Supplemental Table 1. Primers used in Ion Torrent sequencing of HPV. Bar codes id_strSequence IonXpress_1CTAAGGTAAC IonXpress_2TAAGGAGAAC IonXpress_3AAGAGGATTC.

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Supplemental Table 1. Primers used in Ion Torrent sequencing of HPV. Bar codes id_strSequence IonXpress_1CTAAGGTAAC IonXpress_2TAAGGAGAAC IonXpress_3AAGAGGATTC IonXpress_4TACCAAGATC IonXpress_5CAGAAGGAAC IonXpress_6CTGCAAGTTC IonXpress_7TTCGTGATTC IonXpress_8TTCCGATAAC IonXpress_9TGAGCGGAAC IonXpress_10CTGACCGAAC IonXpress_11TCCTCGAATC IonXpress_12TAGGTGGTTC IonXpress_13TCTAACGGAC IonXpress_14TTGGAGTGTC IonXpress_15TCTAGAGGTC IonXpress_16TCTGGATGAC IonXpress_17TCTATTCGTC IonXpress_18AGGCAATTGC IonXpress_19TTAGTCGGAC IonXpress_20CAGATCCATC IonXpress_21TCGCAATTAC IonXpress_22TTCGAGACGC IonXpress_23TGCCACGAAC IonXpress_24AACCTCATTC IonXpress_25CCTGAGATAC IonXpress_26TTACAACCTC IonXpress_27AACCATCCGC IonXpress_28ATCCGGAATC IonXpress_29TCGACCACTC IonXpress_30CGAGGTTATC IonXpress_31TCCAAGCTGC IonXpress_32TCTTACACAC IonXpress_33TTCTCATTGAAC IonXpress_34TCGCATCGTTC IonXpress_35TAAGCCATTGTC IonXpress_36AAGGAATCGTC IonXpress_37CTTGAGAATGTC IonXpress_38TGGAGGACGGAC IonXpress_39TAACAATCGGC IonXpress_40CTGACATAATC IonXpress_41TTCCACTTCGC IonXpress_42AGCACGAATC IonXpress_43CTTGACACCGC IonXpress_44TTGGAGGCCAGC IonXpress_45TGGAGCTTCCTC IonXpress_46TCAGTCCGAAC IonXpress_47TAAGGCAACCAC IonXpress_48TTCTAAGAGAC IonXpress_49TCCTAACATAAC IonXpress_50CGGACAATGGC IonXpress_51TTGAGCCTATTC IonXpress_52CCGCATGGAAC IonXpress_53CTGGCAATCCTC IonXpress_54CCGGAGAATCGC IonXpress_55TCCACCTCCTC IonXpress_56CAGCATTAATTC IonXpress_57TCTGGCAACGGC IonXpress_58TCCTAGAACAC IonXpress_59TCCTTGATGTTC IonXpress_60TCTAGCTCTTC IonXpress_61TCACTCGGATC IonXpress_62TTCCTGCTTCAC IonXpress_63CCTTAGAGTTC IonXpress_64CTGAGTTCCGAC IonXpress_65TCCTGGCACATC IonXpress_66CCGCAATCATC IonXpress_67TTCCTACCAGTC IonXpress_68TCAAGAAGTTC IonXpress_69TTCAATTGGC IonXpress_70CCTACTGGTC IonXpress_71TGAGGCTCCGAC IonXpress_72CGAAGGCCACAC IonXpress_73TCTGCCTGTC IonXpress_74CGATCGGTTC IonXpress_75TCAGGAATAC IonXpress_76CGGAAGAACCTC IonXpress_77CGAAGCGATTC IonXpress_78CAGCCAATTCTC IonXpress_79CCTGGTTGTC IonXpress_80TCGAAGGCAGGC IonXpress_81CCTGCCATTCGC IonXpress_82TTGGCATCTC IonXpress_83CTAGGACATTC IonXpress_84CTTCCATAAC IonXpress_85CCAGCCTCAAC IonXpress_86CTTGGTTATTC IonXpress_87TTGGCTGGAC IonXpress_88CCGAACACTTC IonXpress_89TCCTGAATCTC IonXpress_90CTAACCACGGC IonXpress_91CGGAAGGATGC IonXpress_92CTAGGAACCGC IonXpress_93CTTGTCCAATC IonXpress_94TCCGACAAGC IonXpress_95CGGACAGATC IonXpress_96TTAAGCGGTC

Adaptors A 5'- 3' CCATCTCATCCCTGCGTGTCTCCGACTCAG P1 5'- 3' CCACTACGCCTCCGCTTTCCTCTCTATGGGCAGTC GGTGAT ve/index.php/t html P1 adaptor CCTCTCTATGGGCAGTCGGTGAT HPV Primers F GP5+TTT GTT ACT GTG GTA GAT ACT AC F GP5+ -2TTT GTT ACT GTT GTI GAT ACT AC F GP5+ -3TTT GTT ACT GTT GTI GAT ACC AC F GP5+ -4TTT GTT ACT TGT GTI GAT ACT AC F GP5+ -5TTT TTA ACT GTT GTI GAT ACT AC F GP5+ -6TTT GTT ACT GTG GTA GAC ACT AC F GP5+ -7TTT GTT ACA GTI GTA GAC ACT AC F GP5+ -8TTT GTT ACA GTI GTA GAT ACC AC F GP5+ -9TTT GTT ACT GTG GTA GAT ACT AC F BGMS3AAT ATA TGT GTG CTT ATT TG F GP6+GAA AAA TAA ACT GTA AAT CAT ATT C F GP6+ -bGAA AAA TAA ATT GTA AAT CAT ACT C F GP6+ -cGAA AAA TAA ATT GCA AAT CAT ATT C F BGMS10AGA TTA GGG AAA GTA TTA GA Design F P1-GP5+ R A-barcode-GP6+ Supplemental Table 1. Primers used in Ion Torrent sequencing of HPV. Legend: Sequences of the bar codes, adaptors and primers used in the Ion Torrent sequencing of HPV are shown.

Supplemental Table 2. Predicted somatic mutations in PIK3CA discovered by targeted sequencing of cervical tumors from Mexico, Venezuela, and Guatemala. GenecDNAProtein # mutated in Mexican samples (N=325) # mutated in Venezuelan samples (N=40) # mutated in Guatemalan samples (N=280) PIK3CA112C>TR38C100 PIK3CA113G>AR38H010 PIK3CA115G>AE39K002 PIK3CA223C>GQ75E100 PIK3CA241G>AE81K113 PIK3CA263G>AR88Q001 PIK3CA277C>TR93W100 PIK3CA278G>TR93L100 PIK3CA319_321delN107del*010 PIK3CA331A>GK111E001 PIK3CA333G>CK111N102 PIK3CAG436AV146I*100 PIK3CA686C>TT229I*001 PIK3CAA895GM299V*100 PIK3CA1031T>GV344G100 PIK3CA1048G>AD350N010 PIK3CA1093G>AE365K100 PIK3CA 419_420del H419_C420del*100 PIK3CA 1357G>A E453K002 PIK3CA1360G>AD454Y002 PIK3CA1368G>AL456L001 PIK3CA1624G>CE542Q010 PIK3CA1624G>AE542K36027 PIK3CA1633G>AE545K50642 PIK3CA1633G>CE545Q100 PIK3CA1634A>GE545G001 PIK3CA1637A>GQ546R100 PIK3CA1641G>CE547D100 PIK3CA1645G>CD549H100 PIK3CA2176G>AE726K210 PIK3CAA2582GQ861R*001 PIK3CAG2740CG914R*100 PIK3CA2825A>TK942M*001 PIK3CA2855T>GV952G*001 PIK3CA3100G>CE1034Q*010 PIK3CA3129G>AM1043I011 PIK3CA3139G>AH1047Y001 PIK3CA3140A>GH1047R201 Legend: The position of the transcript, amino acid change and number of mutations in each sample set is shown.

Supplementary Table 3. Predicted somatic mutations in 5 candidate genes discovered by targeted sequencing of cervical tumors. GenecDNAProtein PTENc.G274CD92H PTENc.C352GH118D PTENc.G376A A126T PTENc.G385A G129R PTENc.C388GR130G PTENc.G389AR130Q* PTENc.G389TR130L PTENc.C388TR130X PTENc.T460AF154I PTEN c.473_476delAAGTp.158_159del PTENc.T652C C218R PTENc.C733T Q245X PTENc.G822A W274X PTEN c. c.827_837delp.276_279del PTEN c.862_864 insAAp.E288fs PTEN c.918_919insGAGCGp.I306fs PTEN c.953_956delTACTp.318_319del* PTENc.G1026C K342N PTENc.1117_1120delp.373_374delAATG PTENc.C610G P204A STK11c.G97T E33X STK11c.C109T Q37X* STK11c.C298T Q100X STK11c.T402G C134W STK11c.T474G C158W STK11c.G580A D194N STK11c.C647T S216F STK11c.C910T R304W* STK11c.G911C R304P STK11cG1045A E349K TP53 c.138_185del p.46_62del TP53c.G517T V173L TP53c.C388T L130F TP53 c.G524A R175H TP53 c.C574T Q192X TP53 c.A611G E204G* TP53 c.T613C Y205H* TP53 c.C637T R213X TP53 c.A659G Y220C TP53 c.A704G N235S* TP53 c.G673A V225I TP53 c.G713T C238F TP53c.716_726delp.239_242del TP53c.G731AG244D TP53 c.G738A M246I TP53 c.G743A R248Q TP53 c.T770C L257P TP53 c.C817T R273C TP53 c.G818A R273H* TP53 c.G820T V274F TP53 c.G830A C277Y TP53 c.G839A R280K TP53 c.G853A E285K TP53 c.C991T Q331X HRASc.G37C G13R HRASc.C53T A18V HRASc.A182T Q61L* HRASc.C520T P174S* KRASc.G34T G12C KRASc.G35T G12V* KRASc.G35CG12A KRASc.G35AG12D* KRASc.G37CG13R KRASc.G38A G13D* KRASc.G436A A146T KRASc.G510AM170I KRASc.G535A G179S * observed in multiple tumors

HPV TypeWTNon-helicalHelicalTotal HPV18 or 45 GroupNegativePositiveORCIP WT30394 Any PIK3CA Legend: A. The distribution of HPV types along with PIK3CA mutation status is shown. B. Comparison combining HPV18 and HPV45 (closely related virus types) to all other types is shown in relation PIK3CA mutation status (bottom section; OR=0.43, 95%CI= , P= Supplementary Table 4. Association of HPV type and PIK3CA mutation. A B

Supplementary Table 5. PIK3CA mutations in histologic subtype in this and other published studies Tumor with mutations Tumor without mutations Frequency of mutation (%) Helical domain E542K Proportion of E542K (%) Helical domain E545K Proportion of E545K (%) Proportion of E542K+E545K (%) Other mutatio ns Total mutatio ns Latin American SC # a 31%55 33% 81 48% 81%33 b 169 AC/ASC ## %5 23% 10 46% 68%722 Other6555%3 50% 1 17% 67%26 US a SC152538% % 100%016 AC103025%4 33% 6 50% 83%212 Norway d* SC*85812% 338%3 75% 28 AC*42514% 250%125% 75% 14 Other*3260% 133%00.0% 33% 23 Mexico d** SC** % 133%1 67% 13 AC** 11 50% 00.0%0 22 Canadian & SC*165323% 16.3%1169% 75% 416 AC*31023% 133%00.0% 33% 23 Chinese1 && SC # %9 33% 15 56% 89%227 AC/ASC ## %2 29% 4 57% 86%17 Other1910%0 0.0% 1 100% 01 Chinese2 &&& AC %0 0.0% 1 33% 23 # Squamous ## Adenocarcinoma/Adenosquamous &:&: Wright A. et al. Cancer : d:d:Ojesina et al. Nature : *: 100 Norway samples from Ojesina et al. Nature : **: 15 Mexico samples from Ojesina et al. Nature : &: Mclntyre et al. Gynecol. Oncol : &&: Xiang L. et al. Ocotarget :1- 8. &&&: Chung T. et al. IJC 2015 a: P 0.05; Significance tested using the Pearson's chi-squared test.

Supplementary Table 6. Fig.3A_B_C raw data Tumors with mutations Total patients Frequency of mutations (%) p85 domain Helical domain E542K Helical domain E545K Kinase domain Guatemala % Mexico % Venezuela114028% U.S258031% Swedish151848%1273 COSMIC %27257 Norwegian* %1643 Mexico**31520%1111 Canadian198223%N/A2114 Chinese % N/A Chinese231520%N/A011 European % *:100 Norway samples from Ojesina et al. Nature : **: 15 Mexico samples from Ojesina et al. Nature : A. B. Total mutations p85 domain Proportion of p85 (%) Helical domain E542K Proportion of E542K (%) Helical domain E545K Proportion of E545K (%) Proportion of E542K+E545K (%) Kinase domain mutations Proportion of kinase domain mutations (%) Kinase domain H1047R Proportion of H1047R (%) Guatemala 91 67%2730%4246%76%67%11% Mexico %3634%5047%81%55%22% Venezuela %00%643% 321%00% U.S a 28 14%1036%1657%93%00%0 Swedish b 15 17%213%747%60%320%17% COSMIC c 46 24%715%2554%70%715%37% Norwegian d * 15 17%640%427%67%320%213% Mexico d ** 5 120%1 1 40%120%00% Canadian & 19 N/A211%1158%68%421%211% Chinese1 && 35 N/A 1131%2057%89%39%26% Chinese2 &&& 3 N/A00%133% 1 1 European^ 51 12%1529%3365%94%24%2 *:100 Norway samples from Ojesina et al. Nature : **: 15 Mexico samples from Ojesina et al. Nature : #: Mutation H1047R from clear cell carcinoma (Ojesina et al. Nature : ). a: Wright A. et al. Cancer : b:Cui B. et al. International Journal of Oncokogy : c:COSMIC database d:Ojesina et al. Nature : *: 100 Norway samples from Ojesina et al. Nature : **: 15 Mexico samples from Ojesina et al. Nature : &: Mclntyre et al. Gynecol. Oncol : &&: Xiang L. et al. Ocotarget :1-8. &&&: Chung T. et al. IJC 2015 ^:Spaans V. et al. PLOS ONE :e93451

C. Tumors with mutations Total CC patients Frequency of mutations (%) p85 domain Proport ion of p85 (%) Helical domai n E542K Proportion of E542K (%) Helical domai n E545K Proportion of E545K (%) Proportion of E542K+E545K (%) Kinase domain mutations Proportion of kinase mutations (%) Kinase domain H1047R Proportion of H1047R (%) Total mutationsReferences Colon %911%2126%37%2531%1519%81 Samuels Y et al. Science 304: 2004 Breast %1 00%11%667%556%9 Bachman KE et al. Cancer Biolgy & Therapy 3: Breast %21911%46123%34%127865%126064%1977 COSMIC Endometrial %23%2 7%1933%712%58 Rudd ML. et al. Clinical Cancer Research 17: Endometrial %5812%10422%34%23750%19841%478 COSMIC Intestine %20919%47542%61%40036%33830%1119 COSMIC Ovary %2311%7032%43%11955%10850%216 COSMIC Bladder %4 935%50%312%14%26 Guo G. et al. Nat Genet 45: 2013 Bladder %623%1038%62%312%00%26 Weinstein JN. et al. Nature 507: 2014 Cervical_Guat %2730%4246%76%67%11%91 Guatemala Cervical_Mexico %3634%5047%81%55%22%106 Mexico Cervical_Ven %00%643% 321%00%14 Venezuela