                         SEQUENCE LISTING

<110>  F. Hoffmann-La Roche Ltd
 
<120>  Tumor tissue based biomarkers for bevacizumab combination 
       therapies

<130>  Case 26192

<150>  EP 10151109.5
<151>  2010-01-19

<160>  3     

<170>  PatentIn version 3.5

<210>  1
<211>  232
<212>  PRT
<213>  Homo sapiens

<400>  1

Met Asn Phe Leu Leu Ser Trp Val His Trp Ser Leu Ala Leu Leu Leu 
1               5                   10                  15      


Tyr Leu His His Ala Lys Trp Ser Gln Ala Ala Pro Met Ala Glu Gly 
            20                  25                  30          


Gly Gly Gln Asn His His Glu Val Val Lys Phe Met Asp Val Tyr Gln 
        35                  40                  45              


Arg Ser Tyr Cys His Pro Ile Glu Thr Leu Val Asp Ile Phe Gln Glu 
    50                  55                  60                  


Tyr Pro Asp Glu Ile Glu Tyr Ile Phe Lys Pro Ser Cys Val Pro Leu 
65                  70                  75                  80  


Met Arg Cys Gly Gly Cys Cys Asn Asp Glu Gly Leu Glu Cys Val Pro 
                85                  90                  95      


Thr Glu Glu Ser Asn Ile Thr Met Gln Ile Met Arg Ile Lys Pro His 
            100                 105                 110         


Gln Gly Gln His Ile Gly Glu Met Ser Phe Leu Gln His Asn Lys Cys 
        115                 120                 125             


Glu Cys Arg Pro Lys Lys Asp Arg Ala Arg Gln Glu Lys Lys Ser Val 
    130                 135                 140                 


Arg Gly Lys Gly Lys Gly Gln Lys Arg Lys Arg Lys Lys Ser Arg Tyr 
145                 150                 155                 160 


Lys Ser Trp Ser Val Tyr Val Gly Ala Arg Cys Cys Leu Met Pro Trp 
                165                 170                 175     


Ser Leu Pro Gly Pro His Pro Cys Gly Pro Cys Ser Glu Arg Arg Lys 
            180                 185                 190         


His Leu Phe Val Gln Asp Pro Gln Thr Cys Lys Cys Ser Cys Lys Asn 
        195                 200                 205             


Thr Asp Ser Arg Cys Lys Ala Arg Gln Leu Glu Leu Asn Glu Arg Thr 
    210                 215                 220                 


Cys Arg Cys Asp Lys Pro Arg Arg 
225                 230         


<210>  2
<211>  1255
<212>  PRT
<213>  Homo sapiens

<400>  2

Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu 
1               5                   10                  15      


Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys 
            20                  25                  30          


Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His 
        35                  40                  45              


Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr 
    50                  55                  60                  


Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val 
65                  70                  75                  80  


Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu 
                85                  90                  95      


Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr 
            100                 105                 110         


Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro 
        115                 120                 125             


Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser 
    130                 135                 140                 


Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln 
145                 150                 155                 160 


Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn 
                165                 170                 175     


Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys 
            180                 185                 190         


His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser 
        195                 200                 205             


Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys 
    210                 215                 220                 


Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys 
225                 230                 235                 240 


Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu 
                245                 250                 255     


His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val 
            260                 265                 270         


Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg 
        275                 280                 285             


Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu 
    290                 295                 300                 


Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln 
305                 310                 315                 320 


Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys 
                325                 330                 335     


Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu 
            340                 345                 350         


Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys 
        355                 360                 365             


Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp 
    370                 375                 380                 


Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe 
385                 390                 395                 400 


Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro 
                405                 410                 415     


Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg 
            420                 425                 430         


Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu 
        435                 440                 445             


Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly 
    450                 455                 460                 


Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val 
465                 470                 475                 480 


Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr 
                485                 490                 495     


Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His 
            500                 505                 510         


Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys 
        515                 520                 525             


Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys 
    530                 535                 540                 


Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys 
545                 550                 555                 560 


Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys 
                565                 570                 575     


Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp 
            580                 585                 590         


Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu 
        595                 600                 605             


Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln 
    610                 615                 620                 


Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys 
625                 630                 635                 640 


Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser 
                645                 650                 655     


Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly 
            660                 665                 670         


Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg 
        675                 680                 685             


Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly 
    690                 695                 700                 


Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu 
705                 710                 715                 720 


Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys 
                725                 730                 735     


Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile 
            740                 745                 750         


Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu 
        755                 760                 765             


Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg 
    770                 775                 780                 


Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu 
785                 790                 795                 800 


Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg 
                805                 810                 815     


Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly 
            820                 825                 830         


Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala 
        835                 840                 845             


Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe 
    850                 855                 860                 


Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp 
865                 870                 875                 880 


Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg 
                885                 890                 895     


Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val 
            900                 905                 910         


Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala 
        915                 920                 925             


Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro 
    930                 935                 940                 


Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met 
945                 950                 955                 960 


Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe 
                965                 970                 975     


Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu 
            980                 985                 990         


Asp Leu Gly Pro Ala Ser Pro Leu  Asp Ser Thr Phe Tyr  Arg Ser Leu 
        995                 1000                 1005             


Leu Glu  Asp Asp Asp Met Gly  Asp Leu Val Asp Ala  Glu Glu Tyr 
    1010                 1015                 1020             


Leu Val  Pro Gln Gln Gly Phe  Phe Cys Pro Asp Pro  Ala Pro Gly 
    1025                 1030                 1035             


Ala Gly  Gly Met Val His His  Arg His Arg Ser Ser  Ser Thr Arg 
    1040                 1045                 1050             


Ser Gly  Gly Gly Asp Leu Thr  Leu Gly Leu Glu Pro  Ser Glu Glu 
    1055                 1060                 1065             


Glu Ala  Pro Arg Ser Pro Leu  Ala Pro Ser Glu Gly  Ala Gly Ser 
    1070                 1075                 1080             


Asp Val  Phe Asp Gly Asp Leu  Gly Met Gly Ala Ala  Lys Gly Leu 
    1085                 1090                 1095             


Gln Ser  Leu Pro Thr His Asp  Pro Ser Pro Leu Gln  Arg Tyr Ser 
    1100                 1105                 1110             


Glu Asp  Pro Thr Val Pro Leu  Pro Ser Glu Thr Asp  Gly Tyr Val 
    1115                 1120                 1125             


Ala Pro  Leu Thr Cys Ser Pro  Gln Pro Glu Tyr Val  Asn Gln Pro 
    1130                 1135                 1140             


Asp Val  Arg Pro Gln Pro Pro  Ser Pro Arg Glu Gly  Pro Leu Pro 
    1145                 1150                 1155             


Ala Ala  Arg Pro Ala Gly Ala  Thr Leu Glu Arg Pro  Lys Thr Leu 
    1160                 1165                 1170             


Ser Pro  Gly Lys Asn Gly Val  Val Lys Asp Val Phe  Ala Phe Gly 
    1175                 1180                 1185             


Gly Ala  Val Glu Asn Pro Glu  Tyr Leu Thr Pro Gln  Gly Gly Ala 
    1190                 1195                 1200             


Ala Pro  Gln Pro His Pro Pro  Pro Ala Phe Ser Pro  Ala Phe Asp 
    1205                 1210                 1215             


Asn Leu  Tyr Tyr Trp Asp Gln  Asp Pro Pro Glu Arg  Gly Ala Pro 
    1220                 1225                 1230             


Pro Ser  Thr Phe Lys Gly Thr  Pro Thr Ala Glu Asn  Pro Glu Tyr 
    1235                 1240                 1245             


Leu Gly  Leu Asp Val Pro Val  
    1250                 1255 


<210>  3
<211>  923
<212>  PRT
<213>  Homo sapiens

<400>  3

Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu 
1               5                   10                  15      


Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys 
            20                  25                  30          


Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr 
        35                  40                  45              


His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr 
    50                  55                  60                  


Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg 
65                  70                  75                  80  


Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn 
                85                  90                  95      


Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val 
            100                 105                 110         


Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu 
        115                 120                 125             


Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Ile Phe Lys Arg Gly 
    130                 135                 140                 


Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser 
145                 150                 155                 160 


Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile 
                165                 170                 175     


Val Phe Val Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe 
            180                 185                 190         


Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr 
        195                 200                 205             


Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile 
    210                 215                 220                 


Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser 
225                 230                 235                 240 


Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu 
                245                 250                 255     


Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp 
            260                 265                 270         


Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser 
        275                 280                 285             


Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu 
    290                 295                 300                 


Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp 
305                 310                 315                 320 


Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val 
                325                 330                 335     


Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys 
            340                 345                 350         


Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp 
        355                 360                 365             


Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn 
    370                 375                 380                 


Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile 
385                 390                 395                 400 


Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser 
                405                 410                 415     


Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser 
            420                 425                 430         


Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr 
        435                 440                 445             


Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu 
    450                 455                 460                 


Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr 
465                 470                 475                 480 


Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg 
                485                 490                 495     


Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met 
            500                 505                 510         


Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met 
        515                 520                 525             


Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn 
    530                 535                 540                 


Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg 
545                 550                 555                 560 


Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu 
                565                 570                 575     


Arg Met Glu Leu Leu Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro 
            580                 585                 590         


Thr Thr Pro Asn Gly Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala 
        595                 600                 605             


Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr 
    610                 615                 620                 


Thr Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln 
625                 630                 635                 640 


Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser 
                645                 650                 655     


His Lys Thr Phe Cys His Trp Glu His Asp Asn His Val Gln Leu Lys 
            660                 665                 670         


Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly 
        675                 680                 685             


Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys 
    690                 695                 700                 


Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His 
705                 710                 715                 720 


Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu 
                725                 730                 735     


Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val 
            740                 745                 750         


Trp Met Ala Ile Gly His Gln Gly Asp His Trp Lys Glu Gly Arg Val 
        755                 760                 765             


Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu 
    770                 775                 780                 


Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile 
785                 790                 795                 800 


Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp 
                805                 810                 815     


Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly 
            820                 825                 830         


Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly 
        835                 840                 845             


Asn Val Leu Lys Thr Leu Asp Pro Ile Leu Ile Thr Ile Ile Ala Met 
    850                 855                 860                 


Ser Ala Leu Gly Val Leu Leu Gly Ala Val Cys Gly Val Val Leu Tyr 
865                 870                 875                 880 


Cys Ala Cys Trp His Asn Gly Met Ser Glu Arg Asn Leu Ser Ala Leu 
                885                 890                 895     


Glu Asn Tyr Asn Phe Glu Leu Val Asp Gly Val Lys Leu Lys Lys Asp 
            900                 905                 910         


Lys Leu Asn Thr Gln Ser Thr Tyr Ser Glu Ala 
        915                 920             


