OvaPrint-A Cell-free DNA Methylation Liquid Biopsy for the Risk Assessment of High-grade Serous Ovarian Cancer.

PURPOSE: High-grade serous ovarian carcinoma (HGSOC) is the most lethal epithelial ovarian cancer (EOC) and is often diagnosed at late stage. In women with a known pelvic mass, surgery followed by pathologic assessment is the most reliable way to diagnose EOC and there are still no effective screening tools in asymptomatic women. In the current study, we developed a cell-free DNA (cfDNA) methylation liquid biopsy for the risk assessment of early-stage HGSOC. EXPERIMENTAL DESIGN: We performed reduced representation bisulfite sequencing to identify differentially methylated regions (DMR) between HGSOC and normal ovarian and fallopian tube tissue. Next, we performed hybridization probe capture for 1,677 DMRs and constructed a classifier (OvaPrint) on an independent set of cfDNA samples to discriminate HGSOC from benign masses. We also analyzed a series of non-HGSOC EOC, including low-grade and borderline samples to assess the generalizability of OvaPrint. A total of 372 samples (tissue n = 59, plasma n = 313) were analyzed in this study. RESULTS: OvaPrint achieved a positive predictive value of 95% and a negative predictive value of 88% for discriminating HGSOC from benign masses, surpassing other commercial tests. OvaPrint was less sensitive for non-HGSOC EOC, albeit it may have potential utility for identifying low-grade and borderline tumors with higher malignant potential. CONCLUSIONS: OvaPrint is a highly sensitive and specific test that can be used for the risk assessment of HGSOC in symptomatic women. Prospective studies are warranted to validate OvaPrint for HGSOC and further develop it for non-HGSOC EOC histotypes in both symptomatic and asymptomatic women with adnexal masses.

Radical Prostatectomy or External Beam Radiation Therapy vs No Local Therapy for Survival Benefit in Metastatic Prostate Cancer: A SEER-Medicare Analysis.

PURPOSE: We assessed survival after radical prostatectomy, intensity modulated radiation therapy or conformal radiation therapy vs no local therapy for metastatic prostate cancer adjusting for patient comorbidity, androgen deprivation therapy and other factors. MATERIALS AND METHODS: We identified men 66 years old or older with metastatic prostate cancer treated with radical prostatectomy, intensity modulated radiation therapy, conformal radiation therapy or no local therapy in the SEER-Medicare linked database from 2004 to 2009. Multivariable Cox proportional hazards models before and after inverse propensity score weighting were used to assess all cause and prostate cancer specific mortality. Competing risk regression analysis was done to assess prostate cancer specific mortality. RESULTS: Of 4,069 men with metastatic prostate cancer radical prostatectomy in 47, intensity modulated radiation therapy in 88 and conformal radiation therapy in 107 were selected as local therapy vs no local therapy in 3,827. Radical prostatectomy was associated with a 52% decrease (HR 0.48, 95% CI 0.27-0.85) in the risk of prostate cancer specific mortality after adjusting for sociodemographics, primary tumor characteristics, comorbidity, androgen deprivation therapy and bone radiation within 6 months of diagnosis. Intensity modulated radiation therapy was associated with a 62% decrease (HR 0.38, 95% CI 0.24-0.61) in the risk of prostate specific cancer specific mortality. Conformal radiation therapy was not associated with improved survival compared to no local therapy. Propensity score weighting yielded comparable results. Competing risk analysis revealed a 42% and 57% decrease (SHR 0.58, 95% CI 0.35-0.95 and SHR 0.43, 95% CI 0.27-0.68, respectively) in the risk of prostate cancer specific mortality for radical prostatectomy and intensity modulated radiation therapy. CONCLUSIONS: Local therapy with radical prostatectomy and intensity modulated radiation therapy but not with conformal radiation therapy was associated with a survival benefit in men with metastatic prostate cancer. This finding warrants prospective evaluation in clinical trials.

Genetic admixture and risk of hypertensive disorders of pregnancy among Latinas in Los Angeles County.

BACKGROUND: Latinos are a heterogeneous population in terms of demographics, culture, and genetic admixture from three racial groups (white, African, and Native American). This study examines the role of genetic ancestry and environmental risk factors in the risk of hypertensive disorder of pregnancy among Latinas in Los Angeles County. METHODS: Gestational hypertension, preeclampsia, eclampsia, or hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome cases (n = 125), plus unaffected controls (n = 161), were recruited from Los Angeles County + University of Southern California Women's and Children's Hospital from 1999 through 2008. Diagnoses were confirmed with extensive chart review. Personal information, demographics, and biospecimens were collected from all participants. Ancestry informative markers were used to estimate genetic ancestry proportions. RESULTS: After adjusting for European ancestry and key risk factors, African ancestry was positively associated with hypertensive disorders of pregnancy risk for the highest vs. the lowest quartiles of African ancestry (odds ratio = 2.6 [95% confidence interval = 1.1-6.1]). This association was stronger among women born in Mexico with parents born in Mexico (4.3 [1.4-13]). The results from generalized additive models showed a positive association between joint European/African ancestry and hypertensive disorders of pregnancy risk and an inverse association between Native American ancestry and risk. These associations were stronger among women of Mexican origin. CONCLUSION: Our findings suggest that higher Native American ancestry among Latinas may protect against hypertensive disorders of pregnancy. Further studies are needed to determine whether this protective effect is driven by specific alleles present in this population or by other risk factors that correlate with Native American ancestry.

Using extreme phenotype sampling to identify the rare causal variants of quantitative traits in association studies.

Variants identified in recent genome-wide association studies based on the common-disease common-variant hypothesis are far from fully explaining the hereditability of complex traits. Rare variants may, in part, explain some of the missing hereditability. Here, we explored the advantage of the extreme phenotype sampling in rare-variant analysis and refined this design framework for future large-scale association studies on quantitative traits. We first proposed a power calculation approach for a likelihood-based analysis method. We then used this approach to demonstrate the potential advantages of extreme phenotype sampling for rare variants. Next, we discussed how this design can influence future sequencing-based association studies from a cost-efficiency (with the phenotyping cost included) perspective. Moreover, we discussed the potential of a two-stage design with the extreme sample as the first stage and the remaining nonextreme subjects as the second stage. We demonstrated that this two-stage design is a cost-efficient alternative to the one-stage cross-sectional design or traditional two-stage design. We then discussed the analysis strategies for this extreme two-stage design and proposed a corresponding design optimization procedure. To address many practical concerns, for example measurement error or phenotypic heterogeneity at the very extremes, we examined an approach in which individuals with very extreme phenotypes are discarded. We demonstrated that even with a substantial proportion of these extreme individuals discarded, an extreme-based sampling can still be more efficient. Finally, we expanded the current analysis and design framework to accommodate the CMC approach where multiple rare-variants in the same gene region are analyzed jointly.