Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)

PURPOSE: Gene-expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by non-standardized methods which are not applicable in a clinical setting. We sought to generate a clinical-grade minimal gene-set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. EXPERIMENTAL DESIGN: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene-expression data from 1650 tumors. We applied resulting models to NanoString data on 3829 HGSOCs from the Ovarian Tumor Tissue Analysis Consortium. We further developed, confirmed, and validated a reduced, minimal gene-set predictor, with methods suitable for a single patient setting. RESULTS: Gene-expression data was used to derive the Predictor of high-grade-serous Ovarian carcinoma molecular subTYPE (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor infiltrating lymphocytes, and outcome. The locked-down clinical-grade PrOTYPE test includes a model with 55 genes that predicted gene-expression subtype with >95% accuracy that was maintained in all analytical and biological validations. CONCLUSIONS: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical-grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications

Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Improved statistical efficiency of simultaneous multi-slice fMRI by reconstruction with spatially adaptive temporal smoothing

We introduce an approach to reconstruction of simultaneous multi-slice (SMS)-fMRI data that improves statistical efficiency. The method incorporates regularization to adjust temporal smoothness in a spatially varying, encoding-dependent manner, reducing the g-factor noise amplification per temporal degree of freedom. This results in a net improvement in tSNR and GLM efficiency, where the efficiency gain can be derived analytically as a function of the encoding and reconstruction parameters. Residual slice leakage and aliasing is limited when fMRI signal energy is dominated by low frequencies. Analytical predictions, simulated and experimental results demonstrate a marked improvement in statistical efficiency in the temporally regularized reconstructions compared to conventional slice-GRAPPA reconstructions, particularly in central brain regions. Furthermore, experimental results confirm that residual slice leakage and aliasing errors are not noticeably increased compared to slice-GRAPPA reconstruction. This approach to temporally regularized image reconstruction in SMS-fMRI improves statistical power, and allows for explicit choice of reconstruction parameters by directly assessing their impact on noise variance per degree of freedom

Improved statistical efficiency of simultaneous multi-slice fMRI by reconstruction with spatially adaptive temporal smoothing

We introduce an approach to reconstruction of simultaneous multi-slice (SMS)-fMRI data that improves statistical efficiency. The method incorporates regularization to adjust temporal smoothness in a spatially varying, encoding-dependent manner, reducing the g-factor noise amplification per temporal degree of freedom. This results in a net improvement in tSNR and GLM efficiency, where the efficiency gain can be derived analytically as a function of the encoding and reconstruction parameters. Residual slice leakage and aliasing is limited when fMRI signal energy is dominated by low frequencies. Analytical predictions, simulated and experimental results demonstrate a marked improvement in statistical efficiency in the temporally regularized reconstructions compared to conventional slice-GRAPPA reconstructions, particularly in central brain regions. Furthermore, experimental results confirm that residual slice leakage and aliasing errors are not noticeably increased compared to slice-GRAPPA reconstruction. This approach to temporally regularized image reconstruction in SMS-fMRI improves statistical power, and allows for explicit choice of reconstruction parameters by directly assessing their impact on noise variance per degree of freedom

Recovering task fMRI signals from highly under-sampled data with low-rank and temporal subspace constraints

Recent developments in highly accelerated fMRI data acquisition have employed low-rank and/or sparsity constraints for image reconstruction, as an alternative to conventional, time-independent parallel imaging. When under-sampling factors are high or the signals of interest are low-variance, however, functional data recovery can be poor or incomplete. We introduce a method for improving reconstruction fidelity using external constraints, like an experimental design matrix, to partially orient the estimated fMRI temporal subspace. Combining these external constraints with low-rank constraints introduces a new image reconstruction model that is analogous to using a mixture of subspace-decomposition (PCA/ICA) and regression (GLM) models in fMRI analysis. We show that this approach improves fMRI reconstruction quality in simulations and experimental data, focusing on the model problem of detecting subtle 1-s latency shifts between brain regions in a block-design task-fMRI experiment. Successful latency discrimination is shown at acceleration factors up to R = 16 in a radial-Cartesian acquisition. We show that this approach works with approximate, or not perfectly informative constraints, where the derived benefit is commensurate with the information content contained in the constraints. The proposed method extends low-rank approximation methods for under-sampled fMRI data acquisition by leveraging knowledge of expected task-based variance in the data, enabling improvements in the speed and efficiency of fMRI data acquisition without the loss of subtle features

Recovering task fMRI signals from highly under-sampled data with low-rank and temporal subspace constraints

Recent developments in highly accelerated fMRI data acquisition have employed low-rank and/or sparsity constraints for image reconstruction, as an alternative to conventional, time-independent parallel imaging. When under-sampling factors are high or the signals of interest are low-variance, however, functional data recovery can be poor or incomplete. We introduce a method for improving reconstruction fidelity using external constraints, like an experimental design matrix, to partially orient the estimated fMRI temporal subspace. Combining these external constraints with low-rank constraints introduces a new image reconstruction model that is analogous to using a mixture of subspace-decomposition (PCA/ICA) and regression (GLM) models in fMRI analysis. We show that this approach improves fMRI reconstruction quality in simulations and experimental data, focusing on the model problem of detecting subtle 1-s latency shifts between brain regions in a block-design task-fMRI experiment. Successful latency discrimination is shown at acceleration factors up to R = 16 in a radial-Cartesian acquisition. We show that this approach works with approximate, or not perfectly informative constraints, where the derived benefit is commensurate with the information content contained in the constraints. The proposed method extends low-rank approximation methods for under-sampled fMRI data acquisition by leveraging knowledge of expected task-based variance in the data, enabling improvements in the speed and efficiency of fMRI data acquisition without the loss of subtle features

Ultra-high resolution fMRI at 7T using radial-cartesian TURBINE sampling

Purpose: We investigate the use of TURBINE, a 3D radial-Cartesian acquisition scheme in which EPI planes are rotated about the phase-encoding axis to acquire a cylindrical k-space, for high-fidelity ultra-high isotropic resolution fMRI at 7T with minimal distortion and blurring. Methods: An improved, completely self-navigated version of the TURBINE sampling scheme was designed for fMRI at 7T. To demonstrate the image quality and spatial specificity of the acquisition, thin-slab visual and motor BOLD fMRI at 0.67 mm isotropic resolution (16 mm slab, TRvol = 2.32 s) and 0.8x0.8x2.0 mm (whole-brain, TRvol = 2.4 s) data were acquired. To prioritize the high spatial fidelity, we employed a temporally regularized reconstruction to improve sensitivity without any spatial bias. Results: TURBINE images provide high structural fidelity with almost no distortion, dropout or T2* blurring for the thin-slab acquisitions compared to conventional 3D EPI, owing to the radial sampling in-plane and the short echo train used. This results in activation that can be localized to pre- and post-central gyri in a motor task, for example, with excellent correspondence to brain structure measured by a T1-MPRAGE. The benefits of TURBINE (low distortion, dropout, blurring) are reduced for the whole-brain acquisition due to the longer EPI train. We demonstrate robust BOLD activation at 0.67 mm isotropic resolution (thin-slab) and also anisotropic 0.8x0.8x2.0 mm (whole-brain) acquisitions. Conclusion: TURBINE is a promising acquisition approach for high-resolution, minimally distorted fMRI at 7T and could be particularly useful for fMRI in areas of high B0 inhomogeneity.</p