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Primary Tumor Site 137 Larynix US 20190187143A1 ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0187143 A1 Wallweber ( 43 ) Pub . Date : Jun . 20 , 2019 ( 54 ) COMPOSITIONS AND METHODS TO Publication Classification DETECT HEAD AND NECK CANCER (51 ) Int. Cl. (71 ) Applicant : Laboratory Corporation of America GOIN 33 / 574 ( 2006 .01 ) GOIN 33 /52 (2006 . 01) Holdings , Burlington , NC (US ) (52 ) U . S . CI. (72 ) Inventor : Gerald J . Wallweber , Foster City , CA CPC .. GOIN 33 /57407 ( 2013 .01 ) ; GOIN 33 /5748 (US ) ( 2013 .01 ) ; GOIN 33 /52 ( 2013 .01 ) (57 ) ABSTRACT ( 21 ) Appl. No. : 16 /224 , 974 Disclosed are compositions and methods to detect proteins associated with Head and Neck Cancer, generally , or more ( 22 ) Filed : Dec . 19 , 2018 particularly , biomarkers of Head and Neck Squamous Cell Carcinoma (HNSCC ) . Such markers may be useful to allow Related U . S . Application Data individuals susceptible to HNSCC to manage their lifestyle (60 ) Provisional application No. 62/ 608 ,296 , filed on Dec . and /or medical treatment to avoid further progression of 20 , 2017 . disease . Primary Tumor Site primarytumor Site 137 Larynix Har Oralen cavityel . Gene Accuracy Kappa Sensitivity Specificity 1 CAB39L 0 . 9600 0 . 7745 0 .9831 0 .7818 2 ADAM12 0 . 9688 0 . 7506 0 . 9938 0 .6727 . 3 SH3BGRL2 0 .9596 0 .6972 0 . 9846 0 . 6636 4 NRG2 0 .9553 0 . 6710 0 .9808 0 .6545 5 COL13A11 0 . 9546 0 . 6376 0 . 9854 0 .5909 6 GRIN2D 1 0 . 9539 0 .6326 0 . 9862 0 .5727 7 LOXL2 0 . 9525 0 .5906 0 . 9915 0 .4909 8 HSD1786 0 . 9411 0 . 4890 0 . 9846 0 . 4273 Patent Application Publication Jun . 20 , 2019 Sheet 1 of 23 US 2019 / 0187143 A1 Specificity 0.7818 0.6727 0.6636 0.6545 0.5909 0.5727 0.4909 0.4273 . .. .. 2 . Sensitivity Atttttttttt 0.9831 0.9938 0.9846 0.9808 0.9854 0.9862 0.9915 0.9846 1NIA Oralcavity : : : :: : : : : : : : : : : :: : : : : :: : : : :: : . : . : . : . : . FIG.1 NOX kappa 0.7745 0.7506 0.6972 . 0.6710 0.6376 0.6326 0.5906 0.4890 10Hypopharynx . Accuracy WWWWWWWW 0.9600 0.9688 0.9596 0.9553 0.9546 0.9539 0.9525 0.9411 PrimaryTumorSite Gene 1CAB39L 2ADAM12 3SH3BGRLZ 4NRG2 5COL13A1 6GRIN2D 7LOXL2 8HSD17B6 Patent Application Publication Jun . 20 , 2019 Sheet 2 of 23 US 2019 / 0187143 A1 Specificity 0.9273 0.9273 0.9273 0.8727 Specificity 0.9182 0.9364 0.9182 0.9091 0.8636 FIG.2 0.9985 0.9985 0.9977 0.9992 .' Sensitivity Sensitivity 0.9992 0.9946 0.9969 0.9969 0.9992 kappa 0.9493 0.9485 9445.0 9199.0 Kappa 0.9485 0.9313 0.9338 0.9286 Accuracy 0.9924 0.9929 99220. 9894.0 Accuracy 99290. 0.9901 0.9908 0.9901 0.9887 nanininginpaininsingarinnasiningning Genepanel ) Specificity + sensitivity kappa + fuccuracy QUEwoued CAB39L,ADAMIZNRG2GRIN2D CAB39L,ADAM12NRG2LOXL2 CAB39L,ADAM12NRG2SHBBGRL2 CA839L,ADAM12NRG2COL13A1 CAB39L,ADAM12NRG2H5017B6 CAB39L,ADAM12NRG2GRIN2DCOL13A1 CAB39L,ADAM12NRG2GRIN2DSHBBGRLZ CAB39L,ADAM12NRG2GRIN2DLOXL2 CAB39L,ADAM12NRG2GRIN2DHSD1786 AngenePanel '. Panelgene5- Patent Application Publication Jun . 20 , 2019 Sheet 3 of 23 US 2019 / 0187143 A1 * XURSACOLO ** * Canty Oral 8 Larynika OSNH xxxx18 welcxUKlaudod kiert wwwww NRG2 ADAM12 Oropharynx * xukaerakonic Canty Oral Norra * * * * Honey Sero Alison * XUALE }0g2 ( RNASeq FIG.3 oNormal *HNSCC XULiSudio * xukje doo CavidOral Caviy Oral . Xustiza . OV HNSCC ** CAB39 XULzeudadhi -XUKIPUDAH xukteudo : 0 SH3BGRL2 Oropharynska meo Normal Cavity Oral Larynx Normal ) 1092 ( RNASea ) 132( RNASE Patent Application Publication Jun . 20 , 2019 Sheet 4 of 23 US 2019 / 0187143 A1 www useidojo Xeydog B . weg raio Cavity Oral XUÁ87 OSNH XIKIT SANhe - XUÂSSERCIAH GRIN2D # WWW xusseindouto HSD1786 * Exskrecionet * * times RO * * * * timeo rolo Norrial H Larynx xuksen 2x( ) baswa FIG.4 MMMMMMMMMMMM oNormal *HNSCC Oropharynx 6x36?ketga: 2 . XUE HNSCC xudzes HNSCC tentang ke xuser diod kill ? * x xu kesudad AHA COL13A1 fxUKIE: COMO LOXL3 methods Oropharynxa * * * * * * * * khine 12 Normal Cover Deal (coo ) tasu ) logi( } ANASex Patent Application Publication Jun . 20 , 2019 Sheet 5 of 23 US 2019 / 0187143 A1 kuodoBus301 . : . : : 360} 719 0 RXASOVXeon B33 UKIS 12 BOMB FIG.5 Patent Application Publication Jun . 20 , 2019 Sheet 6 of 23 US 2019 / 0187143 A1 *x-notrepeated EMP8:201260617SAFAVOAA/ BLOX24017 7BARX28538 8MYBL214605 9CRISP310321 10CAMK2N2194032 *ADH18:125 12CP012819 NORG25744733. 1xNo.tiresropeated(7*13)fromRandomForestAnalysis 2xRepeated 29293TMEM1320:1 MELOKER * 2MC12982184793 3COL.33A111305 4KRFA13051 7FAMI07A111170 8SIROM3576199MO21:394263 11MF9:4310 FIG.6A COL2: : : A : 2X (*11) 74*# Na.GeneSymbolGeneDMedianRankNoSymbolOVecianGereIDmedian YAM30 3% (933) wwwwwww 3xRepeated *CA338:. WRC2*6:33AL 62INO *Duo 4X {*9) 07.15 3.FAM381131177 high-2007 ) differentiate to ability( Rank Viedjan 14.5 5.11 8 4xRepeated 3SHAGRI283899. GRIN0:2916 23171:GPOIL6 1CAB39L81617 2NAG20642 KS0178818630 801.02[1740 Patent Application Publication Jun . 20 , 2019 Sheet 7 of 23 US 2019 /0187143 A1 . Xa . .. : . US . GRIN2D . mo . visiems prisimenarenorang mengharamahamshanghenghenghenghenghenghenghengiging isisigigising FIG.6B ** peren ** * MedianFold-change(HNSCC/Normal,log10) 12 Expression in Overlap % Patent Application Publication Jun . 20 , 2019 Sheet 8 of 23 US 2019 / 0187143 A1 Litsearch-Tissue Litsearch-Saliva « • 12 MedianFold-change(HNSCC/Noral,log10) MedianFold-change(HNSCC/Nommal,log10) m-102 FIG.7 3 Expression in Overlap % Expression in Overlap % -* . - . - - . Method*- . SampleType . MarkersfromliteratureSearch freshfromandre issuesive AURKAtreiafinzenandme *FOXVIebren,tiszenDE Wasanosakys YYYYYYY 9HEUStechtegen300 . No.Name 12WAPK 16POLOerstisse 22(UIRR 23MA - ANAAAAAAAAAAAA vesnacas Patent Application Publication Jun . 20 , 2019 Sheet 9 of 23 US 2019 /0187143 A1 Litsearch-Tissue Litsearch-Saliva * MedianFold-change(HNSCC/Normal,log10) MedianFold-change(HNSCC/Normai,log10) $ FIG.8 m ain 100,7 Expression in Overlap % Expression in Overlap SarripleTypeMethod . Frozentissue frozentissue saliva 2RP237% No.Name 1ALASI 2GSPO4 Patent Application Publication Jun . 20 , 2019 Sheet 10 of 23 US 2019 /0187143 A1 . WON * Woo MedianFoldchange- FIG.9A do adelany MedianFold-change(HNSCC/Normal,log10) w 100 Personen Patent Application Publication Jun . 20 , 2019 Sheet 11 of 23 US 2019 /0187143 A1 WWW . .. : :: : . : : .CHOL FIG.9B CancerType a nninumanninunununnniinionininininininninnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn . iniiniininunarinnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnwww Patent Application Publication Jun . 20 , 2019 Sheet 12 of 23 US 2019 /0187143 A1 FIG.10 AM w SH3BGRL211.44744-160 ddPCR(Neataveraged,copies/ul) GeneNormalCancerrold-Change . GeneNormalCancerFold-Change 3 RNASeq(log2)fromTCGA 758 91. ADAM125.33952 * SHBBGRL2 ADAM120. SH3BGRL213. Patent Application Publication Jun . 20 , 2019 Sheet 13 of 23 US 2019 /0187143 A1 FIG.11 KCV 5% yummin )Control URNA SampleReplicates(ddPorCopies/ul) DR1041686Normal14,7158n.d3 )DA0003696CC Median3#2Type1AccessionNo. Replicates 12 web * DA1081983Normal13.9 DA0063595Cancer11 Patent Application Publication Jun . 20 , 2019 Sheet 14 of 23 US 2019 /0187143 A1 sever: minnanna mannana nanananananahan naming home : : . : RNA#5 mangeminmanywaymynamein : : . RNAS . 72** KHORESI-LEX 1.SH3BGRLZ-FAM(biomarker} 2.KHOABS1-HEX(housekeeping! N.TC DugiexdPOR: minoreSHI8GRUZ-FAM HEXKHDR8S?-*FANSHUBGRL2 Bato* FIG.12 duplexdPORmuniDPCRduplex maniyeCONA-caigo CONA:-duplexOPCR wwwmmwaloCONAwwwduplexDPCR RNA 03.13cons OL . endndodhet pintades Res komende* OXYXuiv ne 0.125 Codes 9625m RNAdiluted: 2-foldor10 RNAIsolated (47,43MBDURRA apparemmepimwagong URNA OmOsoris contra Neem Regningsang what kinantotanko ningsest Patent Application Publication Jun . 20 , 2019 Sheet 15 of 23 US 2019 /0187143 A1 oNormal xCancer SH3BGRL2NormalvsCancer: Medianfold-change16 122 DistributionsTCGA AN . ! TCGA ,092 ( Q = RNAS wwwwww Medianfold-change=11 FIG.13 RatioddPCR NormalvsCancer: Normal xCancer marraingaminamaisia DistributionsddPCR * ** SHBEGRUZ mikinn fideshow Patent Application Publication Jun . 20 , 2019 Sheet 16 of 23 US 2019 /0187143 A1 olololololololololo l Samananamannamatumainmakumminammie ** .. Normalreplicates URNAreplicates olololololololo . SH3BGRL2 . .. : : : : : FIG.14 .:, 227 3 jonuou , : Patent Application Publication Jun . 20 , 2019 Sheet 17 of 23 US 2019 /0187143 A1 EMP1 w ww duidentumatamkumkamatamatamkunnianhanatina been have kunne ut/ Copies - - .* - - . - - * - - mo - HORBS1 - KHORBST - - - FIG.15 KRT4 imigrimiminimimine - -*XXXX ADAM12 14 ??????????? ? ??????????? ?? - - KRIA Liimimine - - -. ADAM12 - . tudenterna S 00 . A . 1 0.5 WONO 1,024 0.25 512 0.25 2,048 Copiosiul NoCall 1,024 Copiestul NoCall • +: X ? YA KHORBS1 LOXL2 Xa••Xe KHORAS1 SH3BGRL2 SH3BGR.2 meno LOXI2. • denkenJakakakuntakeskukenkasten menininkmententants Sminkin 0.54 0.25 0.25 048.2 .ui / Copies CallNo uL/ Copies NoCall Patent Application Publication Jun . 20 , 2019 Sheet 18 of 23 US 2019 /0187143 A1 3 ADAM2KMDBS1 TCGA EMpyllox2 SHIAGRL?!KRT: -9.5 9.6 18.2 -686.9-6,7 ) TCGA , log2 ( RNASeq MedianFoldchange ddPCRTCGA -16.0118 FIG.16 3.0 , 35 .Normal xCancer * 1 x met ADAM12. Biomarker SH3BGRL2 EMP1 COXL2 ADAM12 !LOX2 ddPCR EMP SHBEGRI2!KRTU makakuha intendentementeneminentukan 250.0.125 0.031250.015625 )BiomarkeriKHDRBS1 ( Ratio Patent Application Publication Jun . 20 , 2019 Sheet 19 of 23 US 2019 /0187143 A1 ddPCRGenePanel 000204060810 1-Specificity 2 . 11 Sensitivity FIG.17 ddPCRGenePanel einem CancerNormal mit Score ddPCR Patent Application Publication Jun . 20 , 2019 Sheet 20 of 23 US 2019 /0187143 A1 39,3 S 5 HERBST
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