Imaging-associated Top 5 differentially DNP-MRS probes for imaging-associated differential Potential novel -probe pairs Cancer type differentially essential essential essential genes (when none otherwise identified) genes VAC14, RAB10, VAC14: Phosphatidylinositol 3- FAM83H, TNPO2, phosphate, phosphatidylinositol 3,5- 1 Bile Duct TPCN2 bisphosphate TRIM8, ETV6, [2-13C]-Dihydroxyacetone, [U-2H, U-13C]-Glucose, [1- 2 Bone IGF2BP1, FLI1, STAG1 ALDOA, FTO 13C]-Pyruvate TRPS1, SPDEF, [1-13C]-Butyrate, [1-13C]-Glutamate, [1-13C]-Glutamine, 3 Breast FOXA1, ESR1, TFAP2C ACO2, GMPS, PFAS, SDHB [5-13C]-Glutamine, [1-13C]-Pyruvate, [2-13C]-Pyruvate RPP25L, JUN, VRK1, 4 CNS RPS21, PRKAR1A GAPDH [2-13C]-Dihydroxyacetone, [U-2H, U-13C]-Glucose UBE3A, ZER1, LDHA, [1-13C]-Alanine, [1-13C]-Lactate, [1-13C]-Pyruvate, [2- 5 Cervix F2RL3, CKS1B LDHA 13C]-Pyruvate CTNNB1, TCF7L2, 6 Colorectal CDX2, KLF5, SATB2 ALDOC [2-13C]-Dihydroxyacetone, [U-2H, U-13C]-Glucose REXO2, ERBB3, FIS1, [1-13C]-Glutamate, [1-13C]-Glutamine, [5-13C]- 7 Esophagus TIMM17A, TP63 GATB, GATC Glutamine LHX3, OTX2, SCLY: Selenocysteine, alanine, 8 Eye NEUROD1, SCLY, OTP selenium TERF2IP, FANCM, CHTF18, ATG16L1, 9 Fibroblast RAB3GAP1 TCF7L2, CTNNB1, MPI: Fructose-6-phosphate, mannose-6- 10 Gastric KLF5, MPI, HDAC4 phosphate PAX8, HNF1B, SEC23IP, CDH2, 11 Kidney PARD3 [1,3-13C]-3-hydroxybutryate, [1-13C]-Alanine, [1-13C]- Butyrate, [2-13C]-Dihydroxyacetone, [U-2H, U-13C]- CAD, CTPS1, DLD, GFPT1, Glucose, [1-13C]-Glutamate, [1-13C]-Glutamine, [5- MYB, LMO2, RUNX1, GOT2, HMGCL, PFAS, PFKL, 13C]-Glutamine, [1-13C]-Glycerate, [1-13C]-Lactate, [1- 12 Leukemia GFI1, SLC5A3 PPAT, SDHA, SDHB 13C]-Pyruvate, [2-13C]-Pyruvate HNF4A, FGFR1, LDHA, [1-13C]-Alanine, [1-13C]-Lactate, [1-13C]-Pyruvate, [2- 13 Liver HNF1A, HS2ST1 LDHA 13C]-Pyruvate SMARCA2, NFE2L2, 14 Lung ASPM, ECM1, SUCO SH3GL1, ITSN2, EBF1, [1-13C]-Glutamate, [1-13C]-Glutamine, [5-13C]- 15 Lymphoma BCL6, ATP1B3 GLS Glutamine PHLDB2, DUSP1, SLC19A2, FGFR1, 16 Mesothelioma KRTAP4 [1-13C]-Alanine, [2-13C]-Dihydroxyacetone, [2-13C]- IRF4, PRDM1, Fructose, [U-2H, U-13C]-Glucose, [1-13C]-Glutamate, POU2AF1, HERPUD1, [1-13C]-Glutamine, [5-13C]-Glutamine, [1-13C]- 17 Multiple myeloma NFKB1 CA14, CAD, GLS, HK2, PFAS Glycerate, [1-13C]-Lactate, [1-13C]-Pyruvate PAX8, MECOM, PARD3, PARD6B, 18 Ovary XPR1 [1-13C]-Alanine, [1-13C]-Glutamate, [1-13C]-Glutamine, KRAS, DOCK5, ID1, [5-13C]-Glutamine, [1-13C]-Lactate, [1-13C]-Pyruvate, 19 Pancreas WLS, ELMO3 GMPS, LDHA [2-13C]-Pyruvate ISL1, HAND2, MYCN, 20 PNS PHOX2B, PDK1 MDH1B [1-13C]-Pyruvate HOXB13, ERG, FKBP4, [1-13C]-Acetate, [1-13C]-Butyrate, [1-13C]-Pyruvate, [2- 21 Prostate TLE3, GATA2 ACLY 13C]-Pyruvate DCAF5, NABP2, PUM3, 22 Rhabdoid SIVA1, QRICH1 MYOD1, PAX3, MYOG, 23 Rhabdomyosarcoma SOX8, ZBTB18 HSD17B12 [1-13C]-Butyrate SOX10, MITF, BRAF, [1-13C]-Acetate, [1-13C]-Butyrate, [1-13C]-Pyruvate, [2- 24 Skin DUSP4, MAPK1 ACLY 13C]-Pyruvate MEOX2, SACS, CHRNA4, FOXC2, 25 Soft Tissue SS18 GCDH, PDGFRA, 26 Thyroid LRMP, RPL26, RPS27 GCDH: Glutaryl-CoA, crotonyl-CoA [1-13C]-Butyrate, [2-13C]-Dihydroxyacetone, [U-2H, U- TP63, EGFR, ERBB2, 13C]-Glucose, [1-13C]-Glutamate, [1-13C]-Glutamine, 27 Upper aerodigestive ITGB1, ITGA3 ENO1, PC, PSAT1 [1-13C]-Glycerate, [1-13C]-Pyruvate, [2-13C]-Pyruvate PPARG, SOX4, TP63, 28 Urinary tract TEAD3, RXRA CCNE1, PAX8, WRN, [1-13C]-Glutamate, [1-13C]-Glutamine, [5-13C]- 29 MECOM, CCDC102A GLUL Glutamine HNF4A, LDHA, FGFR1, [1-13C]-Alanine, [1-13C]-Lactate, [1-13C]-Pyruvate, [2- 30 HCC* HS2ST1, XYLT2 LDHA 13C]-Pyruvate

Supplementary Table 1: Differentially essential genes by cancer type. This table, organized by cancer type, includes: (1) the top five differentially essential genes in each cancer type, (2) imaging-associated differentially essential genes (where p<0.0005), (3) DNP-MRS probes associated with imaging genes identified in (2) as described by Supplementary Tables 2 and 3, and (4) novel potential protein- probe pairs among genes listed in (1) when no imaging associated genes were identified in (3). Differentially essential genes were identified based on two criteria: (1) the mean CERES score for the cancer type must be < 0 and (2) the mean CERES score must be statistically less than that of all other cancer types studies (p<0.0005). *: HCC is a subset of liver cancers.