Supplementary Figures S1-S5. Supplementary Tables S1-S5. Figure S1. Comparison of SNV mutation signatures across histological and molecular subtypes. Figure S2. Treatment timelines and radiographic outcomes. Figure S3. Mutation signature stability metrics and comparisons to known signatures. Figure S4. Structural variant mutation sigantures. Figure S5. Comparison of mutation burden between aging-driven and non-aging-driven breast tumours. Table S1. Kruskal-Wallis tests. Table S2. HRDetect prediction test metrics. Table S3. Area under the curve of HRD signatures in platinum response prediction. Table S4. Logistic regression model odds ratios of clinical improvement on platinum. Table S5. Accession IDs of genome datasets submitted to the European Genome-Phenome Archive.

Table S4 includes immune signature and iCluster results.

Table S7 contains microbe screening results.

Table S1 contains cohort description, Master Patient Table and MutSigCV results.

Table S2 contains BAP1 analysis results, as well as detailed lists of YY1 and IRF8 target genes.

Supplementary Table 1 from Acquired TNFRSF14 Mutations in Follicular Lymphoma Are Associated with Worse Prognosis

Table S6 contains results from the analysis of DNA methylation in SETD2 mutated and BAP1 inactivated samples.

Supplementary materials and methods, as well as supplementary figures S1-S7.

Table S5: Data from this study have been submitted to the European Genome-Phenome Archive (EGA) (www.ebi.ac.uk/ega/home) under the study accession number EGAS00001001159. This table provides the accession numbers for each dataset included in this study.

Table S3 contains the karyotypes of 16 genome-wide LOH MPM cases from the BWH cohort.

Table S5 contains detailed miRs and lncRNAs results.

Abstract Purpose: Recent studies have identified mutation signatures of homologous recombination deficiency (HRD) in over 20% of breast cancers, as well as pancreatic, ovarian, and gastric cancers. There is an urgent need to understand the clinical implications of HRD signatures. Whereas BRCA1/2 mutations confer sensitivity to platinum-based chemotherapies, it is not yet clear whether mutation signatures can independently predict platinum response. Experimental Design: In this observational study, we sequenced tumor whole genomes (100× depth) and matched normals (60×) of 93 advanced-stage breast cancers (33 platinum-treated). We computed a published metric called HRDetect, independently trained to predict BRCA1/2 status, and assessed its capacity to predict outcomes on platinum-based chemotherapies. Clinical endpoints were overall survival (OS), total duration on platinum-based therapy (TDT), and radiographic evidence of clinical improvement (CI). Results: HRDetect predicted BRCA1/2 status with an area under the curve (AUC) of 0.94 and optimal threshold of 0.7. Elevated HRDetect was also significantly associated with CI on platinum-based therapy (AUC = 0.89; P = 0.006) with the same optimal threshold, even after adjusting for BRCA1/2 mutation status and treatment timing. HRDetect scores over 0.7 were associated with a 3-month extended median TDT (P = 0.0003) and 1.3-year extended median OS (P = 0.04). Conclusions: Our findings not only independently validate HRDetect, but also provide the first evidence of its association with platinum response in advanced breast cancer. We demonstrate that HRD mutation signatures may offer clinically relevant information independently of BRCA1/2 mutation status and hope this work will guide the development of clinical trials. Clin Cancer Res; 23(24); 7521–30. ©2017 AACR.

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.

In an attempt to assess potential treatment options, whole-genome and transcriptome sequencing were performed on a patient with an unclassifiable small lymphoproliferative disorder. Variants from genome sequencing were prioritized using a combination of comparative variant distributions in a spectrum of lymphomas, and meta-analyses of gene expression profiling. In this patient, the molecular variants that we believe to be most relevant to the disease presentation most strongly resemble a diffuse large B-cell lymphoma (DLBCL), whereas the gene expression data are most consistent with a low-grade chronic lymphocytic leukemia (CLL). The variant of greatest interest was a predicted NOTCH2-truncating mutation, which has been recently reported in various lymphomas.

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

Abstract Introduction: The Personalized OncoGenomics (POG) project launched at the British Columbia Cancer Agency uses genome analyses to support cancer treatment decision making. The POG project enrolls patients with incurable cancers for which standard chemotherapy regimens fail or do not exist. Here we report the first genomic sequence of a ghost cell odontogenic carcinoma (GCOC) patient enrolled in the POG program. GCOC is a very rare cancer of the maxillofacial apparatus and only 35 GCOC cases have been reported in the literature. The etiology of GCOC is largely unknown and genomic profiling of this rare cancer-type has not been previously reported. Methods: We performed whole genome sequencing (WGS; ~100X coverage) and transcriptome sequencing (RNA-seq) of a fresh tumor biopsy sample and WGS (~50X coverage) of DNA purified from peripheral blood. Bioinformatics approaches were used to identify genes with somatic single nucleotide variants (SNVs), copy number variants (CNVs), structural variants (SVs), and expression changes. All variants were integrated to build an individual somatic molecular profile, followed by intensive pathway analysis and literature searches to identify the candidate biological processes that are deregulated. Based on the integration of these results, therapeutic options were explored. Results: The tumor genome was highly aneuploid with extensive regions of loss of heterozygosity. Homozygous deletion of RB1 and heterozygous loss of PTEN, RASSF4 and FHIT tumor suppressors was observed. Oncogenes belonging to the sonic hedgehog pathway (GLI1 and SHH) as well as a variety of other oncogenes including AURKA, AKT1, GSK3B, MYCN also showed gains in copy number. Among the genes with predicted protein altering SNVs were APC, HLF, TWIST1 and UBR5. The only translocation resulting in an expressed RNA product, a reciprocal t(3;18), resulted in a novel fusion involving the TCF4 and PTPRG genes. The predicted fusion product lacks all the functional domains of the PTPRG gene including the phosphatase domain, possibly leading to the loss of tumor suppressor activity. Oncogenes involved in tyrosine kinase signaling (EGFR, KIT, FGFR1), various members of the PI3-kinase-mTOR pathway including PIK3R2, PIK3CA and MYCN, members of the NOTCH signaling pathway (NOTCH1, NOTCH3, JAG1, DTX4, HES2 and HEY1), the hedgehog pathway (PTCH1, GLI1, TWIST1 and TWIST2), and the WNT pathway (WNT4, WNT5A, FZD2, FZD10, DVL3 and GSK3B) were highly expressed in the GCOC sample. Conclusions: This study represents the first integrated genomic and transcriptomic analysis of a GCOC genome. Based on alterations in tyrosine kinase, PI3-kinase-mTOR, hedgehog and NOTCH pathways, inhibitors to these pathways were identified as therapeutic options. This abstract is also presented as Poster 06. Citation Format: Pinaki Bose, Erin Pleasance, Martin Jones, Yaoqing Shen, Carolyn Ch'ng, Caralyn Reisle, Jacqueline E. Schein, Andrew Mungall, Richard Moore, Yussanne Ma, Brandon S. Sheffield, Thomas Thomson, Steven Rasmussen, Christopher Lee, Stephen Yip, Marco A. Marra, Janessa Laskin, Cheryl Ho, Steven J. M. Jones. Integrated genomic analysis of a recurrent ghost cell odontogenic carcinoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr PR02.

•First whole genome and transcriptome profiling of ghost cell odontogenic carcinoma.•Mutations were detected in novel and known cancer genes.•Expression profiling shows that GCOC is distinct from previously sequenced cancers.•Therapeutic recommendations were made based on integrative pathway analysis.

We report the most common single-nucleotide substitution/deletion mutations in favorable histology Wilms tumors (FHWTs) to occur within SIX1/2 (7% of 534 tumors) and microRNA processing genes (miRNAPGs) DGCR8 and DROSHA (15% of 534 tumors). Comprehensive analysis of 77 FHWTs indicates that tumors with SIX1/2 and/or miRNAPG mutations show a pre-induction metanephric mesenchyme gene expression pattern and are significantly associated with both perilobar nephrogenic rests and 11p15 imprinting aberrations. Significantly decreased expression of mature Let-7a and the miR-200 family (responsible for mesenchymal-to-epithelial transition) in miRNAPG mutant tumors is associated with an undifferentiated blastemal histology. The combination of SIX and miRNAPG mutations in the same tumor is associated with evidence of RAS activation and a higher rate of relapse and death.

Medullary thyroid cancer (MTC) is a malignancy of the calcitonin-producing parafollicular cells of the thyroid gland. Surgery is the only curative treatment for this cancer. External beam radiation therapy is reserved for adjuvant treatment of MTC with aggressive features. Targeted therapeutics vandetanib and cabozantinib are approved for the treatment of aggressive and metastatic tumors that are not amenable to surgery. The use of these multikinase inhibitors are supported by the observed overactivation of the RET oncoprotein in a large subpopulation of MTCs. However, not all patients carry oncogenic alterations of this kinase. Hence, there is still a need for comprehensive molecular characterization of MTC utilizing whole-genome and transcriptome-sequencing methodologies with the aim of identifying targetable mutations. Here, we describe the genomic profiles of two medullary thyroid cancers and report the presence of a putative oncogenic BRAF fusion in one. Such alterations, previously observed in other malignancies and known targets of available drugs, can benefit patients who currently have no treatment options.