Supplemental Information. Integrated Genomic Analysis of the Ubiquitin. Pathway across Cancer Types
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1 Cell Reports, Volume 23 Supplemental Information Integrated Genomic Analysis of the Ubiquitin Pathway across Zhongqi Ge, Jake S. Leighton, Yumeng Wang, Xinxin Peng, Zhongyuan Chen, Hu Chen, Yutong Sun, Fan Yao, Jun Li, Huiwen Zhang, Jianfang Liu, Craig D. Shriver, Hai Hu, The Cancer Genome Atlas Research Network, Helen Piwnica-Worms, Li Ma, and Han Liang
2 Table S1 Summary of TCGA samples included in this study, related to STAR Methods TCGA abbreviations Number of patients Corresponding cancer types Adrenocortical carcinoma 76 Bladder Urothelial Carcinoma 399 Breast invasive carcinoma 981 Cervical squamous cell carcinoma and endocervical adenocarcinoma 272 Cholangiocarcinoma 36 Colon adenocarcinoma 341 Lymphoid Neoplasm Diffuse Large B-cell Lymphoma 37 Esophageal carcinoma 169 Glioblastoma multiforme 126 Head and Neck squamous cell carcinoma 487 Kidney Chromophobe 65 Kidney renal clear cell carcinoma 352 Kidney renal papillary cell carcinoma 271 Acute Myeloid Leukemia 162 Brain Lower Grade Glioma 57 Liver hepatocellular carcinoma 348 Lung adenocarcinoma 52 Lung squamous cell carcinoma 464 Mesothelioma 82 Ovarian serous cystadenocarcinoma 177 Pancreatic adenocarcinoma 152 Pheochromocytoma and Paraganglioma 161 Prostate adenocarcinoma 479 Rectum adenocarcinoma 118 Sarcoma 229 Skin Cutaneous Melanoma 363 Stomach adenocarcinoma 383 Testicular Germ Cell Tumors 144 Thyroid carcinoma 48 Thymoma 119 Uterine Corpus Endometrial Carcinoma 57 Uterine Carcinosarcoma 56 Uveal Melanoma 8
3 Figure S1 A UBQ Genes UUCD Database UBQ Genes (Downloaded March 217) Filter Step (removes ubiquitin-like genes) E1 8 (1 predicted) E2 39 (2 predicted) E3 882 (368 predicted) E3 Actvity E3 Adapter 387 (78 predicted) 495 (29 predicted) 929 Total UBQ Genes B DUB Genes Kraile et al., Nijman et al., 25 Komander et al., Abdul Rehman et al., Total DUB Genes Figure S1. Curation of UBQ and DUB gene lists, related to STAR Methods A) Distribution of UUCD curated UBQ genes by category and classification. B) Gene intersection of three major DUB journal articles plus the addition of four newly discovered DUB genes.
4 KMT2B CHD4 BRWD3 KEAP1 USP9X VHL CDH1 BAP1 MAP3K1 DCAF4L2 1 CHD3 TRIP12 DCAF12L NWD1 RNF43 SPOP DCAF12L ZBTB2 CUL3 KDM5C USP28 LZTR1 DCAF8L2 CUL1 TLE1 AHR PHF14 ZBTB7B TRIM48 TRAF3 FBXO7 TRAF3IP2 ANAPC4 FBXL2 RNF128 PPP2R2A WRAP53 PPIL2 MTF2 RAE1 WDR5 STAMBPL UBE2A FBXW9 PDLIM2 WDR83 TRIM7 PAK1IP1 UBE2J2 Figure S2 Alternations Frame_Shift_Del Frame_Shift_Ins In_Frame_Del In_Frame_Ins Missense_Mutation Nonsense_Mutation Nonstop_Mutation Splice_Site Translation_Start_Site Multi_Hit Figure S2. Oncoprints of the 55 UBQ/DUB genes identified as potential cancer drivers, related to Figure 1 Each column represents a patient; each row is a UBQ/DUB gene. For each gene, the percentage of patients with mutations among 8,811 patients is shown on the left.
5 C Deletion)enrichment)ratio Amplification))enrichment)ratio Figure S3 A Amplification enrichment ratio Fraction)of)UBQ)genes)GISTIC2)significant Deletion Enrichment ratio Cancer)Types group * ** ** amp del B D Deletion)enrichment)ratio Amplification))enrichment)ratio Enrichment ratio Amplification enrichment ratio Fraction)of)DUB)genes)GISTIC2)significant Cancer)Types E p&=&4&x&1&,2 &Patients SKP2 SKP Alterations AMP1 High,level&Amplification AMP2 Low,level&Amplification MDM2 DEL2 Low,level&Deletion NS F MDM2&SCNA ATM&Mutation p&=&3&x&1&,2&&&&&&&&&&&&&& MDM2 &Patients High%level)Amplification Frame_Shift_Ins In_Frame_Del Missense_Mutation Multi_Hit Nonsense_Mutation Splice_Site Figure S3. Somatic copy-number alterations of UBQ and DUB genes, related to Figure 3 Fractions of (A) UBQ and (B) DUB genes identified in the amplification or deletion peaks by GISTIC2 in each cancer type. Fractions of UBQ (C) and DUB (D) genes residing in the amplification or deletion peaks (identified by GISTIC2, q <.25) compared to non- UBQ/DUB genes in different cancer types. Significant deletion enrichments are detected with * p < 1. E) MDM2 and SKP2 amplifications show a mutually exclusive pattern in. F) MDM2 amplifications show a mutually exclusive pattern with ATM somatic mutations in.
6 Figure S4 A B Figure S4. Upregulation of UBQ/DUB genes in tumor samples, related to Figure 4 A) Tumor normal comparison of UBQ/DUB genes across 16 cancer types. B) Proportions of UBQ and DUB genes whose expression are potentially affected by SCNA, mirna regulators and DNA methylation in seven cancer types.
7 Figure S5 gene&(size:&#&of&interactions) mirna&(size:&#&of&interactions) Interaction&(thickness:&#&of&cancer&types) Figure S5. Network view of mirna regulators of UBQ and DUB genes, related to Figure 4 Each red circle represents a mirna regulator and each blue square represents a UBQ/DUB gene. Lines connecting the circle and squares represent potential mirna regulation of the UBQ/DUB genes; the line thickness represents the number of cancer types in which the interaction is observed.
8 78.92K 59.19K 39.46K 19.73K Figure S6 A 78.92K 78.92K 78.92K 59.19K 59.19K K 39.46K 39.46K Missing Value 39.46K 19.73K 19.73K cluster 1 - (n= 2573, 28%) 2 - (n= 4491, 49%) 3 - (n= 261, 2 Missing Value - (n=, %) Missing Missing Value Value Value K zge-pancan33-coca-final-k3 map for cms2 zge-pancan33-coca-final-k3 map for cms2 zge-pancan33-coca-final-k3 map for cms2 zge-pancan33-coca-final-k3 map for cms2 C cluster cluster cluster 1 - (n= 2573, 28%) (n= - (n= 4491, 2573, cluster 49%) 28%) (n= - (n= 261, 4491, 2 49%) Missing (n= (n= 2573, Value 261, 28%) - 2 (n=, %) 2 Missing - (n= 4491, Value 49%) - (n=, %) Cancer_t 3 - (n= ype 261, 2 Missing - (n= 126, Value - (n=, %) - (n= 126, - (n= 177, - (n= 177, - (n= 52, - (n= 52, - (n= 464, - (n= 464, - (n= 479, - (n= 479, - (n= 57, - (n= 57, - (n= 399, - (n= 399, - (n= 144, - (n= 144, - (n= 169, - (n= 169, - (n= 152, - (n= 152, - (n= 271, - (n= 271, - (n= 348, - (n= 348, - (n= 272, - (n= 272, - (n= 229, - (n= 229, - (n= 981, 1 - (n= 981, 1 - (n= 119, - (n= 119, - (n= 82, - (n= 82, - (n= 341, - (n= 341, - (n= 383, - (n= 383, - (n= 363, - (n= 363, - (n= 36, %) - (n= 36, %) - (n= 352, - (n= 352, - (n= 48, - (n= 48, - (n= 487, - (n= 487, - (n= 162, - (n= 162, - (n= 118, - (n= 118, - (n= 57, - (n= 57, - (n= 37, %) - (n= 37, %) - (n= 65, - (n= 65, - (n= 56, - (n= 56, - (n= 76, - (n= 76, - (n= 161, - (n= 161, - (n= 8, - (n= 8, Missing Value Missing - (n=, Value %) - (n=, %) B Cancer_t ype Cancer_t ype Cancer_t ype - (n= 126, - (n= 177, - Cancer_t (n= 126, ype - -(n= 52, 177, - -(n= - 126, 464, (n= 52, - (n= - (n= 177, - (n= 479, 464, - (n= - 57, (n= 52, 479, - (n= - 399, 464, (n= 57, - (n= - (n= 144, 479, 399, - (n=- 169, (n= 57, 144, - (n= - (n= 399, 152, 169, - -(n= (n=- 271, 144, (n= 152, - (n= 152, - - (n= - (n= 348, 169, 271, - (n= 271, - (n= - (n= 272, 152, 348, - (n= 348, -- (n= - 271, (n= 229, 272, - (n= 272, -- (n= - 348, (n= 981, 229, 1 - (n= 229, - (n= - 272, (n= 119, 981, 1 - (n= 981, 1 - (n= - 229, (n= 82, 119, - (n= 119, - (n= - 981, 341, (n= 82, 1 - (n= 82, Log%rank)p)=)4.)x)1) - (n=- 383, 119, (n= 341, %2 - (n= 341, - - (n= 363, 82, 383, - (n= 383, - (n=- 36, (n= 341, %) 363, - (n= 363, - - (n=- 352, 383, (n= 36, %) - (n= 36, %) - - (n= 48, 363, 352, - (n= 352, - (n= - (n= 487, 36, 48, %) - (n= 48, - -(n= - 352, 162, (n= 487, - (n= 487, - (n= - (n= 118, 48, 162, - (n= 162, - (n= - (n= 57, - (n= 487, 118, - (n= 118, - (n= - (n= 37, 162, 57, %) - (n= 57, - -(n= (n=- 65, (n= 118, 37, %) - (n= 37, %) - (n=- 56, 57, (n= 65, - (n= 65, - (n= - (n= - (n= 76, 37, 56, %) - (n= 56, --(n= 161, - (n= 65, 76, - (n= 76, - (n= 8, - 56, (n= 161, - (n= 161, Missing Value - (n= , (n= 8, (n=, %) - (n= 8, Missing - (n= 161, Value - (n=, %) Missing Value - (n=, - %) (n= 8, Missing Value - (n=, %) D p =)3.6)x)1) %12)) p =)9.9)x)1) %32) p)=)2.5)x)1) %24) p)=)5.)x)1) %5 Figure S6. Associations of COCA clusters with cancer subtypes, related to Figure 5 A) Clusters from individual platforms (RNA-seq, DNA methylation, SCNA). B) Kaplan-Meier plots for overall survival of COCA clusters in. C) Kaplan-Meier plots for disease-specific survival of COCA clusters in nine cancer types. The log-rank p values and the number of patients in each cluster are also shown. D) COCA clusters show significant correlations with established tumor subtypes in,,, and.
9 Figure S7 Molecular&drivers APC/C SCF DNA&Damage& Response Expression&(&q&<&.1&) Figure S7. Gene expression levels in COCA2 samples compared to COCA1 and COCA3 samples, related to Figure 7 Genes with consistently high or low expression in COCA2 compared to COCA1 and COCA3 across multiple cancer types are respectively shown in red and blue (t-test, q <.1).
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