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PDF file - 486KB, Figure S1 (A) Average statistics for depth of coverage at 20X, 30X and 40X of all MOC lines. Robust reads were obtained in all samples with a range of 97-98 percent for 20X, 93-95 percent for 30X and 88-92 percent for 40X. (B) Putative SNVs, nsSNVs (Table S1 and S2) and Indels (Table S4) of all MOC lines. Figure S2 Oncoprints from cBio of AKAP9, MED12L, THSD7A, MUC5B, MYH6, LAMA1, LRP2, and 3 RAS (Table S6) genes representing other candidate tumor promoters as compared to the 3 RAS genes. Note that for AKAPs and MED components, we found 9 AKAP family member mutations in 20.4 percent of tumors, with AKAP9 changes in 7 percent (Fig. 1D). Six components of the mediator complex were mutated in 14.7% of cases, with MED12L changes in 5% (Fig. 1E). Figure S3 Number of nsSNV's per node negative (N0) and node positive (N+) tumor in (A) all TCGA OSCC (note that patient TCGA-D6-6516 (N0) with 1463 mutations is not included in this graph) and (B) TCGA OSCC patients who had smoking history reported. There was no significant difference in the average number of mutations between N0 (3272 nsSNVs) and N+ (3097 nsSNVs) patients regardless of smoking status (Tables S8, S9). This analysis showed 17 genes commonly mutated in mouse indolent and human N0 tumors and 55 common genes mutated in mouse aggressive and human N+ tumors (Supplementary Table S10). However, none of these common genes were mutated at high frequency in the human N0 or N+ datasets (Supplementary Table S11 and 12). Finally, comparing N0 and N+ tumors from human TCGA data also showed that specific mutations occur infrequently in both the metastatic and non-metastatic tumors (data not shown). Figure S4 SAM plotsheet of MOC line microarray data with estimated miss rates for delta=4.68 Figure S5 (A) GSEA data of OCAMP-A on UW/FHCRC data with (B) first condensation of enriched genes. (C) GSEA data of OCAMP-A on MDA data with (D) first condensation of enriched genes. (E) GSEA data of OCAMP-A on TCGA data with (F) first condensation of enriched genes. Figure S6 (A) Disease specific survival (DSS) after weighted voting classification of OCAMP-B signature on the MD Anderson dataset shows worse outcome for those with aggressive classification (p=0.028). Figure S7 (A) Disease specific survival (DSS) and (B) overall survival (OS) after weighted voting classification of OCAMP-B signature on the UW/FHCRC dataset shows worse outcome for those with aggressive classification (p

Purpose: Improved understanding of the molecular basis underlying oral squamous cell carcinoma (OSCC) aggressive growth has significant clinical implications. Herein, cross-species genomic comparison of carcinogen-induced murine and human OSCCs with indolent or metastatic growth yielded results with surprising translational relevance.Experimental Design: Murine OSCC cell lines were subjected to next-generation sequencing (NGS) to define their mutational landscape, to define novel candidate cancer genes, and to assess for parallels with known drivers in human OSCC. Expression arrays identified a mouse metastasis signature, and we assessed its representation in four independent human datasets comprising 324 patients using weighted voting and gene set enrichment analysis. Kaplan–Meier analysis and multivariate Cox proportional hazards modeling were used to stratify outcomes. A quantitative real-time PCR assay based on the mouse signature coupled to a machine-learning algorithm was developed and used to stratify an independent set of 31 patients with respect to metastatic lymphadenopathy.Results: NGS revealed conservation of human driver pathway mutations in mouse OSCC, including in Trp53, mitogen-activated protein kinase, phosphoinositide 3-kinase, NOTCH, JAK/STAT, and Fat1-4. Moreover, comparative analysis between The Cancer Genome Atlas and mouse samples defined AKAP9, MED12L, and MYH6 as novel putative cancer genes. Expression analysis identified a transcriptional signature predicting aggressiveness and clinical outcomes, which were validated in four independent human OSCC datasets. Finally, we harnessed the translational potential of this signature by creating a clinically feasible assay that stratified patients with OSCC with a 93.5% accuracy.Conclusions: These data demonstrate surprising cross-species genomic conservation that has translational relevance for human oral squamous cell cancer. Clin Cancer Res; 20(11); 2873–84. ©2014 AACR.

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XLS file - 6534KB, S1 SNVs indolent lines. S2 SNVs aggressive lines. S3 Distribution of nucleotide changes. S4 MOC line mutations have similarity to 32 most common HNSCC TCGA mutations. S5 MOC line conservation with human OSCC drivers and novel mutations. S6 Indels all MOC lines. S7 Comparison of predicted changes between aggressive and indolent lines. S8 MOC line common mutations. S9 Unique aggressive MOC line mutations. S10 Comparison of MOC line mutations with TCGA N0 and N+ mutations. S11 TCGA mutation burden per tumor in N0 and N+ specimens. S12 MOC line and TCGA common mutations. S13 Rate of alterations of aggressive MOC/TCGA N+ mutations from Table S10. S14 Rate of alterations of indolent MOC/TCGA N0 mutations from Table S10. S15 SAM analysis of aggressive versus indolent expression data. S16 Compiled rank metric scores of OCAMP-A genes across three human datasets. S17 Cross tabulation and multivariable analysis of OCAMP-B on MD dataset. S18 Weighted voting classification with OCAMP-B on independent UPENN dataset. S19 SVM output data for training and test sets. S20 OCAMP-A comparison to three published signatures.

Background: Common variants have been associated with prostate cancer risk. Unfortunately, few are reproducibly linked to aggressive disease, the phenotype of greatest clinical relevance. One possible explanation is that rare genetic variants underlie a significant proportion of the risk for aggressive disease. Method: To identify such variants, we performed a two-stage approach using whole-exome sequencing followed by targeted sequencing of 800 genes in 652 aggressive prostate cancer patients and 752 disease-free controls in both African and European Americans. In each population, we tested rare variants for association using two gene-based aggregation tests. We established a study-wide significance threshold of 3.125 × 10−5 to correct for multiple testing. Results: TET2 in African Americans was associated with aggressive disease, with 24.4% of cases harboring a rare deleterious variant compared with 9.6% of controls (FET P = 1.84 × 10−5, OR = 3.0; SKAT-O P = 2.74 × 10−5). We report 8 additional genes with suggestive evidence of association, including the DNA repair genes PARP2 and MSH6. Finally, we observed an excess of rare truncation variants in 5 genes, including the DNA repair genes MSH6, BRCA1, and BRCA2. This adds to the growing body of evidence that DNA repair pathway defects may influence susceptibility to aggressive prostate cancer. Conclusions: Our findings suggest that rare variants influence risk of clinically relevant prostate cancer and, if validated, could serve to identify men for screening, prophylaxis, and treatment. Impact: This study provides evidence that rare variants in TET2 may help identify African American men at increased risk for clinically relevant prostate cancer. Cancer Epidemiol Biomarkers Prev; 25(11); 1456–63. ©2016 AACR.

SummaryWe describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

SummaryEstrogen receptor alpha-positive (ERα+) luminal tumors are the most frequent subtype of breast cancer. Stat1−/− mice develop mammary tumors that closely recapitulate the biological characteristics of this cancer subtype. To identify transforming events that contribute to tumorigenesis, we performed whole genome sequencing of Stat1−/− primary mammary tumors and matched normal tissues. This investigation identified somatic truncating mutations affecting the prolactin receptor (PRLR) in all tumor and no normal samples. Targeted sequencing confirmed the presence of these mutations in precancerous lesions, indicating that this is an early event in tumorigenesis. Functional evaluation of these heterozygous mutations in Stat1−/− mouse embryonic fibroblasts showed that co-expression of truncated and wild-type PRLR led to aberrant STAT3 and STAT5 activation downstream of the receptor, cellular transformation in vitro, and tumor formation in vivo. In conclusion, truncating mutations of PRLR promote tumor growth in a model of human ERα+ breast cancer and warrant further investigation.

Summary Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.

Purpose: Improved understanding of the molecular basis underlying oral squamous cell carcinoma (OSCC) aggressive growth has significant clinical implications. Herein, cross-species genomic comparison of carcinogen-induced murine and human OSCCs with indolent or metastatic growth yielded results with surprising translational relevance. Experimental Design: Murine OSCC cell lines were subjected to next-generation sequencing (NGS) to define their mutational landscape, to define novel candidate cancer genes, and to assess for parallels with known drivers in human OSCC. Expression arrays identified a mouse metastasis signature, and we assessed its representation in four independent human datasets comprising 324 patients using weighted voting and gene set enrichment analysis. Kaplan–Meier analysis and multivariate Cox proportional hazards modeling were used to stratify outcomes. A quantitative real-time PCR assay based on the mouse signature coupled to a machine-learning algorithm was developed and used to stratify an independent set of 31 patients with respect to metastatic lymphadenopathy. Results: NGS revealed conservation of human driver pathway mutations in mouse OSCC, including in Trp53, mitogen-activated protein kinase, phosphoinositide 3-kinase, NOTCH, JAK/STAT, and Fat1-4. Moreover, comparative analysis between The Cancer Genome Atlas and mouse samples defined AKAP9, MED12L, and MYH6 as novel putative cancer genes. Expression analysis identified a transcriptional signature predicting aggressiveness and clinical outcomes, which were validated in four independent human OSCC datasets. Finally, we harnessed the translational potential of this signature by creating a clinically feasible assay that stratified patients with OSCC with a 93.5% accuracy. Conclusions: These data demonstrate surprising cross-species genomic conservation that has translational relevance for human oral squamous cell cancer. Clin Cancer Res; 20(11); 2873–84. ©2014 AACR.