Methods related to bronchial premalignant lesion severity and progression

Abstract

The technology described herein is directed to methods of treating and diagnosing bronchial premalignant lesions, e.g. by determining the lesion subtype using one or more biomarkers described herein.

What is claimed herein is: 
     
         1 . A method comprising measuring the level of expression of at least one module 9 gene in a sample obtained from a subject, wherein the at least one module 9 gene is selected from the group consisting of:
 LAP3; NUB1; CD74; BTN3A1; EIF2AK2; PARP12; SP100; IFI35; LAG3; PSME1; APOL4; APOL1; PSME2; TRIM14; DDX58; OAS3; OAS2; BTN3A3; BTN2A1; XRN1; IFIH1; STAT1; GBP1; IFIT3; TNFSF10; OPTN; NMI; ZNFX1; RNF114; BTN2A2; IRF1; IFI6; APOL3; APOL2; BST2; KLHDC7B; HELZ2; IDO1; TRIM21; TRIM22; EPSTI1; CMPK2; TRAFD1; TOR1B; DDX60; IFI44L; IFI44; PARP9; HERC6; CXCL9; WARS; PML; NLRC5; IFIT5; UBE2L6; MX1; USF1; ADAR; LY6E; GBP4; DTX3L; IL15; IFI27; C2; B2M; BATF2; TAP1; LGALS9; CXCL10; PARP14; RNF213; SAMD9L; HLA-DQB1; CIITA; SOCS1; SP140L; TRIM69; BTN3A2; ISG15; RUFY4; PLSCR1; HLA-DRB1; HLA-DQA1; ACSL5; C5orf56; HLA-DOA; HLA-DMA; TAPSAR1; PSMB8; HLA-DRA; HLA-C; HLA-E; HLA-F; PSMB10; EXOC3L4; HCP5; HLA-A; UBD; IRF9; APOL6; HLA-DPB1; PSME2P2; GBP1P1; HLA-DPA1; TAPBP; HLA-DQB2; HLA-B; OR2I1P; PSMB9; and HLA-DMB.   
     
     
         2 . The method of  claim 1 , wherein the at least one module 9 gene is selected from the group consisting of:
 CIITA; NLRC5; EPSTI1; UBE2L6; B2M and TAP1.   
     
     
         3 . The method of  claim 1 , wherein the at least one module 9 gene is selected from the group consisting of:
 CIITA; NLRC5; and EPSTI1.   
     
     
         4 . The method of  claim 1 , further comprising measuring the level of expression of at least one module 10 gene in the sample, wherein the at least one module 10 gene is selected from the group consisting of:
 CACNB3 and MAPK10.   
     
     
         5 . The method of  claim 1 , wherein the sample comprises morphologically-normal tissues or morphologically-normal cells. 
     
     
         6 . The method of  claim 5 , further comprising bronchial premalignant lesion cells. 
     
     
         7 . The method of  claim 1 , wherein the sample consists of morphologically-normal tissues or morphologically-normal cells. 
     
     
         8 . The method of  claim 1 , wherein the sample comprises a bronchial brushing obtained from the right or left mainstem bronchus, an endobronchial biopsy, an endobronchial brushing sample, a large airway biopsy, a large airway brushing sample, a nasal epithelial cell, or sputum. 
     
     
         9 . The method of  claim 1 , wherein the subject is subject having bronchial premalignant lesions. 
     
     
         10 . The method of  claim 1 , wherein the subject is presently lung cancer-free. 
     
     
         11 . The method of  claim 1 , wherein the subject is a smoker or former smoker. 
     
     
         12 . The method of  claim 1 , wherein the subject is one who does not presently have and has not previously had lung cancer. 
     
     
         13 . The method of  claim 1 , wherein the level of expression of no more than 1,000 genes is determined. 
     
     
         14 . The method of  claim 1 , wherein the level of expression of no more than 200 other genes is determined. 
     
     
         15 . The method of  claim 1 , further comprising administering to the subject a chest CT scan. 
     
     
         16 . The method of  claim 1 , further comprising administering to the subject a bronchoscopy-based procedure. 
     
     
         17 . The method of  claim 1 , further comprising administering to the subject at least one anti-proliferative drug or at least one immune stimulating drug. 
     
     
         18 . The method of  claim 1 , further comprising measuring the level of expression of at least one module 5 gene, wherein the at least one module 5 gene is selected from the group consisting of:
 RACGAP1; TPX2; C1orf112; POLDIP2; DBF4; E2F2; NCAPD2; ANLN; DEPDC1; UHRF1; SPDL1; TSPAN17; RFC2; RAD51; NOP58; ASPM; PRR11; HMMR; GTSE1; WDR62; UBE2T; NDC80; ORC1; RAD54L; PIGS; AURKA; BIRCS; KIF4A; ORC6; CDC45; CDC6; CDC7; MCM5; CDKN3; LGMN; GINS1; MYBL2; E2F1; SUV39H1; CENPI; GABPB1; MCM4; RNASEH2A; ASF1B; ILVBL; EZH2; UBE2S; NCAPG; FOXM1; RAD51AP1; RFCS; TIMELESS; MCM3; BYSL; TTK; KIF20A; LMNB1; SMC4; LRRC42; HDAC1; TTF2; CDC20; STMN1; CENPF; KIF14; HELLS; MTHFD1L; MASTL; CCDC77; TMPO; NCAPH; KIF18A; CCDC18; HNRNPA2B1; ZWINT; CENPK; TUBA1B; HJURP; CKS2; CSE1L; SOX4; C17orf53; HNRNPR; DLGAP5; PKMYT1; A4GALT; KNSTRN; FAM64A; PVRL2; GINS2; ABCB7; TOP2A; MRPL35; PCNA; CCNB1; CDCA8; TROAP; ESPL1; URB2; STX6; CKAP2; BORA; BRIP1; CTSV; CPEB2; NUSAP1; KIF23; CASC5; CENPO; KIF11; CEP55; WDR12; CENPE; BRCA2; DENR; DIAPH3; FANCI; PLK4; KIF2C; NUF2; DTL; INTS7; ILF2; CHAC2; FANCD2; CCNA2; SKP2; G3BP1; MTFR2; CDCA5; NCAPG2; NONO; RBMX; GINS4; MKI67; CHEK1; TEX30; CENPH; SKA1; EME1; BUB1B; CCNB2; CHAF1B; SPC24; C16orf59; CCNF; KIAA1524; KIF15; RPL39L; SLBP; CDC25A; MAD2L1; PTTG1; MELK; SKA3; CENPN; KIAA0101; PLK1; CDT1; TK1; PBK; DTYMK; RFWD3; FEN1; USP39; CKAP2L; BUB1; CDK1; SHCBP1; ESCO2; RRM2; CKS1B; ZWILCH; UBE2C; CKAP5; CCNE2; TYMS; B3GNT8; AURKB; RCC2; FARSA; MAF1; KPNA2; SKA2; TRAIP; LIN9; IQGAP3; CDCA2; PARPBP; KIF18B; ERCC6L; PTMA; FANCA; H2AFX; FAM72B; FAM111B; XRCC6; FAM72A; XRCC2; HYLS1; ARHGAP11A; PRC1; CENPW; LSM2; TRIM59; FAM72D; DHFR; KIFC1; and PGAM5.   
     
     
         19 . The method of  claim 1 , further comprising measuring the level of expression of at least one module 6 gene, wherein the at least one module 6 gene is selected from the group consisting of:
 NEK11; IFT88; STPG1; KLHL13; SLC7A2; ZMYND10; ARX; DHX33; WDR54; ARHGAP44; CDKL3; PROM1; DNAH9; GAS7; RHBDF1; TEAD3; JARID2; FUZ; LRRC23; MKS1; TTC19; PPP5C; IL20RA; GLT8D1; PLEKHB1; NRXN3; CCDC28A; HSF2; TOMM34; CD44; EFCAB1; USP2; NSUN2; DNAH5; SPATA7; TRIT1; CC2D2A; SNX29; R3HDM1; SRD5A2; NEDD4L; PPP1R3F; ARHGEF5; POLQ; LY75; SDCCAG8; HHAT; GALC; GYG2; DCBLD2; LAMC2; SPA17; SNCAIP; ANKS1A; DGKA; TBC1D22B; FOXJ2; DIP2B; ZMYND12; NGEF; EML1; EVI5; TP53BP1; ATP11A; IFT80; PPP2R5B; MNT; AP3M2; ST6GALNAC2; C16orf80; TRIP13; RPS6KA6; RHOBTB1; XRCC1; CLCN4; SLC24A1; ARHGEF10L; SRI; GRAMD4; TMEM131; KIFAP3; SPAG6; POLD3; FKBP6; TULP3; ZCWPW1; TP73; OSBPL6; CDC14A; RFX3; PIH1D3; HSP90AA1; HSPB11; ULK2; MAPRE3; CD59; WDR47; NFX1; IPO11; MTMR2; ATXN7L3; SF3B2; TFAP2C; RFX2; GP6; REM1; KIF9; NSFL1C; PLK1S1; DYNLL1; SLC8B1; DZANK1; C20orf26; TASP1; NUDC; CERS4; NAT14; IL5RA; TEKT2; PSMD5; NUP188; ITPR3; IFT74; SEC14L3; ANKRD54; CENPM; CBY1; RTDR1; RAB36; TTLL1; MCAT; MYH9; DESI1; CERK; KHNYN; PRMT5; CDKL1; SAMD15; AHSA1; SIX4; RPS6KA5; IFT52; SPEF1; EPPIN; MOSPD1; ASB9; PCYT1B; KLF8; FGF14; CDADC1; MRPS31; SLC25A15; KATNAL1; GDPD3; MMP15; CCDC113; SLC38A7; HSDL1; NAGPA; USP10; METRN; CLUAP1; RPGRIP1L; CCP110; IQCH; CORO2B; ACSBG1; ZNF106; CEP152; RP1; NIPAL2; ZC2HC1A; CHRAC1; NCALD; SQLE; TUSC3; POLR2I; ZFR2; CAPS; TTC26; RNF32; IQCE; HIBADH; TAX1BP1; FAM188B; RPA3; NRF1; CEP41; FSD1L; AK1; RGP1; MPDZ; GLIS3; HPS1; LZTS2; SH3PXD2A; PBLD; TRIM37; DHX40; GALK1; B9D1; PEX12; HNF1B; PPP1R9B; PRKAR1A; EFNB3; IFT20; SLAIN2; WFS1; TBC1D19; WHSC1; SNX25; LRP2BP; C11orf63; SNX15; KIAA1377; PPFIBP1; ELK3; PRMT8; AKAP3; KCNA1; LTBR; OGFOD2; STX2; MDM1; UHRF1BP1L; ENO2; ST8SIA1; RSPH4A; MAK; MCM9; FAM184A; TPD52L1; SASH1; RBM24; CAP2; PACRG; C6orf118; MDFI; FAM120B; DNPH1; ENPP5; NME5; IK; MSH3; RAD1; C5orf15; WWC1; CLDN16; ARL6; IFT57; HHLA2; IQCG; KIAA1257; PLCH1; NEK4; STEAP3; STAM2; NRBP1; DNAH6; PECR; GGCX; PPP1R7; TAF1B; ORC4; THADA; C2orf42; GRIN3B; ALMS1; BCL9; TRIM62; DNAJC6; PHTF1; OSCP1; TBCE; RIMS3; CCDC181; RCAN3; IFT46; CASC1; FILIP1; HMGN3; UBE3D; ARMC2; WDR35; DNAH7; C2orf40; FAM206A; WDR34; CNTRL; TRIM32; FBXW2; CCDC176; ACYP1; IFT43; DNAL1; TTLL5; DLST; PPP4R4; ZC2HC1C; FKBP1B; CCDC147; C10orf95; LRP11; CCDC170; MYCT1; CYSTM1; ENOX1; PROSER1; HSPH1; AKAP1; ZSCAN18; TRMT1L; CRY2; FAM35A; BBS9; IFT81; TTC21B; B9D2; DAW1; ENKD1; C20orf85; TCP11; COL21A1; BBS2; PTGER2; TEKT3; TTF1; C20orf195; TRIP10; PANK2; MGME1; ID1; ERGIC3; HECTD3; FRMD8; PRDX5; PCNXL4; KTN1; SIX1; WDR60; LRRC61; TUBA4A; TNFRSF19; AKAP9; STYXL1; C22orf23; RIBC2; CDHR3; RABL5; KLHDC10; TTBK2; C15orf57; CALML4; THAP10; BBOX1; LRRC6; EGLN3; FOXJ1; CDC16; RSPH3; STK33; CACNG6; SSBP4; UBAC1; TUBGCP2; ARHGEF16; ATPIF1; PRRG1; KIF3A; PSMC3IP; NPHP4; MAP1B; PDHA1; ZSCAN5A; RHPN2; ABHD12B; ZSWIM4; FBXW9; ZNF20; SPATA6; GAS2L2; CNGA4; IQCA1; VPS13B; RGS22; BTBD3; POLR3F; DPH2; PIK3C2B; SLC41A1; SPG20; STOML3; MORC4; EPHB2; PDE6B; SEC14L4; ACTR3B; LRRIQ1; TMEM254; LRRCC1; UNC79; MEIS2; PTGFRN; ISCA1; CCDC146; HILPDA; KIAA1009; LCA5; PRPH; KCNH3; CD164; LACE1; PKIB; REPS1; ARMC9; TSGA10; TGFBRAP1; APPL2; TTC5; NMT1; MYCBPAP; VEZF1; SAP130; ODF2; WDR38; SLC22A23; BPHL; FAM8A1; C6orf52; TTC29; ANKRD42; NEK1; C11orf70; BTG4; PAQR5; LRRC49; GIPC2; IFT172; DYNC2L11; SMEK2; ARL3; MDH1B; CIR1; ABI2; MNS1; HCN4; FAM13A; RASGEF1B; CDKL2; SHROOM3; MTTP; CCDC65; CERS5; MORN3; C14orf37; SLC38A6; EFCAB11; PTGR2; AK7; SLC27A2; DNAJA4; BBS4; CCDC33; WDR93; FURIN; SH3GL3; GLYR1; NUDT7; GALNS; GASB; GFOD2; LRRC46; BCAS3; WRAP53; TP53; WDR45B; FBX015; FHAD1; PEX14; IL22RA1; STRIP1; NME7; UCK2; UFC1; USP21; DYRK3; SMYD2; ADAM15; AQP10; C1orf131; SCCPDH; CNIH3; CALM2; WDPCP; NPHP1; AMMECR1L; SPAG16; ANKMY1; CCDC39; TRMT10A; NAF1; ROPN1L; FAM50B; FARS2; DCDC2; RNF44; TCTE1; CYP39A1; TPBG; IRAK1BP1; ARHGAP18; GBAS; PSPH; AGBL3; TMEM27; ZNF157; DIAPH2; PRPS1; CXorf57; MCPH1; CETN2; CHMP7; C9orf72; IDNK; ASTN2; WDR31; CAMK2G; LRRC27; CNNM2; ZNF214; C11orf49; CCDC81; TTC12; C11orf52; GLB1L2; MTA2; MPZL2; PLCB3; CTF1; TMEM218; N6AMT2; SPATA4; FSIP1; DIXDC1; PIH1D2; C2orf50; ENKUR; DCP1B; AKAP6; MIPOL1; NUBPL; VIPAS39; TEX9; INPP1; CCDC122; NBAS; CCDC74B; RPP38; TRIM36; SPEF2; CAPSL; WDR78; IFLTD1; CLGN; CETN3; CCDC148; FAM81B; ADPRHL1; FBXL2; UBP1; LURAP1L; CFDP1; FAM92B; FBXO36; ZNF599; DDAH1; ANKFN1; FAM105B; FAM134B; CEP112; ENAH; CCDC173; SORBS2; SLFN13; RAB6B; ACSS1; RSPH10B; AK9; AZIN1; AGPAT5; LRGUK; KDM8; ALS2CR12; SPAG17; FMN2; GRIP1; ELMSAN1; GNA14; FAM161B; DRAM2; C8orf37; C15orf26; WHAMM; TIAM1; RPGR; SH3RF2; GALK2; MMP14; C1orf158; HYDIN; ZNF19; FAM81A; DSCR3; LCA5L; C9orf43; WDR19; DRC1; RAB28; WDR66; LRRC43; AAED1; FAIM; SLC13A3; RIBC1; C2orf62; KCNB1; DNAH3; AGPAT6; B4GALT3; C21orf59; C2orf81; CHCHD6; TPPP3; ZDHHC1; IQCC; KALRN; TMPRSS3; RSPH1; C9orf116; PCSK7; RUSC1; UBQLN4; TONSL; ORAI2; LRWD1; FBXL13; DUSP14; LRRC56; FDXR; ALOX15; HS3ST6; SHANK2; PPP1R32; RPS6KA4; UBXN10; C1orf87; OMA1; DNAJB4; LRRIQ3; WDR63; KLHDC9; FLVCR1; SPATA17; DUSP19; CCDC104; CCDC138; CCDC74A; TEKT4; SPATA18; INHBB; BBS5; RPRD2; PACRGL; DHX57; FZD5; C1orf189; FAM175A; HIPK1; NEK10; AZI2; GLB1L; EFHB; ICA1L; KIAA1407; CDS1; GMPS; ABHD6; LZTFL1; MEAF6; DNALI1; EXO5; PRSS12; MAPS; CEP44; ZNF474; PRIMPOL; GDF9; GJB7; TXLNB; DCBLD1; KIAA0895; KIF6; SYTL3; IQUB; C7orf57; MED30; HEATR2; TP531NP1; TMEM67; FAM219A; C9orf24; ABCA1; C8orf34; KDM1B; C9orf64; SVEP1; CXorf22; KIAA1958; STRBP; GAPVD1; ARMC3; LRRC18; DNAAF2; TTC8; AK8; C9orf9; ZMYND19; STOX1; PPP1R36; CKB; DPCD; LARP6; C16orf71; FAM227B; STXBP4; C10orf32; SMPD1; APBB1; C11orf65; C11orf74; TUB; XRRA1; C16orf46; ZNF3; IQCD; RRAD; WDR16; CCNDBP1; MS4A8; MAP1A; DUSP18; TTC16; COQ4; CCDC103; ENDOG; COQ7; KATNAL2; SPATA33; RHEBL1; TUBA1A; DNAAF3; HSD11B1L; CYB5D2; TEKT1; TMEM68; ZNF598; C2CD3; ULK4; MOBP; DEGS2; BMP1; SLC20A2; DYNLRB2; VWA3B; LDLRAD4; PKIG; FAM178B; CXXC4; TCTN2; TNIP2; PPIC; ZBBX; ARMC4; NSMCE1; RAB3B; ARL13B; MUC15; TPST1; TOR1AIP2; FABP6; FAM161A; C14orf142; SPATA24; SLC23A1; HSD17B13; KIAA0232; DCDC1; PRKCE; MORN4; RBKS; NAT1; LPAR3; MAP6; ZNF584; DNAI2; LRRC34; CTPS1; KNDC1; AQP4; LRRC48; SNTB1; COPRS; CCDC11; RSPH9; KLHL6; ZFAND4; ADH6; CCDC96; ABCD2; IQCB1; APOBEC4; PIFO; CEP19; FAM174A; GSTA3; CHRNA9; C12orf76; BBS1; ZNF497; IQCK; SH3PXD2B; WDR49; THAP6; BTC; CATSPERD; APITD1; EIF1AD; TEX26; GPR156; RUVBL1; UNC119B; TMPRSS7; BNIP3; SMIM19; PRR18; EID2B; PLA2G16; CNTD1; MAP3K19; CCDC121; SEC24C; DSCAML1; MRVI1-AS1; UMODL1; C8orf47; IRX3; CASC2; AGTRAP; C2orf73; MLF1; GRAMD1C; PPP1R42; DALRD3; NT5DC1; MCMDC2; P4HTM; ERBB4; ZNF713; GPS; RIIAD1; C1orf173; TMEM107; CCDC89; C10orf67; ZNF664; PLD6; FAM216B; C1orf194; TRNAU1AP; FGD6; TIGD2; GLIPR1L2; KCNE1; WDFY3-AS2; ZFP3; OXTR; BBS12; NME9; RNF135; GPR135; WRB; CYB5D1; CEP97; FAM104B; NGRN; SPATA13; CSMD1; FANCF; RUVBL2; CCDC60; CDC125; C10orf107; TNFAIP8L3; DGCR6; C11orf88; EFHC2; C9orf66; BTBD9; ANKRD45; DNAH2; HIST2H4A; LRTOMT; EFNA5; C21orf128; PROS1; NELL2; FAM110C; PIGW; RBM43; ZFP90; TMEM121; EFCAB10; LRRC37B; PGBD2; WBP5; PPIL6; KIAA0825; CDNF; ARL15; TNFAIP8L1; RAD51D; SMYD3; MRPL40; MORN5; THNSL1; RASA3; AGBL4; CYP2R1; C2orf76; SLC51B; KLHL32; PRELID2; TMEM212; ANKRD37; AKAP14; ZNF396; FAM86B1; KATNA1; KIF24; LYRM7; TMEM17; TMEM232; FAM183A; EFCAB6; TEAD1; SLIT1; TSPYL4; DYNC2H1; WDR86; IFT140; C17orf97; C1orf170; DNAJB13; AMY1C; MORN2; NWD1; TUBB4B; ENO4; FOCAD; TCTEX1D4; CERKL; C9orf171; C12orf55; FAM154B; SNTN; PTPLAD2; C1orf192; FAM47E; PTPRT; KIF19; TUBB; XPNPEP3; GRM7; ZNF569; C20orf96; ESRRG; MYO18A; TTC30B; ZNF33B; AMZ2; MVB12B; KIAA1211L; HIST3H2BB; DTHD1; SRC; NEK5; SLC22A4; BCO2; KCNMB2; C5orf42; DNAH10; WDR96; C4orf22; MEIG1; LEKR1; CCDC151; NUP62CL; MB; HMGN5; ZNF607; ZNF627; KCNRG; CCDC69; CALM1; FAM179B; PPP1R14C; FOXJ3; INPP5F; TSEN15; CIPC; DZIP3; L3MBTL3; DMD; ARMCX6; INF2; FAM83H-AS1; EFCAB2; TATDN3; ECT2L; FAM229B; DDO; ATP1A1OS; EFCAB7; LDLRAD1; LRRC73; SYS1; TRAF3IP1; NELFE; HSPA1L; LY6G5C; GPANK1; C10orf115; TRIM39; CASC10; C9orf135; TTC25; TCTN1; FAM201A; LRRC10B; TMEM231; C4orf47; TTLL10-AS1; OR7E36P; DENND6B; ITPRIPL2; CRYZL1; PPAPDC2; C21orf49; HN1L; ANKUB1; CCDC19; TCTEX1D2; ZNF625-ZNF20; TMEM110; CENPBD1P1; LIPE-AS1; CLDN9; MYCBP; AMZ2P1; BBIP1; FAM187A; CPEB1; IFRD2; FAM166B; C5orf49; SIAH3; TSTD1; FAM228B; C6orf226; AP4M1; TIAF1; DCDC2B; ZNF844; DNAJC27-AS1; SLC25A5-AS1; LAMTOR5-AS1; PPP1R26-AS1; BAIAP2-AS1; FAM66C; LINC01132; DNMBP-AS1; LINC00948; SRGAP3-AS2; UBAC2-AS1; VIM-AS1; TOB1-AS1; ANKRD66; STMND1; LINC00326; LINC00271; TSPAN19; LYRM9; NKAPP1; PINLYP; SDCBP2-AS1; TEX21P; LINC00094; C12orf75; TOPORS-AS1; SMKR1; LINC00886; HOGA1; SOX2-OT; ZNF709; ARHGEF26-AS1; ZNF487; WDR92; LINC00883; WDR65; WDR86-AS1; TUBA4B; LIFR-AS1; USP2-AS1; BDNF-AS; CRNDE; H2AFJ; ZBED5-AS1; USP51; DYNLL1-AS1; SRP14-AS1; CCDC153; FMN1; UGDH-AS1; SPATS1; LINC01018; LRRC37BP1; GPR162; APITD1-CORT; FAM86EP; STAU2-AS1; ATXN7L3B; RHPN1-AS1; ABCC6P2; DYX1C1; C21orf119; LINC01171; NHLRC4; OR7E47P; LINC00638; AQP4-AS1; C15orf65; LINC00908; MAFG-AS1; ILF3-AS1; C19orf82; RNF157-AS1; NAPA-AS1; HMGN3-AS1; FGF14-AS2; and CASC15.   
     
     
         20 . The method of  claim 1 , further comprising measuring the level of expression of at least one module 7 gene, wherein the at least one module 7 gene is selected from the group consisting of:
 RPS20; EIF4B; RPL18; RPL31; RPS5; STARD7; RPL6; RPLP0; IGBP1; EIF3L; RPL3; EIF3D; CCNB1IP1; EIF3E; EEF1D; RPS16; FBL; RPS19; GLTSCR2; RPL18A; DDX50; RPL28; RPL19; SMARCD2; RPL34; RPS13; C12orf57; RPS12; RPL24; EEF1B2; RPS15; RPL22; DPH5; RPS25; CCNI; RPL21; RPL5; RPS10; RPL23; SNRPD2; UROD; SERGEF; ECSIT; RPL36; MRPL34; COX4I1; RPL27; TPT1; RPS15A; ATP5G2; RNASEH2B; CCDC115; RPL35; POLR1E; RPS6; RPLP1; RPL7P9; RPS24; RPL14P1; GCSH; RPS2; RPS11; RPL13A; RPL11; RPS8; RPS27A; RPL32; SLC25A26; RPS3A; RPL37; BTF3; RPL10; RPL7; EBAG9; EIF3H; RPL7A; RPS3; FAU; TMEM18; RPL30; EEF1A1; ZNF689; RPL8; RPL26; RPL29; PMVK; RPL9; RPS14; RPL27A; MRPL16; RPL13; RPSA; SLC25A6; CNBP; RPS9; RPS21; RPS7; RPL38; TOMM20; RPL4; MRPL11; RPL15; FAM211A-AS1; EIF3F; ZFAS1; RPLP2; RPS27; RPS17L; RPL35A; RPS7P1; RPS17; RPS23; COMMD6; RPL14; RPS2P46; EEF1A1P5; NACA; TOMM7; RPL37A; RPL12; RPS4X; RPL23A; ZNF511; RPL10A; RPL39; C6orf48; GNB2L1; RPSAP58; RPL15P3; RPL18AP3; RPLP0P6; RPS29; RPL21P75; SMIM7; LYRM4; RPS3AP26; RPL7P1; PHB2; RPL21P28; UBA52; RPL41P1; RPL41; RPL4P4; RPS23P8; RPS18; EEF1B2P3; RPL3P4; EEF1A1P6; RPS28; GAS5; RPS3AP6; RPL24P2; RPL6P27; RPL13AP5; RPS2P5; RPL36A; RPL7AP6; SNHG6; EEF1G; RPL17; and SNHG8.   
     
     
         21 . The method of  claim 1 , further comprising measuring the level of expression of at least one module 4 gene, wherein the at least one module 4 gene is selected from the group consisting of:
 MRPS24; NDUFB4; NDUFB2; PSMD8; NDUFB7; TOMM22; TCEB2; CHCHD2; PSMD9; MRPL51; COX6A1; COX7A2; ATP5F1; NDUFB3; PDZD11; NDUFA1; MRPS7; ROMO1; COX6B1; TIMM17B; UQCR11; EMC6; COX7B; BLOC1S1; COX5B; PSMB7; NDUFB10; ANAPC11; TXNL4A; SNRPG; NDUFS6; TIMM8B; NDUFC2; DBI; C14orf2; THOC7; UQCRQ; COX6C; NDUFB6; STOML2; NDUFB8; ATP5I; UQCRFS1; MRPL36; MYEOV2; CHCHD1; MINOS1; USMG5; COX8A; POLR2L; TMEM11; COX5A; MRPL54; UQCR10; NDUFA12; DRG1; NDUFA13; SUMO2; NDUFA4; GPN1; C11orf83; NDUFS3; ATP5J2; and MRPL12.