Lucinda Hughes

Whole exome sequence analysis of serous borderline tumors of the ovary

OBJECTIVE Serous borderline tumor (SBT) is a unique histopathologic entity of the ovary, believed to be intermediate between benign cystadenoma and invasive low-grade serous carcinoma. While somatic mutations in the KRAS or BRAF, and rarely ERBB2, genes have been well characterized in SBTs, other genetic alterations have not been described. Toward a more comprehensive understanding of the molecular genetic architecture of SBTs, we undertook whole exome sequencing of this tumor type. METHODS Following pathologic review and laser capture microdissection to enrich for tumor cells, whole exomes were prepared from DNA of two independent SBTs and subjected to massively parallel DNA sequencing. RESULTS Both tumors contained an activating mutation of the BRAF gene. A total of 15 additional somatic mutations were identified, nine in one tumor and six in the other. Eleven were missense mutations and four were nonsense or deletion mutations. Fourteen of the 16 genes found to be mutated in this study have been reported to be mutated in other cancers. Furthermore, 12 of these genes are mutated in ovarian cancers. The FBXW7 and KIAA1462 genes are noteworthy candidates for a pathogenic role in serous borderline tumorigenesis. CONCLUSIONS These findings suggest that a very small number of somatic genetic mutations are characteristic of SBTs of the ovary, thus supporting their classification as a relatively genetically stable tumor type. The mutant genes described herein represent novel candidates for the pathogenesis of ovarian SBT.

Genetic variation in IL-16 miRNA target site and time to prostate cancer diagnosis in African-American men

BACKGROUND:Men with a family history of prostate cancer and African-American men are at high risk for prostate cancer and in need of personalized risk estimates to inform screening decisions. This study evaluated genetic variants in genes encoding microRNA (miRNA) binding sites for informing of time to prostate cancer diagnosis among ethnically diverse, high-risk men undergoing prostate cancer screening.METHODS:The Prostate Cancer Risk Assessment Program (PRAP) is a longitudinal screening program for high-risk men. The eligibility includes men aged between 35 and 69 years with a family history of prostate cancer or African descent. Participants with ⩾1 follow-up visit were included in the analyses (n=477). Genetic variants in genes encoding miRNA binding sites (ALOX15 (arachidonate 15-lipooxygenase), IL-16, IL-18 and RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1)) previously implicated in prostate cancer development were evaluated. Genotyping methods included Taqman SNP Genotyping Assay or pyrosequencing. Cox models were used to assess time to prostate cancer diagnosis by risk genotype.RESULTS:Among 256 African Americans with ⩾one follow-up visit, the TT genotype at rs1131445 in IL-16 was significantly associated with earlier time to prostate cancer diagnosis vs the CC/CT genotypes (P=0.013), with a suggestive association after correction for false discovery (P=0.065). Hazard ratio after controlling for age and PSA for TT vs CC/CT among African Americans was 3.0 (95% confidence interval: 1.26–7.12). No association with time to diagnosis was detected among Caucasians by IL-16 genotype. No association with time to prostate cancer diagnosis was found for the other miRNA target genotypes.CONCLUSIONS:Genetic variation in IL-16 encoding miRNA target site may be informative of time to prostate cancer diagnosis among African-American men enrolled in prostate cancer risk assessment, which may inform individualized prostate cancer screening strategies in the future.

Assessing the Clinical Role of Genetic Markers of Early-Onset Prostate Cancer among High-Risk Men Enrolled in Prostate Cancer Early Detection

Background: Men with familial prostate cancer and African American men are at risk for developing prostate cancer at younger ages. Genetic markers predicting early-onset prostate cancer may provide clinically useful information to guide screening strategies for high-risk men. We evaluated clinical information from six polymorphisms associated with early-onset prostate cancer in a longitudinal cohort of high-risk men enrolled in prostate cancer early detection with significant African American participation. Methods: Eligibility criteria include ages 35 to 69 with a family history of prostate cancer or African American race. Participants undergo screening and biopsy per study criteria. Six markers associated with early-onset prostate cancer [rs2171492 (7q32), rs6983561 (8q24), rs10993994 (10q11), rs4430796 (17q12), rs1799950 (17q21), and rs266849 (19q13)] were genotyped. Cox models were used to evaluate time to prostate cancer diagnosis and prostate-specific antigen (PSA) prediction for prostate cancer by genotype. Harrells concordance index was used to evaluate predictive accuracy for prostate cancer by PSA and genetic markers. Results: Four hundred and sixty participants with complete data and ≥1 follow-up visit were included. Fifty-six percent were African American. Among African American men, rs6983561 genotype was significantly associated with earlier time to prostate cancer diagnosis (P = 0.005) and influenced prediction for prostate cancer by the PSA (P < 0.001). When combined with PSA, rs6983561 improved predictive accuracy for prostate cancer compared with PSA alone among African American men (PSA = 0.57 vs. PSA + rs6983561 = 0.75, P = 0.03). Conclusions: Early-onset marker rs6983561 adds potentially useful clinical information for African American men undergoing prostate cancer risk assessment. Further study is warranted to validate these findings. Impact: Genetic markers of early-onset prostate cancer have potential to refine and personalize prostate cancer early detection for high-risk men. Cancer Epidemiol Biomarkers Prev; 21(1); 53–60. ©2011 AACR.

Validation of association of genetic variants at 10q with prostate‐specific antigen (PSA) levels in men at high risk for prostate cancer

To validate six previously identified markers among men at increased risk of prostate cancer (African‐American men and those with a family history of prostate cancer) enrolled in the Prostate Cancer Risk Assessment Program (PRAP), a prostate cancer screening study.

Racial differences in prediction of time to prostate cancer diagnosis in a prospective screening cohort of high-risk men: effect of TMPRSS2 Met160Val

What’s known on the subject? and What does the study add?

Validation of Association of Genetic Variants at 10q with PSA Levels in Men at High Risk for Prostate Cancer

To validate six previously identified markers among men at increased risk of prostate cancer (African‐American men and those with a family history of prostate cancer) enrolled in the Prostate Cancer Risk Assessment Program (PRAP), a prostate cancer screening study.

Validation of association of genetic variants at 10q with prostate-specific antigen (PSA) levels in men at high risk for prostate cancer: Genetic correction of PSA in men at high-risk for PCA

To validate six previously identified markers among men at increased risk of prostate cancer (African‐American men and those with a family history of prostate cancer) enrolled in the Prostate Cancer Risk Assessment Program (PRAP), a prostate cancer screening study.

Abstract 1820: Genetic polymorphisms in microRNA target sites in IL-16 and IL-18 may be informative of time to prostate cancer diagnosis in African American men

Background: MicroRNAs (miRNAs) have recently been identified as promising markers to study for genetic susceptibility to cancer and have potential clinical utility in prostate cancer (PCA) risk assessment. Single nucleotide polymorphisms (SNPs) in genes encoding miRNA target sites for mRNA may interfere with miRNA binding to the mRNA, leading to aberrant mRNA expression and carcinogenesis. Here, we studied SNPs in 4 genes (ALOX15, IL-16, IL-18, and RAF1) with biologic relevance to PCA that encode mRNA with miRNA target sites. We evaluated these SNPs for association to race and time to PCA diagnosis in men at high risk for PCA (men with a family history [FH] of PCA and African American [AA] men) enrolled in a prospective early detection program to determine their future role in personalizing PCA early detection. Methods: The Prostate Cancer Risk Assessment Program (PRAP) is a prospective screening program for high risk men. PRAP has > 800 participants, and 60% are AA. Average follow-up is 4 years. Eligibility for PRAP includes men ages 35-69 years with one first degree relative with PCA, two second degree relatives with PCA on the same side of the family, any AA man regardless of FH of PCA, and men with BRCA1/2 mutations. Criteria for biopsy and biopsy approach have been reported previously. Genotyping methods included either Taqman® SNP Genotyping Assay (Applied Biosystems) or pyrosequencing. Standard sequencing was performed on 2% of the samples to confirm genotype calls. Standard statistical methods were used to determine risk-genotype distributions. Cox models were used for time to PCA diagnosis by risk genotype. Results: SNP genotypes were available for the following: n=749 for ALOX15, n=754 for RAF1, n=753 for IL-16, and n=766 for IL-18. There was a significant difference in distribution of miRNA target SNPs by race in ALOX15 (p one follow-up visit, the TT genotype at rs1131445 in IL-16 was found to be significantly associated with earlier time to PCA diagnosis vs. the CC/CT genotypes (p=0.013). Hazard ratio after controlling for age and PSA for TT vs. CC/CT among AA men was 2.27 (p=0.0091). In addition, among 283 AA men with > one follow-up visit, the TT genotype at rs360727 in IL-18 was found to predict earlier time to PCA diagnosis vs CC/CT (p=0.017). Hazard ratio for PCA after controlling for age and PSA for TT vs. CC/CT among AA men was 4.44 (p=0.042). No trends in time to PCA diagnosis were seen among Caucasian men in PRAP for any of the miRNA target SNP genotypes. Conclusions: Genetic polymorphisms in miRNA target sites in IL-16 and IL-18 may be informative of time to PCA diagnosis among AA men enrolled in PCA risk assessment and may help to tailor screening and prevention recommendations in the future. Further study among high-risk men is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1820. doi:10.1158/1538-7445.AM2011-1820

Abstract A9: Genetic polymorphisms in the vitamin D receptor gene and androgen pathway gene SRD5A2 may be informative of prostate cancer risk in African American men undergoing prostate cancer screening

Background: Men with a family history (FH) of prostate cancer (PCA) and African American (AA) men are at 2 to 7‐fold increased risk for the disease. Assessing risk for PCA in these high‐risk men has been challenging due to the lack of available genetic testing. The vitamin D and androgen pathways have been studied for years for association to prostate cancer risk with single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene and genes encoding enzymes involved in testosterone biosynthesis found to have no substantial association to prostate cancer risk. However, a recent study found an interaction between the FokI SNP in VDR and the V89L SNP in SRD5A2 (converts testosterone to dihydrotestosterone) in non‐Hispanic white men. In addition, in Hispanic white men, the V89L SRD5A2 polymorphism and the CDX2 VDR SNP was associated with prostate cancer. We evaluated these particular genetic variants in VDR and SRD5A2 for association to prostate cancer and time to prostate cancer diagnosis in high‐risk men enrolled in the Prostate Cancer Risk Assessment Program (PRAP)‐ a screening and research program with 60% African American participation. Methods: Eligibility for PRAP includes men ages 35–69 years with one first degree relative with PCA, two second degree relatives with PCA on the same side of the family, any AA man regardless of FH of PCA, or men with BRCA1/2 mutations. Current criteria for biopsy include PSA > 2.0 ng/mL, PSA 1.5–2.0 ng/mL with free PSA Results: 661 PRAP men had genotype data available for FokI and V89L, while 380 men had genotype data for CDX2 and V89L. Among 236 AA men with at least one follow‐up visit included in the FokI‐V89L analysis, a significant interaction was seen between FokI and V89L genotypes after adjusting for age and PSA at entry (p=0.01). Hazard ratio estimates for AA men with the FokI CC genotype and V89L LV/LL genotypes vs. VV was 2.51 (95% CI 1.07–5.90). No interaction was seen between FokI and V89L genotypes among 194 Caucasian men, where FokI genotype alone was found to have a significant association to PCA (Hazard Ratio for FokI TT/CT vs CC = 0.29, 95% CI 0.14–0.62). No significant association to PCA was seen for CDX2 either alone or in combination with V89L for AA and Caucasian men in this analysis. Conclusions: FokI CC in VDR and V89L LV/LL in SRD5A2 appear to be informative of time to PCA diagnosis and risk for PCA in AA men undergoing PCA screening. FokI TT/CT genotype appears to have a protective effect in Caucasian men for PCA. Further study is warranted. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A9.

Abstract B54: Prostate cancer screening characteristics in high-risk men with genetic risk markers at 8q and 17q

B54 Background Men with a family history (FH) of prostate cancer (PCA) and African American (AA) men are at 2 to 7-fold increased risk for the disease. Assessing risk for PCA in these high-risk men has been challenging due to the lack of available genetic testing. Recently, five genetic single nucleotide polymorphisms (SNPs) at chromosomal loci 8q and 17q (rs1859962, rs6983267, rs4430796, rs1447295, and rs16901979) were found to have a cumulative increased association with PCA in multiple studies. These genetic variants need to be characterized in screening populations to determine their utility in the early detection of PCA. The Prostate Cancer Risk Assessment Program (PRAP) at Fox Chase Cancer Center is a prospective screening program for high-risk men. Currently there are over 700 participants, and 60% are AA. This study evaluates the clinical characteristics of high-risk men carrying these risk SNPs and time to PCA diagnosis based on the presence of these 8q/17q risk markers. Methods Eligibility for PRAP includes men ages 35-69 years with one first degree relative with PCA, two second degree relatives with PCA on the same side of the family, any AA man regardless of FH of PCA, and men with BRCA1/2 mutations. Current criteria for biopsy include PSA > 2.0 ng/mL, PSA 1.5-2.0 ng/mL with free PSA Results Genotypes for all five SNPs was able to be determined on 633 PRAP participants of whom 60% were AA. Average follow-up for these participants in PRAP has been 3-4 years. There was a statistically significant difference in the baseline distribution of risk alleles and risk genotypes of these five SNPs within self-reported race groups (p Conclusions Five genetic risk markers at 8q/17q may be useful in tailoring screening approaches in high-risk men, particularly AA men. Further follow-up is needed to firmly determine how these risk markers influence time to PCA diagnosis. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B54.