<p> Pharmacogenetic and Germline Prognostic Markers of Lung Cancer</p><p>Anne M. Horgan, MB BCh, MRCPI; Boming Yang; Abul Kalam Azad, MBBS, MSc, PhD; Eitan Amir, MB ChB; Thomas John, MBBS, PhD, FRACP; David W. Cescon, MD; Paul Wheatley-Price, MB BCh; Rayjean J. Hung, PhD, MSc; Frances A. Shepherd, MD, FRCP(C); Geoffrey Liu, MD, MSc, FRCPC</p><p>Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada, M5G 2M9</p><p>1 Supplementary Table 1A. Pathways/Polymorphisms most frequently studied </p><p>R Genetic Studies Comment: Positive Findings I</p><p>A Polymorphism</p><p>P XRCC1 4-13 E</p><p>R XRCC1 Arg399Gln 10 studies TREATMENT WITH PLATINUM 4-6</p><p>A 4 Asian; 6 Caucasian Gln allele → better OS in three Caucasian studies 9 N n= 38-229 Gln/Gln → worse OS in one US study D Gln/- → worse grade 3 or 4 toxicity in a single Asian study [AOR 2.05 (p=0.04)] 13. XRCC1 Arg194Trp 4 studies Arg/Trp → better RR to platinum in single study (p=0.04) 7. 3 Asian; 1 Caucasian Trp/- → worse toxicity with gemcitabine/docetaxel (p=0.03) 10 n=36-229 Arg/Arg → better PFS (radiation alone) (p=0.03) 11 Arg/Arg → no association with cisplatin in single study 13. XRCC1 Arg280His 1 study No significant associations 11 Asian; n=229 ERCC15,6,20-26,75,82 ERCC1 C118T 9 studies TREATMENT WITH PLATINUM 4 Asian; 5 Caucasian C/C → better OS/RR in three Asian studies20-22 n=65-245 C/C → No associations in 4 Caucasian studies6,24-26 C/- → independently associated with better response in a single European study compared to T/T [OR 0.10; p=0.03] 5 ERCC1 C8092A 6 studies C/C → better OS in 2 studies 23,26. 2 Asian; 4 Caucasian C/C → poorer OS in 2 studies 5,75. n= 119-423 C/C → less toxicity in a single study 24. ERCC1(G262T;T433C 1 study 262T/T → worse OS [AHR 1.98; p=0.02] :SCLC only, treated ; C4855T) Asian; n=162 with carboplatin/VP16 82 XPD 4,5,8-10,21,25,83,84 XPD Asp312Asn 6 studies TREATMENT WITH PLATINUM 2 Asian; 4 Caucasian 312Asn/Asn →worse OS in a single study (p=0.003) 9. n=39-209 No significant associations in remaining studies 5,21,25,83,84 XPD Lys751Gln 7 studies 751Lys/Lys → higher incidence Gr 4 neutropenia (p=0.02) 10. 2 Asian; 5 Caucasian No significant associations in remaining studies 4,5,8,21,25,83 n=39-248 XPD C156A 1 Study 156A/A → higher incidence of grade 3/4 haematological XPD Asp711Asp Asian; n=209 toxicity in platinum-treated patients than C/C or C/A (p=0.01)84 RRM1 6,85-89 RRM1 -A37C 6 studies NO GEMCITABINE RRM1-C524T 1 Mixed; 2 Caucasian 37C/C - 524T/T haplotype → better DFS compared to 37A/C- RRM1 T756C 3 Asian 524C/T [AHR 0.59; p= 0.05] 85 RRM1 C269A n=53-214 524C/T → better RR than 524C/C or T/T with platinum therapy (p=0.05) 86 TREATMENT WITH GEMCITABINE 37A/C-524C/T haplotype → better RR compared to other allelotypes (p=0.04) 88 No association in the overall population in a second study 6 Pathway analyses 75,76 25 SNPs in 16 genes in 1 Study 6 polymorphisms in nucleotide excision gene associated with DNA repair pathways Caucasian; n=229 OS, though not significant 75</p><p>109 SNPs in 50 DNA 1 Study 15 polymorphisms associated with OS mostly in nucleotide repair genes Caucasian; n=700 excision and base excision repair pathways; interactions with platinum76</p><p>2 Supplementary Table 1A cont’d. Pathways/Polymorphisms most frequently studied</p><p>R Genetic Studies Comment: Positive Findings I</p><p>A Polymorphism</p><p>P Others 7,22,25,73,87,89-92 E</p><p>R iASPP A67T 1 Study iASPP 67A/- → better RR (p=0.01) only in a 22</p><p>A ATM A60G Asian; n=230 cisplatin/radiation subgroup </p><p>N APE1 Asn148Glu D MDR1 (C3435T; 2 Studies 3435C/C → better RR in Asian study compared to T/- 2677GT/3435CT*) 1 Asian; 1 Caucas (p=0.03) 92. No association in Caucasian study 87 n=54-62 CDA Lys27Gln 2 Studies CDA Lys/Lys → better OS in a single study (p=0.002) CDA C435T 1 Asian, 1 Caucas compared to Lys/Gln or Gln/Gln 25 n=53, 65 hMSH2 gIVS12-6T/C 1 Study hMSH2 T/T →worse OS (p=0.003) in a single study compared Asian; n=156 to C/C or T/C 91. XPG (His46His; 2 Studies XPA G/- → better response than AA to platinum-based therapy His1104As Asian; n=82-115 [OR 0.2; p=0.004] 90 p; XPA No association in second study 7 A23G BRCA1 Tagging 1 Study AACC wild type haplotype → shorter survival [AHR 2.10; polymorphisms Asian; n=300 p=0.001] 73 EGFR 32-39,93-95 I EGFR intron 1 7 studies TREATMENT WITH GEFITINIB K 32</p><p>T (CA)nS/L 4 Asian; 3 Caucasian LL → worse OS in a single Asian study (p=0.04) 35</p><p>R (S=short ; L=long) n = 70-170 L/- → worse PFS in a Caucasian study [AHR 1.9; p=0.03] </p><p>F LL → worse RR in an Asian study alone or with a D994D G polymorphism (p<0.001) 37 E L → worse RR (p=0.03) and TTP (p=0.01) in Asian study 36 NO GEFITINIB L → better OS in a single US study [HR 0.66; p=0.03] 38 EGFR -G216T 3 studies TREATMENT WITH GEFITINIB EGFR -216G/-191C* 3 Caucasian 216G/G → worse PFS, alone or in combination with Intron 1 n= 92-173 L allele in one study 35 EGFR*1(-216G/-191C) haplotype → worse OS (p=0.02), only in ECOG PS 0 /1 patients, in 2nd study 33 EGFR G2607A 3 Studies TREATMENT WITH GEFITINIB EGFR C2982T Asian n=46 - 84 2607G/G → better OS than A/- (p=0.07)94 2982 C/C → longer PFS compared to T/- (p=0.002)37 ABCG2 C421A 2 studies TREATMENT WITH GEFITINIB ABCG2 G34A; Caucasian; n=173,349 ABCG2 421A/- →.higher incidence of diarrhea (p=0.005) 39 ABCC3 C211T; NO GEFITINIB ABCC3 G3890A; ABCG2 421A/- → worse OS than C/C [HR 1.6 (1.04-2.47)] ABCC3 C3942T; (with platinum) 93 ABCC3 211T/- variants → poorer PFS [HR 1.8 (1.13-2.82)] in a small cell subgroup 93 p53 / MDM2 43-50 43 R p53 Arg72Pro 7 studies Arg/Pro → worse OS in 1 study [AHR 2.3; p=0.02] E p53 Intron 3 (single 3 Asian; 4 Caucasian Pro/Pro → worse OS in 1study 44 and worse PFS in a 2nd46 H 45</p><p>T study) n=101-619 Pro/Pro → worse OS on subgroup analysis in a third study 50 O MDM2 T309G 2 studies 309G/G → worse OS in early stage [AHR 1.6; p=0.04] 1 Asian; 1 Caucasian 309G/- → worse OS in advanced disease [AHR 1.7;p=0.03 46 n=148, 383 GST 5,52,53,63,65,66,96-99 GSTM1-null/present 10 studies GSTM1-null → shorter OS in two studies [RR of death 1.36] 52 GSTT1-null/present 4 Asian & [AHR 4.1] 53 GSTP1 Ile105Val 6 Caucasian GSTT1-null → shorter OS in a single study [AHR 2.1; p=0.01] GSTP1 A/G n=81-425 98. Similar trend in 2nd study but small numbers (n=6) 5 GSTP1Ala114Val GSTP1 114 Val/- → longer survival in one study [AHR 0.75; γ-GCS-7/8 p=0.037] compared to Ala114Ala 97</p><p>3 Supplementary Table 2A. Additional polymorphisms assessed in multiple studies Pathway/Gene Studies Comment: Positive Findings</p><p>Matrix Metalloproteinase 54,55,100 MMP1 1607 1G/2G ; MMP2 3 studies Two large studies assessed multiple SNPs 54,55. (C1306T, C735T ) ; MMP3 1 Asian; MMP12 1082G/- alleles → worse OS in stage I NSCLC (1171 5A/6A, A706G, 2 Caucasian [AHR 1.94; p=0.002] compared to A/A 54 Glu45Lys) ; MMP7 A181G n=90 - 561 MMP9 279 Gln/Gln → worse OS compared to Arg/- [HR MMP9 (C1562T, Pro574Arg, 1.6; p=0.023] in a large Asian study 55 Arg279Gln, Arg668Gln) MMP2 -735C/C → worse prognosis than T/- alleles in a MMP12 (A79G; A1082G) smaller study [RR of death 2.6; p=0.05] 100 FGFR 101,102 FGFR4 Gly388Arg 2 studies Arg/- → poorer OS in a single study (adenocarcinoma) [HR Caucasian 1.6; p=0.008] compared to Gly/Gly 102; n=274, 619 Arg/- → no association in the larger study (SCLC+NSCLC) Irinotecan Metabolism 56,57,103-105 UGT1A7 (*1,*2,*3,*4) 3 studies UGT1A1*6 /6→ shorter PFS (p=0.001) and OS (p=0.17) in UGT1A1 (*6,*28,*60) 2 Asian; a single Asian study (irinotecan treated) 56 UGT1A16/7; UGT1A9*22 1 Caucasian No association with other SNPs and survival OR response in n=47-118 irinotecan treated patients103,104. ABCB1 (G2677T/A, C1236T, 1 study ABCC2 24T/T and 3972T/T → higher RR (p= 0.31 and 0.05) C3435T); ABCC2 (-C24T, Asian; n=107 and longer PFS (p=0.01 and 0.02) than ABCC2 24 C/- and G1249A, C3972T) 3972 C/- 57 SLCO1B1 G11187A 1 study SLCO1B1 521C/- → higher incidence of Grade 4 SLCO1B1 A388G SLCO1B1 Asian; n=81 neutropenia (p=0.008) 105. No association with response. T521C Vitamin D Receptor58,59 VDR Cdx-2 G/A 2 studies Early stage (Squamous Cell):VDR Cdx-2 A/- → better VDR Fokl C/T Caucasian survival [AHR 0.56; p=0.05] Combined “protective” VDR Bsml C/T n=294, 373 genotypes and A-C-T haplotype better OS 59 Advanced stage: VDR Fokl T/-, and G-T-C haplotype → worse survival 58 Folate Metabolism 60,61,106,107 MTHFR (Ala222Val, 1 study Val222Val → shorter OS in SCLC only [HR 1.92 (1.0-3.58)] Arg594Gln) Caucasian compared to Ala222Ala MTHFS Thr202Ala n=619 Arg594Gln → longer OS in overall population [HR 0.68 MTRR Ser175Leu (0.46-1.0)] compared to Arg594Arg. (14 SNPS genotyped) Thr202Ala and Ser175Leu variant carriers → shorter OS in NSCLC 60 MTHFR C677T 3 studies C677T → no association with OS in two studies 106,107 T677T MTHFR A1289C 1 Asian → better PFS than C/T or C/C on univariate analysis in a TS VNTR H/- vs L/L 2 Caucasian n=127 third study (p=0.03) 61 - 295 TS L-group →longer OS only in combination with stage I and MTHFR C-group (p=0.03) 107. VEGF 62 VEGF (G405C, C936T, 1 study VEGF 405 C/- → better 5year OS [AHR 0.70; p=0.008]. T460C) Caucas; n=462 L-myc 63,64,108-111 L-myc Ser362Thr 6 studies L-mycEcoR1 RFLP S allele → shorter OS in one Asian L-mycEcoR1 RFLP 3 Asian; 3 Caucas study64, longer OS in a second Asian study 63and no n=83-252 association in two Caucasian studies 108,111 CYP 65-67 CYP2E1; 2 studies CYP2E1 wild type → better 5 year survival (p=0.02) 66 CYP1A1 Mixed; n=87 CYP1A1 non-susceptible homozygous → better OS in Asian; n=232 advanced NSCLC (p=0.005)65 CYP2D6*4; CYP3AP1*3; 1 study Treatment with Vinorelbine 67 CYP3A5*3; CYP2C19*2 Asian; n=59 CYP2D6*4 C/C (p=0.02) and CYP3AP1 A/A → better RR CYP2C19*3; CYP2D6*2 (p=0.004) CYP3A4*53 G/G → worse RR (p=0.004)</p><p>4 Supplementary Table 3A. Polymorphisms assessed in single studies</p><p>Pathway/Gene Studies Comment : Positive Findings</p><p>TRIT1110 TRIT1 Phe202Leu 1(+ replication ) Leu allele → worse OS in Italian group Predominantly (adenocarcinoma) [HR 1.7; p=0.04)]. Caucasian Leu allele → better OS in Norway group: [HR n=246,335 0.5; p=0.02]. Inflammatory 112 TGF-β codon (10T/C, G25C); IL-6 G174C; 1 study TGF-β T/T → better OS compared to C/C IL-10 (G1082A, C592A,C819T); Caucasian; n=44 (p=0.01). IFN-γ T874A; TNFα G308A IGF 113 3’UTR IGF2R-A2/B2 1 study A2/B2 → worse OS (p=0.05) and +ve synergistic Caucas; n=103 effect with p53 inactivation. Immune 114 MBL2 Y/X -289G>C; MBL L/H -618G>G; 1 study MBL2 X/- → improved survival in Caucasians, MBL A/D Exl -34C>T; MBL A/B Ex 1- Mixed; n=731 p=0.001. 27G>A; MBL A/C Ex1 -18G>A MBL2 LXA haplotype → improved survival. Others 61,89,93,115-120 KRAS2 Rsal A1/A2; PTHLH VNTR; 1 study KRAS2 A2/- → better survival (p=0.008). CDKN1B Val/Gly; M4(BstXI; StuI) Caucas; n=213 PTHLH allele2 → worse survival (p=0.03) 116 LRMP (Val141Leu; Ser197Cys) 1 study LRMP 141 Val/Val → better OS in <65years CASC1 (rs12367971, rs10842496, Caucasian (p=0.005) 117 rs10842501,rs10842502) n=361 No association with OS in overall population. Polysomy 7 1 study Treatment with Gefitinib: Caucas; n=82 High Polysomy 7 → better OS (p=0.004) 115 MUC1 VNTR LS 1 study LL → worse OS only in adenocarcinoma Asian; n=56 compared to S/- (p=0.11) 118 PDCD5 rs1862214 C/G 1 study G/- → worse survival [HR 1.8, p=0.003) Caucas; n=254 compared to C/C 120 FAS G1377A; FAS A670G; FASL C844T 1 Study FAS 670G/- → worse OS than AA [HR 1.5, Asian; n=338 p=0.047] 119 DCK C3122T; DCTD T315C; POLA2 1 Study S28A2 65 T/- → independently associated with G1747A; S28A1 (419 Ins/Del, G565A, Asian; n=53 improved OS [HR 0.3, p=0.002] 89 C709A, G1368A, C1528T, G1561A); S28A2 (C65T, C225A); S28A3 A338G; TYMS (1002R/3R, G58C, 15705Ins/Del) GGH C452T; SLC 19A1 G80A; TS 5UTR 1 Study No significant associations with PFS or toxicity 61 T/R; TS 5UTR 3C/G Asian; n=127 CCND1 A870G 1 Study GG → better response to platinum compared to Caucas; n=244 A/- (p=0.04). No association with survival 121 CDKN1A (p21 codon) 31Ser31Arg 1 Study Ser/Ser shorter survival compared to Ser/Arg or Mixed; n=155 Arg/Arg (p=0.097) 122</p><p>Abbreviations Tables1A-3A: Caucas: Caucasian; DFS: disease-free survival; AHR: adjusted hazard ratio; OS: overall survival; RR: response rate; GI: gastrointestinal; gem: gemcitabine; tox: toxicity; PFS: progression-free survival; ECOG PS: European Cooperative Oncology Group Performance Status; SCC: squamous cell carcinoma; NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer. *Haplotype.</p><p>References 1-81 are found in the main text and 82-122 are found in the supplemental text as supplementary references. Supplementary Tables 1B,2B,3B show the RefSNP identifiers of the corresponding polymorphisms in Tables 1A,2A,3A.</p><p>5 Supplementary Table 1B. Sequence variants and their RefSNP corresponding to Supplementary Table 1A</p><p>Gene SNP RefSNP Gene SNP RefSNP DNA Synthesis / Repair p53 XRCC1 Arg399Gln rs25487 P53 Arg72Pro rs1042522 Arg194Trp rs1799782 Intron 3 N/A Arg280His rs25489 MDM2 MDM2 T309G rs2279744 ERCC1 C118T rs11615 Glutathione S-transferase C8092A rs3212986 GSTP1 Ile105Val rs1695 G262T rs2298881 A/G N/A T433C rs3212930 Ala114Val rs1138272 C4855T rs3212961 γ-GCS 7/8 N/A XPD Asp312Asn rs1799793 Lys751Gln rs13181 C156A rs238406 Asp711Asp rs1052555 RRM1 -A37C N/A -C524T N/A T756C N/A C269A N/A iASPP A67T rs6966 ATM A60G rs664143 APE1 Asn148Glu rs1130409 MDR 3435C/T rs1045642 G2677T rs2032582 CDA Lys27Gln rs2072671 A79C rs2072671 C435T rs1048977 hMSH2 gIVS12-6T/C rs2303428 XPA A23G rs1800975 XPG His46His rs1047768 His1104Asp rs17655 EGFR EGFR 1(CA)nS/L N/A -G216T rs712829 -A191C rs712830 D994D rs2293347 C2982T rs2293347 G2607A rs1050171 ABCG2 C421A rs2231142 G34A rs2231137 ABCC3 C211T N/A G3890A rs11568591 C3942T rs2277624 CNT1 G565A rs2290272 N/A: not available</p><p>Supplementary Table 2B. Sequence variants and their RefSNP corresponding to Supplementary Table 2A</p><p>6 Gene SNP RefSNP Gene SNP RefSNP Matrix Metalloproteinase Vitamin D Receptor MMP1 1607 1G/2G rs1799750 VDR Cdx-2G/A N/A MMP2 C1306T rs243865 Fokl C/T N/A C735T rs2285052 Bsml C/T N/A MMP3 1171 5A/6A rs3025058 Folate Metabolism A706G N/A MTHFR Ala222Val rs1801133 Glu45Lys rs679620 Arg594Gl rs2274976 MMP7 A181G rs11568818 n rs1801131 A1289C MMP9 C1562T rs3918242 MTRR Ser175Leu rs1532268 Pro574Arg rs2250889 MTHFS Thr202Ala rs8923 Arg279Gln rs17576 TS VNTR H/- N/A L/L Arg668Gln rs17577 CYP MMP12 A79G N/A CYP2E1 N/A N/A A1082G rs652438 CYP1A1 N/A N/A L-myc CYP2D6 *4 rs3892097 L-myc Ser362Thr rs3134614 *2 rs16947 EcoRI RFLP N/A CYP2C19 *2 rs4244285 FGFR *3 rs4986893 FGFR4 Gly388Arg rs351855 CYP3A5 *3 rs776746 Irinotecan Metabolism CYP3AP1 *3 N/A UGT1A1 *6 rs4148323 *28 N/A *60 N/A 6/7 N/A UGT1A7 *1 N/A *2 N/A *3 N/A *4 N/A UGT1A9 *22 N/A ABCB1 T2677A rs2032582 C1236T rs1128503 C3435T rs10456642 ABCC2 -C24T rs717620 G1249A rs2273697 C3972T rs3740066</p><p>SLCO1B1 G11187A rs4149015 A388G rs2306283 T521C rs4149056 N/A: not available</p><p>Supplementary Table 3B. Sequence variants and their RefSNP corresponding to Supplementary Table 3A</p><p>7 Gene SNP RefSNP Gene SNP RefSNP TRIT1 Others TRIT1 Phe202Leu rs3738671 FAS G670A rs1800682 VEGF G1377A rs2234767 VEGF G405C rs2010963 FASL C834T rs763110 C936T rs3025039 NQO1 T/C rs1800566 T460C rs833061 STK15 T31A rs2273535 Inflammatory G57A rs1047972 TGF-b codon 10T/C rs1800470 PDCD5 C/G rs1862214 codon 25G/C rs1800471 CDA A79C rs2072671 IL-6 G174C rs1800795 C435T rs1048977 IL-10 G1082A rs1800896 DCK C3122T rs3775289 C592A rs1800872 DCTD T315C N/A 819C/T rs1800871 POLA2 G1747A N/A TNFa G308A rs1800629 S28A1 416Ins/Del rs17215836 IFN-γ T874A rs2430561 G565A rs2290272 IGF C709A rs8187758 IGF2R 3'UTR A2/B2 N/A G1368A rs2242048 Immune C1528T rs2242047 G1561A rs2242046 MBL2 Y/X -289G>C rs7096206 S28A2 C65T rs61637002 MBL L/H -618G>G rs11003125 C225A rs1060896 A/D ExI -34C>T rs5030737 A/B ExI -27G>A rs1800450 S28A3 A338G rs10868138 A/C Exl -18G>A rs1800451 TYMS 1002R/3R N/A Others G58C N/A 15705Ins/Del N/A KRAS2 RsaI A1/A2 N/A GGH C452T N/A PTHLH VNTR N/A SLC19A1 G80A rs1051266 CDKN1B Val/Gly N/A TS 5UTR T/R N/A M4 BstXI, StuI N/A 5UTR 3C/G N/A LRMP Val141Leu rs7969931 ABCC3 C211T N/A Ser197Cys rs1908946 G3809A rs11568591 CASC1 R33S rs10842496 C3942T rs2277624 Intronic rs12367971 RAD23 C/T rs1805329 Intronic rs10842501 Intronic rs10842502 CCND1 A870G rs603965 Chr7 Polysomy 7 N/A CDKN1A Ser31Arg rs1801270 MUCI VNTR LS N/A N/A: not available</p><p>SUPPLEMENTARY REFERENCES:</p><p>8 82. 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