Systems-level Analysis of 32 TCGA Cancers Reveals Disease-Dependent tRNA Fragmentation Patterns and Very Selective Associations with Messenger RNAs and Repeat Elements

Abstract

Methods of treating a disease by leveraging positive and negative correlations between tRNA-derived fragments (tRF) and messenger RNA (mRNA) wherein said correlations can be used to establish a level of granularity that is specific to a disease of interest wherein said disease-specific positive and negative correlations can allow a level of therapeutic intervention that will be unprecedented because it will have been informed by three dimensions: at least one mRNA of interest; at least one tRF that are positively/negatively correlated with it; and, the identity of the disease in which one wishes to modulate the abundance of the at least one mRNA of interest.

1 - 110 . (canceled) 
     
     
         111 . A method of treating a cancer in a patient comprising administering a gene modulating therapy, wherein at least one gene that is transcribed in an ailing tissue of the patient is correlated with the deficiency of at least one cancer regulating tRF that is transcribed in the ailing tissue, wherein the ailing tissue is selected from the group comprising ACC (Adrenocortical carcinoma), BLCA (Bladder Urothelial Carcinoma), BRCA (Breast invasive carcinoma), CESC (Cervical squamous cell carcinoma and endocervical adenocarcinoma), CHOL (Cholangiocarcinoma), COAD (Colon adenocarcinoma), DLBC (Lymphoid Neoplasm Diffuse Large B-cell Lymphoma), ESCA (Esophageal carcinoma), HNSC (Head and Neck squamous cell carcinoma), KICH (Kidney Chromophobe), KIRC (Kidney renal clear cell carcinoma), KIRP (Kidney renal papillary cell carcinoma), LAML (Acute Myeloid Leukemia), LGG (Brain Lower Grade Glioma), LIHC (Liver hepatocellular carcinoma), LUAD (Lung adenocarcinoma), LUSC (Lung squamous cell carcinoma), MESO (Mesothelioma), OV (Ovarian serous cystadenocarcinoma), PAAD (Pancreatic adenocarcinoma), PCPG (Pheochromocytoma and Paraganglioma), PRAD (Prostate adenocarcinoma), READ (Rectum adenocarcinoma), SARC (Sarcoma), SKCM (Skin Cutaneous Melanoma), STAD (Stomach adenocarcinoma), TGCT (Testicular Germ Cell Tumors), THCA (Thyroid carcinoma), THYM (Thymoma), UCEC (Uterine Corpus Endometrial Carcinoma), UCS (Uterine Carcinosarcoma), or UVM (Uveal Melanoma). 
     
     
         112 . The method of  claim 111 , wherein the ailing tissue and the tRF transcribed in the ailing tissue is selected from the group comprising ACC (Adrenocortical carcinoma) and the tRF is selected from the group of sequences consisting of SEQ 1 through SEQ 31; BLCA (Bladder Urothelial Carcinoma) and the tRF is selected from the group of sequences consisting of SEQ 32 through SEQ 40; BRCA (Breast invasive carcinoma) and the tRF is selected from the group of sequences consisting of SEQ 41 through SEQ 58; CESC (Cervical squamous cell carcinoma and endocenrical adenocarcinoma) and the tRF is selected from the group of sequences consisting of SEQ 59 through SEQ 71; COAD (Colon adenocarcinoma) and the tRF is selected from the group of sequences consisting of SEQ 72 through SEQ 77; DLBC (Lymphoid Neoplasm Diffuse Large B-cell Lymphoma) and the tRF is selected from the group of sequences consisting of SEQ 78 through SEQ 88; ESCA (Esophageal carcinoma) and the tRF is selected from the group of sequences consisting of SEQ 89 through SEQ 94; HNSC (Head and Neck squamous cell carcinoma) and the tRF is selected from the group of sequences consisting of SEQ 95 through SEQ 109; KICH (Kidney Chromophobe) and the tRF is selected from the group of sequences consisting of SEQ 110 through SEQ 120; KIRC (Kidney renal clear cell carcinoma) and the tRF is selected from the group of sequences consisting of SEQ 121 through SEQ 128; KIRP (Kidney renal papillary cell carcinoma) and the tRF is selected from the group of sequences consisting of SEQ 129 through SEQ 132; LAML (Acute Myeloid Leukemia) and the tRF is selected from the group of sequences consisting of SEQ 133 through SEQ 165; LGG (Brain Lower Grade Glioma) and the tRF is selected from the group of sequences consisting of SEQ 166 through SEQ 180; LIHC (Liver hepatocellular carcinoma) and the tRF is selected from the group of sequences consisting of SEQ 181 through SEQ 186; LUAD (Lung adenocarcinoma) and the tRF is selected from the group of sequences consisting of SEQ 187 through SEQ 194; LUSC (Lung squamous cell carcinoma) and the tRF is selected from the group of sequences consisting of SEQ 195 through SEQ 217; MESO (Mesothelioma) and the tRF is selected from the group of sequences consisting of SEQ 218 through SEQ 235; OV (Ovarian serous cystadenocarcinoma), and the tRF is sequence SEQ 236; PAAD (Pancreatic adenocarcinoma) and the tRF is selected from the group of sequences consisting of SEQ 237 through SEQ 242; PCPG (Pheochromocytoma and Paraganglioma) and the tRF is selected from the group of sequences consisting of SEQ 243 through SEQ 251; PRAD (Prostate adenocarcinoma) and the tRF is selected from the group of sequences consisting of SEQ 252 through SEQ 261; READ (Rectum adenocarcinoma) and the tRF is selected from the group of sequences consisting of SEQ 262 through SEQ 270; SARC (Sarcoma) and the tRF is selected from the group of sequences consisting of SEQ 271 through SEQ 275; SKCM (Skin Cutaneous Melanoma) and the tRF is selected from the group of sequences consisting of SEQ 276 through SEQ 283; STAD (Stomach adenocarcinoma) and the tRF is selected from the group of sequences consisting of SEQ 284 through SEQ 291; TGCT (Testicular Germ Cell Tumors) and the tRF is selected from the group of sequences consisting of SEQ 292 through SEQ 308; THCA (Thyroid carcinoma) and the tRF is selected from the group of sequences consisting of SEQ 309 through SEQ 324; THYM (Thymoma) and the tRF is selected from the group of sequences consisting of SEQ 325 through SEQ 331; UCEC (Uterine Corpus Endometrial Carcinoma) and the tRF is selected from the group of sequences consisting of SEQ 332 through SEQ 344; UVM (Uveal Melanoma) and the tRF is selected from the group of sequences consisting of SEQ 345 through SEQ 372. 
     
     
         113 . The method of  claim 111 , wherein the ailing tissue is ACC (Adrenocortical carcinoma), and the gene is selected from the group consisting of: CSDC2, CSGALNACT1, RERG, PCMTD1, PLCB3, YEATS2, BIRC2, MVP, MYST3, ARL6IP5, TRANK1, TMEM45A, ACVR1, PGCP, VCL, MSRA, C10orf54, DCUN1D3, CTDSPL2, SIK2, TMCO6, SRCAP, TMEM159, PLEKHO2, HLA-E, TAXIBP3, C11orf75, RCE1, NDRG4, MR1, MARK2, FAM21B, HLA-B, RBL2, CABC1; the disease type is BLCA (Bladder Urothelial Carcinoma), and the gene is selected from the group consisting of: ACTG2, TGFBR3, PRELP, RERE, OSR1, TCEAL1, NNAT, GCOM1, MMP2, MYST4, SYNPO2, C16orf45, FYCO1, MYH11, CSRP1, MEIS2, ACTA2, CLU, LOXL1, IGFBP4, TXNIP, SLIT3, CHRDL2, MYL9; the disease type is BRCA (Breast invasive carcinoma), and the gene is selected from the group consisting of: CRTC1, CALCOCO1, SLC27A1, CROCC, PGPEP1, PSD4, TBC1D17, PHF15, ARAP1, TNFRSF14, NISCH, MED16, RGS12, MYO15B, AGXT2L2, RFX1, C21orf2, NEURL4, TPCN1, HOOK2, LTBP3, SPHK2, ABTB1, ABCD4, ZBTB48, CIRBP, CYTH2, ZNF446, PHF1, RPS9, MZF1, FAM160A2, KIF13B, GLTSCR2, WDR81, SH2B1, RHOBTB2, CRY2, LTBP4, HDAC7, ZNF219, MUM1, RBM5, RAPGEF3, CCDC9; the disease type is CESC (Cervical squamous cell carcinoma and endocervical adenocarcinoma), and the gene is selected from the group consisting of: NBPF10, JRK, SMG5, ALDH1A2, MFAP4, ZFYVE1, CDC42BPB, ENTPD4, IGF1, ZFYVE26, APOLD1, L0C200030, KIAA0430, UBN1, VASH1, RANBP10, WDR37, MGP, MON1B, CNN1, MAT2A, PGR, KIAA0100, C14orf21, HCFC1, LRP10, DIDO1, FBXL18, ATP6V0A1, RGS2, MLXIP, TRIM56, CTGF, KIAA0284, DES, SFRP4, PDPK1, TAOK2, SMCR8, CLN8, UNC119B, TRIM25, CYB561D1, TBC1D2B, DNAJC5, CRAMP1L, ZNF646, ZC3HAV1, KHNYN, PSKH1, RGS1; the disease type is COAD (Colon adenocarcinoma), and the gene is selected from the group consisting of: ATP8B2, SYNE1, WIPF1, AOC3, LIMS1, FZD1, CYBB, MAFB, GIMAP6, REST, STAB1, FPR3, MSRB3, FRMD6, CALCRL, MPEG1, MYLK, ELTD1, FGL2, SPARCL1, PLXDC2, LAIR1, ITGB2, NRP1, MRC1, ZEB1, SYT11, NCKAP1L, AXL, APLNR, ZEB2, EDIL3, FERMT2, PTPRM, RASSF2, PKD2, PHLDB2, TCF4, IL10RA, HEG1, HIPK3, NEXN, TMEM140, AMOTL1, A2M, TIE1, AKT3, CD163, LPHN2, OSMR, CSF1R, DAAM2, 11.1R1, GPC6, SLC8A1, FBN1, GNB4, GPNMB, DOCK2, KIAA1462, CSF2RB, MYO5A, 51 PR1, ARHGEF6; the disease type is DLBC (Lymphoid Neoplasm Diffuse Large B-cell Lymphoma), and the gene is selected from the group consisting of: GOLGA2, DCHS1, CLDND1, CSRNP2, FRMD8, SLCO2A1, ARHGAP23, NID1, DUSP7, TBC1D20, YAP1, WDR82, TMEM43, TJP1, CARD8, ZNF213, KIAA0232, EPAS1, VPS11, PHC1, SKI, DAG1, ANKRD40, FAT1, PHF12; the disease type is ESCA (Esophageal carcinoma), and the gene is selected from the group consisting of: SSC5D, PDLIM3, CELF2, TIMP3, ABCC9, CALD1, COL8A1, GREM1, THBS4, PRUNE2, TMEM47, PBXIP1, PLN, CCDC80, C7, PODN, DDR2, PPP1R12B, MRVI1, LMOD1, C7orf58, HSPB7, TAGLN, PPP1 R16B, GFRA1, L00728264, SGCD, PGM5; the disease type is HNSC (Head and Neck squamous cell carcinoma), and the gene is selected from the group consisting of: GABBR1, C14orf179, METT11D1, C6orf125, ZNF692, FKBP2, FAM113A, L0C388789, TAZ, WASH3P, CDK5RAP3, PLBD2, SDR39U1, CPT1B, UBL5, C14orf2, L0C146880, THAP3, ANKRD13D, C12orf47, ATP5E, ATPIF1, SYF2, C8orf59, WASH7P, NPIPL3, CDK10, C1orf151, MRPS21, C19orf60, C7orf47, CENPT, GAS5, KIFC2, NFIC, RPL39, UQCRB, COX6C, LUC7L, CCS, COMMD6, ZNF133, SNHG12, C11orf31, NPEPL1; the disease type is KICH (Kidney Chromophobe), and the gene is selected from the group consisting of: BMPR1A, EXT1, TFAM, PDCD11, MTIF2, POLR3A, MAPK8, PRDX3, COQ5; the disease type is KIRC (Kidney renal clear cell carcinoma), and the gene is selected from the group consisting of: ARHGAP19, KIAA1671, KIAA0754, KIAA1147, ZNF45, KLF13, MYO9A, FUT11, ASH1L, KIF13A, TUBGCP3, MTF1, FAM168A; the disease type is KIRP (Kidney renal papillary cell carcinoma), and the gene is selected from the group consisting of: GLCCI1, CDK13, POGZ, UBN2, CREBZF, NPHP3, VEZF1, CHD1, YPEL2, LRRC37B2, GPATCH8, ENC1, TTC18, C11orf61, RSBN1L, EFNB2, PHIP, RBAK, SPEN, RBM9, SMURF2, ZNF264, ZNF587, PTPN12, TPBG, RBM33, DMTF1, CCNT2, ARID4B, ARGLU1, CREB1, KIAA0753, BTAF1, C17orf85, RLF, MLL5, ZFC3H1, ZNF160, PRPF38B, SETD5, ARRDC4, HOOK3, RC3H1, MLL3, RNF207, MAP3K1, PLEKHH2, CCDC57, DAPK1, LUC7L3; the disease type is LAML (Acute Myeloid Leukemia), and the gene is selected from the group consisting of: SUPT5H, SKIV2L, IKBKG, HGS, MIB2, MED15, STK25, ANAPC2, RHOT2, SFI1, CUL9, ARHGEF1, GTPBP2, KIAA0892, MBD1, UCKL1, DHX16, ZFYVE27, APBA3, PI4 KB, C19orf6, SPSB3, CAPN10, FLYWCH1, ATG4B, CDC37, LZTR1, MAN2C1, C1orf63, DVL1, EDC4, DHX34, PCNXL3, EXOC3, FUK, FBXL6, LMF2, HDAC10, E4F1, TSC2, ZDHHC8, CPSF3L, FAM160B2, CLCN7, LRRC14, D2HGDH, ZNF335, FHOD1, SOLH, ZBTB17, POLRMT, SLC26A1, KIAA0415, SELO, SAPS2, NME3, KLHL36, SCYL1, USP19, DGKZ, CYHR1, ATG2A, VPS16, XAB2, ACTR5, ZNF76, ATP13A1, RNF31, GPN2, MUS81, FAM73B, TTC15, CXXC1, TRMT2A, WDR8, PTGES2, TELO2, RFNG, SLC39A13; the disease type is LGG (Brain Lower Grade Glioma), and the gene is: EXD3; the disease type is LIHC (Liver hepatocellular carcinoma), and the gene is: DYRK2; the disease type is LUAD (Lung adenocarcinoma), and the gene is selected from the group consisting of: CROCCL1, RHPN1, ABCA7, RGL3, PDXDC2, ENGASE, ATG16L2, CSAD, TTLL3, ARHGEF12, ANKS3, LOC100132287, SGSM2, HEXDC, LPIN3, ACCS, PLEKHM1P, ANO9, ELMOD3, KIAA0895L, AP1G2, ACAP3, ECHDC2, NXF1, JMJD7-PLA2G4B, TMEM175, CCDC64B, ANKMY1; the disease type is LUSC (Lung squamous cell carcinoma), and the gene is selected from the group consisting of: PKD1, CHKB-CPT1B, WDR90, MACF1, RBM6, LENG8, TAF1C, COL16A1, CAPN12, RBM39, ACIN1, FNBP4, PILRB, DMPK, SFRS5, AHSA2, RBM25, PLCG1, SNRNP70, NCRNA00201, GIGYF1, SRRM2, GOLGA8B, ZGPAT, RTEL1, COL27A1, MAPK8IP3, PABPC1L, HSPG2, AKAP13, LRP1, NKTR, ATAD3B, TUBGCP6, ZNF276, MICALL2, CLCN6, NSUN5P2, NEAT1, LAMAS, CHD2, PPP1R12C, FAM193B, NPIP, CDK11A, STX16, LTBP2, LOC91316, NBEAL2, FLJ45340, LRDD, CCDC88B, GOLGA8A; the disease type is MESO (Mesothelioma), and the gene is selected from the group consisting of: C15orf40, SNUPN, CHTF8, CLNS1A, CSNK1D, DPF2, PCIF1, DNAJC4, SECISBP2, C5orf32, RPRD1B, RPL38, NDUFA10, RPRM, BAT4, RSL1 D1; the disease type is OV (Ovarian serous cystadenocarcinoma), and the gene is selected from the group consisting of: KIAA0907, ULK3; the disease type is PAAD (Pancreatic adenocarcinoma), and the gene is selected from the group consisting of: NUAK1, KBTBD4, HMCN1, DSTYK; the disease type is PCPG (Pheochromocytoma and Paraganglioma), and the gene is selected from the group consisting of: CACNA2D1, TP53BP1, KIAA1 244, MARCH8, PCDHGC4, ESYT2, DHX15, TECPR1, MAP3K2, TBC1D24, PCDH1, IPO11, MGAT5, TRAM2, ADAM10, GNA11, CBX6, SNURF, RIF1, CNTN1, LMBRD2, CAND1, TRIP12, RC3H2, PAK3, TMCO3, CSNK2AIP, ASB1, AKAP2, ROCK2, NUP155, PIK3C3, KLHDC10, RAB35, GTF2I, HSPA8, FAM49A; the disease type is PRAD (Prostate adenocarcinoma), and the gene is selected from the group consisting of: FEM1B, TGOLN2, SEPT9, MYOCD, LUZP1, TLN1, PIAS1, RNF111, DCBLD2, URB1, ZBTB40, ZNF516, ATXN1L, RHBDD1, HUWE1, VPS13D, ITPR1, NNT, ERC1; the disease type is READ (Rectum adenocarcinoma), and the gene is selected from the group consisting of: FZD4, CD93, DYNC1 I2, ENG, ELK3, KDR, FAM101B, PXDN, GIMAP4, F13A1, VCAM1, ARHGAP31, CD34, GNG2, LCP2, VWF, CSF1, GPR116, KIRREL, MMRN2, ETS1, ITGA4, FAM120B; the disease type is SARC (Sarcoma), we found that the mRNAs of the following genes satisfy these criteria: SH3BGRL, SORBS1, MAPK4, LYNX1, MICAL3, AKAP1, LIMS2, RNF38, LOC283174, CAND2, PLIN4, MOAP1, RNF19A, RABGAP1, C5orf4, FRY, ARHGEF17, SETMAR, SSH3, NUMA1, PBX1, TOR1AIP1, TACC2, RAB3D, BBS1, CEP68, GPRASP1, SV1L, CRBN, CRTC3, ZFYVE21, SLMAP, RASL1 2, SCAPER, STAT5B, ZAK, EZH1; the disease type is SKCM (Skin Cutaneous Melanoma), and the gene is selected from the group consisting of: MLL4, LMTK2, APBB3, C17orf56, LOC388796, ANO8; the disease type is STAD (Stomach adenocarcinoma), and the gene is selected from the group consisting of: KCNMA1, MAST4, FHL1, ATP2B4, TENC1, C20orf194, ASB2, C10orf126, TTC28, FAM13B, ITPKB, GNAO1, FAM1 29A, ZBTB4, FNBP1, FLNA, CCDC69, STON1, NFASC, PAPLN, ADCY5, LPP, NEGR1, ABI3BP, INPP5B, TNXB, ANGPTL1, ANK2, EPHA3, ZCCHC24, SETBP1, PRICKLE2, LTBP1, RGMA, DARC, KANK2, SYNPO; the disease type is TGCT (Testicular Germ Cell Tumors), and the gene is selected from the group consisting of: ATF6, CTDSP2, MKL2, TEAD1, ZNF407, TRAPPC9, AHDC1, LANCL1, KCTD20, OXR1, SNX1, CSNK1G1, KIAA0247, LDOC1L, EPC1, GRLF1, ABHD2, RAI1, ARID1B, ITFG1, MUT, KIAA1737, LAMA2, KIAA1109, CCNI, DIXDC1, C6orf89, RNF144A, APPBP2, KLF12, ZFP91; the disease type is THCA (Thyroid carcinoma), and the gene is selected from the group consisting of: KIAA0495, PHF21A, ZBTB5, SFRS6, NCOA5, ZNF814, IP6K2, IFT140, INTS3, ZNF559, SETD4, TGIF2, V1LL, KCNC3, UBE2G2, FBXO9, IPW, DUOXA1, CACNA2D2, EFHC1, FAM189A2, GTF2IRD2P1, KIAA1683, AP4B1, SCAND2, CDRT4, UNKL, NYNRIN, ARMC5, MAPKBP1, USP40, VEGFA, OLFM2, FBF1, TCF7L1, MXD4, IKBKB, POFUT2, BOC, TCF7L2, RMST, TRO; the disease type is THYM (Thymoma), and the gene is selected from the group consisting of: ZFYVE9, LOC399959, SIX1, PDGFC; the disease type is UCEC (Uterine Corpus Endometrial Carcinoma), and the gene is selected from the group consisting of: RNMT, SON, MDN1, CELF1, RIPK1, YLPM1, XRN2, BPTF, RQCD1, PAFAH1B2, BOD1 L, SBNO1, RNF169, PIK3R4, LRCH3, DCP1A, SF3A1, SLC9A8, TNRC6A, BRPF3; the disease type is UCS (Uterine Carcinosarcoma), we found that the mRNA of the following gene satisfies these criteria: RHBDF1; the disease type is UVM (Uveal Melanoma), and the gene is selected from the group consisting of: MAP1A, TCIRG1, ECM1, C14orf159, WARS, PCYOX1L. 
     
     
         114 . The method of  claim 111 , wherein the tRF and the gene are positively correlated. 
     
     
         115 . The method of  claim 111 , wherein the tRF and the gene are negatively correlated. 
     
     
         116 . The method of  claim 114 , wherein the tRF's abundance is increased. 
     
     
         117 . The method of  claim 116 , comprising administering a preparation comprising a therapeutic agent to increase the abundance of the tRF's. 
     
     
         118 . The method of  claim 115 , wherein the tRF's abundance is increased. 
     
     
         119 . The method of  claim 118 , comprising administering a preparation comprising a therapeutic agent to increase the abundance of the tRF's. 
     
     
         120 . The method of  claim 114 , wherein the gene's abundance is increased. 
     
     
         121 . The method of  claim 120 , comprising administering a preparation comprising a therapeutic agent to increase the abundance of the gene. 
     
     
         122 . The method of  claim 115 , wherein the gene's abundance is increased. 
     
     
         123 . The method of  claim 122 , comprising administering a preparation comprising a therapeutic agent to increase the abundance of the tRF's. 
     
     
         124 . The method of  claim 121 , wherein the gene's abundance is raised by proxy. 
     
     
         125 . The method of  claim 121 , wherein the gene's abundance is directly raised. 
     
     
         126 . The method of  claim 123 , wherein the gene's abundance is raised by proxy. 
     
     
         127 . The method of  claim 123 , wherein the gene's abundance is directly raised.