phenotypes. Analyses were stratified by country of residence and Ashkenazi Jewish ancestry. After quality control filtering, data from 18,086 SNPs were available for analysis in 3,881 BRCA2 mutation carriers diagnosed with breast cancer and 4,330 unaffected BRCA2 mutation carriers. We confirmed previously reported genetic modifiers of breast cancer risk including SNPs in FGFR2 and TOX3. For six regions previously shown to be associated with breast cancer risk for BRCA2 mutation carriers, including FGFR2 and PTHLH, we found SNPs with p-values smaller than those previously reported. We identified a novel locus that was associated with breast cancer risk at genome-wide significance level (per allele HR=0.85, 95% CI 0.80-0.90, P=3.9x10-8). There was no evidence of association of this locus with breast cancer risk either in the general population, based on 42,599 breast cancer cases and 46,451 controls from the Breast Cancer Association Consortium (OR=1.00, 95%CI: 0.98-1.02, P=0.74), or breast cancer risk for BRCA1 mutation carriers (HR=0.99, 95%CI: 0.94-1.04, P=0.75), based on 5,920 BRCA1 carriers with breast cancer and 5,783 without from CIMBA. The 6p24 locus lies within a region containing TFAP2!
EMBASE:71009579
ISSN: 0936-5931
CID: 250322
Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies
The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (P(LYM) = 3.89x10(-8), OR = 1.29) and rs948562 (P(LYM) = 5.85x10(-7), OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, P(NHL) = 5.72x10(-7)) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (P(FL) = 2.69x10(-12), OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.
PMCID:3547842
PMID: 23349640
ISSN: 1553-7390
CID: 232712
The melanoma risk loci as determinants of melanoma prognosis [Meeting Abstract]
Background: Genetic risk factors of human cancer emerge as promising markers of clinical outcome. The recent melanoma genome-wide scans (GWAS) have identified loci associated with the disease risk, nevi or UV/pigmentation, but the prognostic potential of these variants is yet to be determined. In this study, we performed the first-to-date systematic evaluation of the association between established melanoma risk loci and melanoma progression. Methods: 891 melanoma patients prospectively accrued and followed up at NYU Medical Center were studied. We examined the association of 108 melanoma susceptibility single nucleotide polymorphisms (SNPs), selected or imputed from recent GWASs on melanoma, nevi or pigmentation, with recurrence-free survival (RFS) and overall survival (OS). The genotyping was performed using Sequenom I-plex. Cox PH model was used to test the association between each SNP and RFS and OS adjusted by age at diagnosis, gender, tumor stage and histological subtype. ROC curves were used to measure predictive utility of SNPs in predicting 3-year recurrence. Results: The strong association was observed for rs7538876 (RCC2) with RFS (HR=2.445, 95% CI 1.57 - 3.8, p=0.0006) and rs9960018 (DLGAP1) with both RFS and OS (HR=4.7, 95% CI=2.11-10.43, p=0.0061, HR=1.55, 95% CI=1.11-2.17, p=0.0094, respectively) using adjusted multivariate analysis. In addition, we identified the classifier with rs7538876 and rs9960018, stage and histological type at primary tumor diagnosis, achieving a higher area under the ROC curve (AUC=84%) compared to the baseline (AUC=78%) in predicting 3-year recurrence. Univariate survival analyses have identified associations of several SNPs with ulceration and/or tumor thickness. Conclusions: Our data revealed an association between specific melanoma susceptibility variants and worse clinicopathological variables at the time of diagnosis as well as worse disease outcome. The strength of associations observed for rs7538876 and rs9960018 suggest biological implication of!
EMBASE:71004907
ISSN: 0732-183x
CID: 306092
Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2
Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
PMCID:3387216
PMID: 22768030
ISSN: 1932-6203
CID: 232722
Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers
BACKGROUND: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). METHODS: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. RESULTS: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 x 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 x 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 x 10(-3)). CONCLUSIONS: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. IMPACT: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.
PMCID:3319317
PMID: 22351618
ISSN: 1055-9965
CID: 232732
Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers
INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). METHODS: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. RESULTS: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). CONCLUSIONS: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
PMCID:3496151
PMID: 22348646
ISSN: 1465-5411
CID: 232742
Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers
Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 x 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 x 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 x 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.
PMCID:3458423
PMID: 22253144
ISSN: 1059-7794
CID: 232752
