The Cancer Genome Atlas (TCGA) Cancers Selected for Study

• Relatively few mutations were found per AML patient (with an avg. of 13 mutated genes per tumor)
• Recurrently mutated genes can be clustered into 9 categories based on the gene's function or pathway involvement (including transcription factor genes, the gene encoding nucleophosmin (NPM1), myeloid transcription factors, cohesin complex genes, and signaling genes).
• Integrated previously fragmented genomic information, providing a comprehensive picture of the cancer.

Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia

• Chromosome copy number changes are a probable driver of adrenocortical carcinoma (as whole genome doubling occurred in 51% of tumors studied and hypoploidy was observed 31% of cases studied).
• Further evidence that overexpression of IGF2 and mutation of TP53 are hallmarks of adrenocortical carcinoma.
• Novel mutations that likely contribute to the development of adrenocortical carcinoma, including mutations in PRKAR1A (which were found in 8% of patients in the study and have previously been associated with tumors and other diseases of the adrenal cortex). 

Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

• 64 significantly mutated genes were identified. 
• Altered signaling pathways and protein expression include p53/cell cycle, DNA repair, PI3K/AKT, as well as chromatin modifications and regulation, which may have applicable therapies currently under development that should be further investigated. 
• Multiple subtypes of muscle-invasive bladder cancer exist, each with unique underlying molecular characteristics and potential treatment strategies (e.g., luminal-papillary subtype has a lower risk of progression and a lower likelihood of response to cisplatin-based neoadjuvant chemotherapy, luminal-infiltrated subtype resembles a previously TCGA-established cancer subtype known to respond to immune checkpoint therapy, luminal subtype may respond to neoadjuvant chemotherapy and requires further research to identify an appropriate targeted therapy, basal-squamous subtype shows signs of immune infiltration and may benefit from immune checkpoint therapy or cisplatin-based neoadjuvant chemotherapy, and the neuronal subtype may behave similarly to neuroendocrine neoplasms of other tissue sites and may respond to etoposide-cisplatin therapy).
• Smoking is strongly associated with bladder cancer, as over half of tumors were from patients with a history of smoking. Smokers also had a higher incidence of both mutations in the ERCC2 gene and the ERCC2 mutation signature.

Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma

Comprehensive Molecular Characterization of Muscle Invasive Bladder Cancer

• The cancer can be categorized into four molecular subtypes: HER2-enriched, Luminal A, Luminal B, and Basal-like
• Basal-like subtype shares many genetic features with high-grade serous ovarian cancer, suggesting that the cancers have a common molecular origin and may share therapeutic opportunities.

Comprehensive Molecular Portraits of Human Breast Tumors

• Genomic characteristics of lobular carcinoma distinguish it from the more common ductal carcinoma, providing unique opportunities for targeted therapy (e.g., all lobular carcinoma tumors were defined by loss of E-cadherin through varied routes of genomic disruption, lobular carcinomas demonstrated frequent mutations in different genes involved in estrogen receptor signaling compared to ductal carcinoma, and lobular carcinomas contained a greater degree of Akt signaling pathway activation than ductal carcinomas).
• Revealed 3 subtypes of lobular carcinoma that show distinct clinical outcomes: reactive-like (associated with best outcomes), immune-related, and proliferative (associated with the poorest outcomes)
• Tumors that could not be identified as lobular or ductal based on histology were a mixed subtype, as they could be grouped with either lobular or ductal types based on their molecular features.

Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer

• Novel mutated genes in cervical cancer include MED1, ERBB3, CASP8, HLA-A, and TGFBR2.
• Some genomic changes in cervical cancer indicate the disease may be treated with available drugs (e.g., altered genes involved in regulating the immune system may be targeted by immunotherapeutic agents, tumors with BCAR4 gene fusions may be sensitive to lapatinib, and nearly 3/4 of cervical cancers had genomic alterations in either one or both of PI3K/MAPK and TGF-beta signaling pathways).
• Several cancers studied did not demonstrate HPV involvement, indicating that a small percentage of cervical cancers arise in other ways.

Integrated Genomic and Molecular Characterization of Cervical Cancer

• 38 cholangiocarcinoma tumors characterized by TCGA had alterations to known tumor suppressor genes and oncogenes (e.g., alterations limiting the expression of tumor suppressor genes CDKN2, BAP1, and ARID1, as well as alterations increasing the expression of oncogenes FGFR2 and IDH1/2).
• Cholangiocarcinomas can by categorized into four subgroups based on their mRNA expression patterns, DNA methylation, and copy numbers of chromosome segments. Also, a new subtype characterized by mutations in the IDH gene was identified.
• Cholangiocarcinoma tumors closely resemble a subset of liver cancers analyzed by a previous TCGA study, suggesting the two cancers may exist on a continuous spectrum.

Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles

• Molecular differences distinguish chromophobe renal cell carcinoma from clear cell renal cell carcinoma, suggesting that these cancers should be treated as clinically distinct diseases. 
• Chromophobe renal cell carcinoma demonstrated a low rate of somatic mutation compared to most tumors, and specifically, three times lower than the mutation rate of clear cell renal cell carcinoma.
• Gene expression data suggests that chromophobe renal cell carcinoma originates from distal regions of the kidney while clear cell renal cell carcinoma arises in the proximal tissue of the kidney.
• Some metabolic pathways related to energy production in mitochondria were enriched in chromophobe renal cell carcinoma, while these same pathways were suppressed in clear cell renal cell carcinoma.
• Two well-established tumor suppressor genes were frequently mutated in chromophobe renal cell carcinoma: TP53 and PTEN.
• Structural rearrangements of the TERT gene promoter, a regulatory area for the chromosome elongation enzyme telomerase, may drive this cancer.

The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

• Molecular alterations in clear cell carcinoma modulate cell signaling. 
• Clear cell carcinoma tumors contained frequent alterations in VHL and its interaction partners, genes involved in cellular oxygen sensing.
• Genes of the PI(3)K/AKT pathway were highly mutated, suggesting that tumors may respond to specific inhibitors of this pathway.
• SETD2 was frequently mutated, leading to global hypomethylation and vast changes in gene expression.
• Altered cellular metabolism distinguished clear cell carcinoma from other cancers. A shift to favor certain metabolic pathways and reduce the use of others was associated with poor outcomes. In some cases, a metabolic shift may be caused by changes in the PI3K/AKT/mTOR pathway, which was altered in 28% of cases.
• Clear cell carcinomas may be categorized into four subtypes based on mRNA and microRNA expression, each subtype associated with differential survival.

Comprehensive Molecular Characterization of Clear Cell Renal Cell Carcinoma

• Colon and rectal cancers are a single type of cancer
• Tumors with hypermutation, in which the rate of genetic mutations is abnormally high because DNA repair mechanisms are disrupted, are more aggresive.
• Genes significantly mutated in colorectal cancer include novel potential drivers: ARID1A, SOX9, and FAM123B/WTX
• Overexpression of the genes ERBB2 and IGF2, which help regulate cell proliferation, may represent therapeutic opportunities for this disease.
• Mutations in certain signaling pathways, such as WNT, are also potential targets.

Comprehensive Molecular Characterization of Human Colon and Rectal Cancer

• Significant molecular differences between esophageal adenocarcinoma and esophageal squamous cell carcinoma may help improve how they are classified. Esophageal squamous cell carcinomas share more genetic features with head and neck squamous cell carcinomas than with esophageal adenocarcinomas and may therefore benefit from similar therapeutic approaches. Adenocarcinomas contain molecular changes similar to the chromosomal instability (CIN) subtype of stomach cancer. 
• Genomic alterations may represent effective targets for therapy. Frequent alterations of genes that regulate the cell cycle may be treated with existing drugs. 1/3 of esophageal adenocarcinomas studied harbored an alteration to the ERBB2 gene, which encodes the HER2 protein, and may be targeted with HER2 inhibitors.

Integrated Genomic Characterization of Esophageal Carcinoma

• The disease can be categorized into four genomic subtypes of stomach cancer.
• The Epstein-Barr virus (EBV) subtype, comprised of 9% of cancers studied, had amplified expression of genes that suppress the immune response and frequent alterations in the PIK3CA gene.
• The microsatellite instability (MSI) subtype made up 22% of tumors and was characterized by an elevated rate of mutations.
• A genomically stable (GS) subtype (20% of tumors studied) was distinguished by few structural changes in the chromosomes.
• A chromosomal instability (CIN) subtype (5% of tumors studied) demonstrated high chromosomal instability and increased expression of receptor tyrosine kinases (RTKs).

Comprehensive Molecular Characterization of Gastric Adenocarcinoma

• A novel subtype of GBM, established by TCGA, affects younger adults and has an increased survival rate. These tumors are distinguished by a methylation signature which may account for the improved survival of these patients.
• 4 distinct molecular subtypes of GBM respond differently to aggressive therapies: proneural, neural, classical, and mesenchymal
• Selective pressure to lose mismatch repair function may cause some tumors to become resistant to temozolomide (a chemotherapy). This finding could be used to develop new strategies  that will not activate this drug resistance mechanism.
• Alterations of the EGFR gene, as well as a region on a chromosome containing MDM2 and CDK4 genes, may be important to the development of GBM.
• Pinpointed five gene mutations that may provide new insights into the biology of this disease: NF1, ERBB2, TP53, PIK3R1, and TERT
• GBM mutations are enriched for chromatin modification genes.

Comprehensive Genomic Characterization Defines Human Glioblastoma Genes and Core Pathways

The Somatic Genomic Landscape of Glioblastoma

• Head and neck cancers associated with human papillomavirus (HPV) and tobacco-smoking are molecularly distinct.
• The integration of HPV, a virus harboring oncoproteins E6 and E7 that cause HPV+ head and neck squamous cell carcinomas, is linked to increased somatic copy number variants. HPV+ tumors are also characterized by shortened or deleted TRAF3, amplification of E2F1, and mutations in PIK3CA.
• HPV- tumors contained novel co-amplifications of 11q13 and 11q22, an event that likely promotes the interaction of BIRC2 and FADD, genes that together work to inhibit cell death.
• Smoking-related tumors featured TP53 mutations, CDKN2A inactivation, and frequent copy number alterations.
• Molecular characteristics may help clinicians improve the specificity of the diagnosis and treatment of head and neck squamous cell carcinomas.
• Cell cycle proteins are altered in differently in HPV+ and HPV- cancers, suggesting that treating these cancers should be treated according to their subtype.

Comprehensive Genomic Characterization of Head and Neck Squamous Cell Carcinomas

• An analysis of 196 hepatocellular carcinoma cases confirmed frequent mutations in the TERT promotor region, TP53, and CTNNB1.
• Mutations of the TERT promotor, found in 44% of the cancers studied, may be targeted with telomerase inhibitors that are under development.
• In many tumors, TP53 was not genetically altered but inhibited by expression of MDM4, which in turn may be inhibited by investigational drugs.
• 20% of tumors studied showed elevated expression of immune evasion genes, suggesting that this subset may be sensitive to immunotherapies that strengthen the immune system’s surveillance.

Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

• Mutations and chromosomal alterations define three lower grade glioma subtypes with distinct clinical outcomes.
• IDH mutant and 1p/19q co-deletion: The 1p/19q abnormality consists of deletion of a short arm of chromosome 1 and longer arm of chromosome 19; Mutations in IDH1 and IDH2 lead to abnormal enzyme activity, hypermethylation, and deviant gene expression; This subtype is associated with the most favorable prognosis
• IDH mutant without 1p/19q co-deletion is associated with intermediate prognosis.
• IDH wild-type is associated with the poorest outcomes.
• IDH wild-type subtype shares genomic markers and similar clinical outcomes with glioblastomas, indicating that this subtype of lower grade glioma may be a precursor to the more aggressive counterpart.
• Molecular signatures and subtypes may inform the classification, diagnosis, and treatment of lower grade gliomas.
• Lower grade gliomas without IDH mutations may benefit from treatment with protocols adapted from current glioblastoma treatments.
• Recently developed therapies may target the aberrant activity of IDH1/2 proteins in lower grade glioma.

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas

• Found further evidence that lung adenocarcinoma has a high rate of mutations compared to other cancers.
• 76% of cases studied harbored activation of a variety of receptor tyrosine kinase pathways, which alter signaling and causes increased cell proliferation. The activation may be caused by 18 significantly mutated genes (including previously known drivers KRAS, EGFR, and BRAF) and novel oncogenic drivers, such as tumor suppressor NF1.
• The cancer can be categorized into three distinct subtypes based on gene expression data: proximal proliferative, proximal inflammatory, and terminal respiratory unit

Comprehensive Molecular Profiling of Lung Adenocarcinoma

Distinct Patterns of Somatic Genome Alterations in Lung Adenocarcinomas and Squamous Cell Carcinomas

• Promising therapeutic targets in lung squamous cell carcinoma were identified, including 3 families of tyrosine kinases, 2 gene families called ERBBs and FGFRs, as well as a family of kinases called JAKs.
• Key tumor suppressor genes are altered in a majority of tumors. TP53 was altered in 90% of samples, and CDKN2A was inactivated in 72% of tumor samples.
• Inactivating mutations in HLAA, a gene that normally helps the body watch out for mutated cells, are common in the disease.
• 4 subtypes of lung squamous cell carcinoma were molecularly described.

Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

Distinct Patterns of Somatic Genome Alterations in Lung Adenocarcinomas and Squamous Cell Carcinomas

• Defined multiple histology-independent, prognostic subtypes of mesothelioma from an integrative analysis of 74 cases of the disease.
• Identified a novel genomic subtype accounting for about 3% of samples with TP53 and SETDB1 mutations, as well as genomic "near haploidization" (i.e., loss of one copy of nearly all chromosomes).
• Alterations to known cancer gene BAP1 were present in over half of cases studied, and may affect transcription factor activity and perturb immune signaling.
• The immune checkpoint gene VISTA, strongly expressed in epithelioid mesothelioma, may be restraining anti-tumor immune responses in some cases.

Integrative Molecular Characterization of Malignant Pleural Mesothelioma Available

• Mutations in the gene TP53 (a tumor suppressor) are present in more than 96% of ovarian cases studied.
• Certain gene expression patterns correlate with poor or better survival. Patients with the poorest survival gene expression pattern lived 23% shorter period than other patients.
• Tumors can be categorized into four distinct subtypes according to gene expression and DNA methylation patterns.
• Patients with mutations in BRCA1 and BRCA2 genes have better odds of survival than patients without mutations in those genes. ~21% of tumor cases in the study exhibited these mutations.
• Therapeutic opportunities for ovarian cancer lie in existing drugs targeting specific genomic errors. The cases studied contained 68 genes that could be targeted by existing FDA-approved or experimental therapeutic compounds.

Integrated Genomic Analyses of Ovarian Carcinoma

• TCGA developed and employed deep and targeted genomic analysis techniques to study pancreatic cancer, which is particularly difficult to study because pancreatic tumors often have a low percentage of cancer cells compared to cells from normal or surrounding tissue.
• KRAS and the RAS-MAPK signaling pathway are key to understanding pancreatic cancers. KRAS was mutated in 93% of cancers in the study. 60% of cancers studied that did not harbor a KRAS mutation had a mutation in a different gene in the RAS-MAPK signaling pathway.
• RREB1, another member of the RAS-MAPK pathway, may also promote pancreatic cancer when mutated.
• 42% of tumors studied had a genomic alteration that may qualify for a current clinical trial.
• Identified signatures of microRNAs, long noncoding RNAs, and DNA methylation characteristic of basal-like and classical subtypes of pancreatic cancer.

Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

• Type 1 and Type 2 papillary renal cell carcinoma, defined by differences in the appearance of the tissue under the microscope, are distinct in their genomic profiles.
• 81% of Type 1 tumors contained an alteration of the MET gene and may be receptive to specific inhibitors of the MET pathway.
• Type 2 is a heterogeneous disease with multiple distinct subtypes.
• The CpG island methylation phenotype subtype was found almost exclusively in Type 2 papillary carcinoma and was associated with the least favorable outcomes.
• Type 2 is also associated with loss of expression of the tumor suppressor CDKN2A was associated with a poor prognosis.

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma

• Identified novel, non-inherited, genomic changes underlying pheochromocytomas (PCC) and paragangliomas (PGL) in the most comprehensive study to date.
• Mutations in the gene CSDE1, which prevents the cell from destroying itself when its behavior becomes abnormal, play a significant role in allowing PCC and PGL cells to grow and thrive.
• Fusions involving the gene MAML3 activate the Wnt signaling pathway and lead to cell growth and metastasis.
• PCC and PGL may be subtyped into four groups based on genomic alterations, including Wnt-altered (a novel subtype containing CSDE1 and MAML3 alterations, which was associated with the shortest survival), cortical admixture (a novel subtype displaying increased expression adrenal cortex genes), kinase signaling, and pseudohypoxia.

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

• Prostate cancer is a highly heterogeneous disease, as 26% of tumors examined could not be categorized into a molecular subtype.
• 7 molecular subtypes of prostate cancer describe the remaining 74% of tumors.
• 4 subtypes are characterized by cancer-driving gene fusions.
• 3 subtypes are characterized by cancer-driving genetic mutations.
• Fusion-driven and mutation-driven cancers demonstrated different genomic profiles.
• Mutations in SPOP and FOXA1 showed high levels of androgen receptor-mediated gene expression, suggesting that these subtypes may respond to targeting androgen.

The Molecular Taxonomy of Primary Prostate Cancer

• Few somatic mutations and numerous copy number changes dominate complex karyotype sarcomas, while gene fusions are a defining feature of simple karyotype sarcoma.
• TP53, ATRX, and RB1 were among the few genes recurrently mutated across sarcoma types.
• Copy number alterations frequently occurred in complex karyotype sarcomas, affecting cell cycle and other pathways.
• synovial sarcomas expressed fusions in SSX1 or SSX2 genes, and frequently also in TERT.
• Mutational signatures found in sarcomas are novel, but contain elements of previously described patterns, including those resulting from clock-like mutational processes.
• In individual sarcoma types, a wide diversity of genomic and regulomic changes associate with patient outcome.
• For dedifferentiated liposarcoma, JUN amplification associates with worse survival and should be considered as a therapeutic target.
• Gynecologic and soft tissue site subtypes of leiomyosarcoma are molecularly distinct enough to support different clinical approaches, but as a whole may benefit from inhibitors of the PI3K-AKT-mTOR pathway.
• Undifferentiated pleomorphic sarcoma and myxofibrosarcoma are molecularly similar despite histological differences and may be driven by alterations in the Hippo pathway.
• The level of immune infiltration associates differentially with patient outcome for different types of sarcoma.
• Immune checkpoint inhibitors may be beneficial to certain sarcoma subtypes, such as undifferentiated pleomorphic sarcoma, myxofibrosarcoma, and certain cases of dedifferentiated liposarcoma.

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

• 4 major subtypes of cutaneous melanoma were established: BRAF mutant, RAS mutant, NF1 mutant, and triple wild-type
• Mutations in each of the identified driver genes, BRAF, RAS, and NF1, contribute to deregulation of the MAPK/ERK pathway, leading to uncontrolled cell growth.
• The most common subtype found was the BRAF subtype, with 52% of tumors harboring BRAF somatic mutations.
• Distinct molecular profiles of cutaneous melanoma may help clinicians improve diagnosis and treatment.
• Tumors of triple wild-type patients often contained mutations in receptor tyrosine kinases that may be responsive to receptor tyrosine kinase inhibitors.
• RAS and NF1 mutant melanomas have deregulated MEK signaling, indicating that these subtypes may be responsive to MEK inhibitors.
• RAS, NF1, and triple wild-type cancers all demonstrated overexpression of AKT3, a protein kinase that affects MEK and mTOR signaling pathways. This suggests that MEK and PI3K/AKT/mTOR pathway inhibitors could target this molecular alteration.
• The immune system plays a role in cutaneous melanoma. Patients with metastatic melanoma with greater numbers of immune cells infiltrating tumors in the lymph nodes and enhanced T-cell signaling experienced better outcomes.

Genomic Classification of Cutaneous Melanoma

• In a study of 137 testicular germ cell tumors (TGCTs), distinct molecular patterns characterized each of the major histological subtypes of the disease: seminoma, embryonal carcinoma, yolk sac, and teratoma
• All histology types exhibited extensive aneuploidy and low mutation frequency.
• Global DNA methylation and miRNA expression differ greatly between histology types, implicating a likely major role of epigenomic processes in determining histologic fates. 
• A subset of pure seminomas are defined by KIT mutations, distinct DNA methylation and immune infiltration profiles, and decreased KRAS copy number.
• Significant somatic mutations are present only in TGCTs with seminoma components.
• Certain molecular features may potentially be used as biomarkers for risk stratification. 

Integrated Molecular Characterization of Testicular Germ Cell Tumors

• 4 major subtypes were defined from multi-omic data on 117 samples. The subtypes correspond to known hisopathological subtypes B, TC, AB, and a mix of A and AB, as well as are associated with differential survival.
• Thymomas have among the lowested mutational burden among all adult cancers.
• Enrichment of HRAS, NRAS, TP53, and recurrent GTF2I mutations was observed.
• Expression of autoimmune targets and aneuploidy links thymoma to myasthenia gravis.
• A specific mutation within GTF2I occurred only in thymoma of all TCGA samples and may present a potential drug target.

The Integrated Genomic Landscape of Thymic Epithelial Tumors

• The majority of papillary thyroid carcinomas studied were driven by mutations in either BRAF (specifically, BRAF-V600E) or RAS, both of which deregulate the MAPK signaling pathway.
• Novel driver gene EIF1AX impairs the MAPK pathway and is mutually exclusive from BRAF and RAS mutations.
• Oncogenic drivers were identified in 96.5% of tumor samples.
• Classification of papillary thyroid carcinomas may potentially be refined to include a tumor’s likeness to BRAF-V600E driven tumors versus RAS driven tumors.
• BRAFV-600E driven tumors and RAS driven tumors showed distinct molecular profiles that differentially affect downstream signaling: BRAF-V600E driven tumors demonstrate high MAPK-signaling while RAS driven tumors demonstrate lower MAPK-signaling.
• A thyroid differentiation scoring system helps determine whether tumors are BRAF-V600E driven or RAS driven.
• Heterogeneous gene expression for the BRAF-V600E subtype suggests further stratification of the subtype could lead to better prognostic value.
• Potential therapeutic avenues based on molecular features may be pursued. BRAF-V600E and RAS driven tumors may respond differently to treatments such as radioactive iodine and targeted therapy.

Integrated Genomic Characterization of Papillary Thyroid Carcinoma

• Uterine Carcinosarcomas (UCSs) resemble both carcinomas and sarcomas on a molecular level.
• UCSs had the largest variation of epithelial to mesenchymal transition (EMT) scores, which are related to the ability of cancers to metastasize, among all cancer types studied by TCGA.
• Almost all (91%) UCS tumors studied contained mutations in TP53.
• Half of the tumors had altered genes in the PI3K pathway, which contains several known drug targets.
• More than a fifth of the tumors studied contained altered genes.

Integrated Molecular Characterization of Uterine Carcinosarcoma

• 4 molecular subtypes of endometrial cancer are POLE ultra-mutated, microsatellite instability hypermutated, copy number low, and copy number high.
• Endometrial cancer shares genomic features with serous ovarian cancer, the basal-like subtype of breast cancer, and colorectal cancer.
• Some endometrioid and serous endometrial tumors are molecularly distinct, while others are similar, suggesting some may benefit from a common treatment.
• Serous and some of the endometrioid tumors are characterized by frequent mutations in TP53, extensive copy number alterations, and few methylation changes.
• Other endometrioid tumors are characterized by few copy number alterations, scarce mutations in TP53, and frequent mutations in PTEN and KRAS.

Integrated Genomic Characterization of Endometrial Carcinoma

• A comprehensive analysis of 80 uveal melanoma tumors confirmed previous research findings, such as the clinical significance of the monosomy 3 (M3) and disomy 3 (D3) subtypes.
• Novel DNA-seq and RNA-seq assembly methods identified long and complex alterations to the BAP1 gene.
• BAP1 mutations in M3, metastasis-prone, uveal melanoma are of great significance to the disease. 83.3% of M3 tumors studied harbor an alteration to BAP1, and BAP1 mutated tumors are associated with a unique global DNA methylation profile. Though BAP1 mutations may be acquired early on during cancer development, the altered gene may also play a key role during later genetic events driving metastasis.
• Uveal melanoma is molecularly distinct from cutaneous melanoma, with lower somatic mutation density, no ultraviolet radiation mutational signature, and a discrete set of significantly mutated genes.
• Specific gene expression patterns and molecular pathways associate with differential time to metastasis.
• Distinct global DNA methylation profiles, copy number alterations, and cellular pathway activity profiles can distinguish certain subtypes of the cancer.

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma