Supplemental file 1: The whole list of tumor aberrations by time tumor biopsy ctDNA 2002 (T1) 2012 (M1) 2015 (M2) 08/2015 09/2015 11/2015 02/2016 05/2016 07/2016 11/2016 02/2017 05/2017 07/2017 11/2017 PIK3CA Q546R PIK3CA Q546R PIK3CA Q546R PIK3CA Q546R 0.30% PIK3CA Q546R 1.30% PIK3CA Q546R 5.40% PIK3CA Q546R 12.50% PIK3CA Q546R 9.50% PIK3CA Q546R 32.58% PIK3CA Q546R 44.30% PIK3CA Q546R 15.40% PIK3CA Q546R 41.00% TP53 E180K TP53 E180K TP53 E180K TP53 E180K 0.30% TP53 E180K 1.00% TP53 E180K 4.80% PIK3CA M1043I 0.20% PIK3CA M1043I 0.70% PIK3CA E453K 0.69% PIK3CA E453K 3.20% PIK3CA E453K 0.55% PIK3CA M1043I 0.20% PIK3R2 S688* PIK3R2 S688* ATR E2579K VHL E173Q 0.40% PTEN Q245* 0.20% PTEN Q245* 0.30% PIK3CA E726K 1.50% PIK3CA E245Q 0.10% PIK3CA M1043I 0.36% PIK3CA M1043I 1.20% TP53 E180K 11.80% PIK3CA E453K 0.25% PLCG2 P737T PLCG2 P737T PIK3CA E726K VHL E173Q 1.10% RB1 R556* 3.10% TP53 E180K 11.00% PIK3CA E726K 0.20% PIK3CA E726K 0.23% PIK3CA E726K 0.44% TP53 I195F 1.20% PIK3CA E39Q 0.53% CDKN1B Q163* PIK3CA M1004I MET S1061F MET L229F 0.30% CCND1 E9K 0.10% PTEN Q245* 0.80% TP53 E180K 7.30% TP53 E180K 24.28% TP53 E180K 35.40% TP53 L137Q 1.30% TP53 E180K 38.40% ERBB2 R487W PTEN S229* TBX3 S435* MET W112C 1.20% NF1 D1556N 1.30% TP53 I195F 0.20% TP53 R175G 0.20% TP53 I195F 1.70% ESR1 E380Q 7.10% TP53 I195F 0.56% ALK E1407K RB1 Q217* SPEN Q743* NF1 R1176T 1.00% NF1 E76K 0.30% ESR1 E380Q 0.90% TP53 I195F 1.37% TP53 L137Q 2.10% ESR1 L391V 0.41% TP53 I254M 0.25% APC E2637K PIK3CA D1017N PTEN I253M VHL E173Q 1.20% RB1 R556* 7.20% NF1 R1176T 0.50% TP53 I254S 0.12% ESR1 E380Q 7.70% TP53 R175G 0.12% TP53 L137Q 0.89% ARID1B G2144E NF1 E924K APC F2762L 0.20% MET W112C 0.10% NF1 D1556N 0.30% TP53 L137Q 1.43% ESR1 L391V 0.51% PTEN D252N 0.37% ESR1 E380Q 28.30% PTCH1 D599H SRC I429M AR R832P 0.20% AR R832P 0.50% APC E633K 0.20% ESR1 E380Q 2.44% ESR1 M357I 0.20% PTEN K66N 1.30% ESR1 L391V 0.27% ERBB4 D335N EGFR M952I 1.30% EGFR M952I 2.40% AR R832P 0.60% NF1 Q2531* 8.16% PTEN D252N 1.01% NF1 R1176T 0.59% PTEN D252N 0.36% BARD1 R664K MET L229F 3.90% APC E633K 0.40% PTEN Q245* 0.30% NF1 R1176T 7.00% PTEN K128N 0.18% NF1 Q2531* 1.20% PTEN K66N 1.50% Promoter PIK3CG G725S KIT S464L 1.10% APC F2762L 0.30% TERT –122C>T 0.40% PTEN K66N 2.14% PTEN K66N 7.40% FGFR1 K656E 1.40% NF1 Q2531* 0.88% LRP1B E1467Q NOTCH1 S2341F 1.00% PTPN11 Q57E 2.10% EGFR M952I 1.10% EGFR M952I 9.16% PTEN L25F 0.36% EGFR M952I 1.34% NF1 S1150* 0.26% RB1 R556* MYC G175S 0.50% VHL E173Q 3.30% FGFR3 S249C 0.10% MET W112C 7.50% PTEN Q171H 0.30% MET W112C 0.61% NF1 R1176T 0.89% MLL K2855N NF1 E2558K 1.50% MET W112C 0.40% PTPN11 Q57E 0.38% NF1 Q2531* 1.80% FOXL2 E118Q 0.20% NF1 L552V 0.19% PIK3C2B D791H APC M526I 0.30% PTPN11 Q57E 0.30% MTOR K1465N 13.05% NF1 D1556N 0.32% BRCA2 E2846K 0.28% FGFR1 K656E 1.80% FAT1 D2913N PTEN P190L 0.20% RB1 R556* 3.40% MTOR R2505Q 0.57% NF1 R1176T 1.70% ERBB2 E1021K 0.26% EGFR M952I 1.19% MET L229F KIT S464L 2.00% VHL E173Q 0.70% NPM1 D172N 4.57% NF1 E924K 0.27% CDKN2A F5L 0.55% ERBB2 E405K 0.27% Promoter RAF1 L613V NOTCH1 S2341F 2.40% CDKN2A F5L 0.10% MET L229F 22.52% TERT –122C>T 0.45% MET L229F 6.30% MET W112C 0.70% HSP90AA1 L342V NOTCH1 L2067M 1.00% KIT S464L 1.10% ESR1 G442R 0.41% CCND1 S111C 0.25% NF1 E2558K 0.73% GNA11 E191K 0.18% NSD1 K717N BRCA1 S616F 0.40% MET L229F 5.70% NF1 E2558K 6.77% MET W112C 2.16% FOXL2 H293Y 0.29% BRCA2 E2846K 0.22% TET2 E330Q NTRK1 V341M 0.40% MYC G175S 0.70% FOXL2 H293Y 0.43% BRCA2 E2846K 0.57% NPM1 D172N 0.48% MET L229F 7.40% CSF1R V406I CDKN2A F5L 0.20% NF1 E2558K 1.10% EGFR M952I 3.01% MTOR K1465N 4.17% NF1 E2558K 0.89% PIK3C2B E807Q ARID1A L1029F 0.20% NOTCH1 S2341F 1.10% FGFR1 K656E 0.55% EGFR M636L 0.15% RAD50 Q966E MET L229F 9.40% NOTCH1 L2067M 0.50% ERBB2 E1021K 0.71% MTOR K1465N 4.47% MCL1 R80W NTRK1 V341M 0.30% FOXL2 E118Q 0.26% NPM1 D172N 0.38% RANBP2 K997N MTOR K1465N 3.40% PTPN11 Q57E 0.34% CDK6 L33F 0.91% FAT1 V912I MTOR K1465N 19.14% CDKN2A F5L 2.76% NOTCH2 L2048H CDK4 I51M 0.21% BRCA1 E1527Q 0.13% PRKDC S503C CDK6 L33F 0.19% VEGFA G39A 0.44% MTOR K1465N CDKN2A F5L 0.80% KIT D439H 0.36% FGFR2 I217M 0.20% MDM2 E273Q 0.16% FOXL2 H293Y 1.54% GNAQ T175M 0.46% MET L229F 28.40% ESR1 L469V 0.15% NF1 E2558K 2.04% NPM1 D172N 1.08% PDGFRB A789T 0.21% PTEN P190L 0.53% SMO R726* 0.33% Supplemental file 1: The whole list of tumor aberrations. Driver and predicted drivers by Cancer Genome Interpreter (CGI) are shaded in green. Sample T1 and M1 are sequenced and analyzed in Avera with results filtered by driver status. Sample M2 is tested with FoundationOne with a 315 gene panel. Liquid biopsies from 2015 to 2016 are sequenced with Guardent360 with a 70 gene panel. liquid biopsies from 2017 are sequenced with FoudationAct with a 67 gene panel. Supplemental File 2: Detailed information of driver and predicted driver mutations Genomic coordinates Gene (GRCh37) HGVS cDNA HGVS protein Variant type dbSNP/COSMIC GenotypeID NM_004304: ALK chr2:29416734 c.4219G>A p.E1407K missense COSM7126334 heterozygous NM_000038: APC chr5:112179254 c.7909G>A p.E2637K missense . heterozygous NM_000038: APC chr5:112179575 c.8286C>A p.F2762L missense . heterozygous NM_000038: APC chr5:112170801 c.1897G>A p.E633K missense . heterozygous NM_000044: AR chrX:66942714 c.2495G>C p.R832P missense . heterozygous NM_017519: ARID1B chr6:157528745 c.6431G>A p.G2144E missense . heterozygous NM_001184: ATR chr3:142171996 c.7735G>A p.E2579K missense . heterozygous NM_000465: BARD1 chr2:215595145 c.1991G>A p.R664K missense rs1574706698 heterozygous NM_000059: BRCA2 chr13:32945141 c.8536G>A p.E2846K missense . heterozygous NM_053056: CCND1 chr11:69456106 c.25G>A p.E9K missense COSM6975262 heterozygous NM_053056： CCND1 chr11:69457932 c.332C>G p.S111C missense . heterozygous NM_004064: CDKN1B chr12:12871770 c.487C>T p.Q163* nonsense . heterozygous NM_005228: EGFR chr7:55268016 c.2856G>A p.M952I missense . heterozygous NM_004448: ERBB2 chr17:37872138 c.1459C>T p.R487W missense rs375382055 heterozygous NM_004448: ERBB2 chr17:37883158 c.3061G>A p.E1021K missense . heterozygous NM_004448: ERBB2 chr17:37871603 c.1213G>A p.E405K missense . heterozygous NM_005235: ERBB4 chr2:212576896 c.1003G>A p.D335N missense . heterozygous NM_000125: ESR1 chr6:152332832 c.1138G>C p.E380Q missense COSM3829320 heterozygous NM_000125: ESR1 chr6:152332865 c.1171C>G p.L391V missense . heterozygous NM_000125: ESR1 chr6:152265618 c.1071G>C p.M357I missense . heterozygous NM_005245: FAT1 chr4:187539003 c.8737G>A p.D2913N missense rs752221845 heterozygous NM_023110: FGFR1 chr8:38272308 c.1966A>G p.K656E missense rs869320694 heterozygous NM_000142: FGFR3 chr4:1803568 c.746C>G p.S249C missense rs121913483 heterozygous NM_023067: FOXL2 chr3:138665213 c.352G>C p.E118Q missense . heterozygous NM_002067: GNA11 chr19:3115036 c.571G>A p.E191K missense rs1317391449 heterozygous NM_018557: LRP1B chr2:141625339 c.4399G>C p.E1467Q missense . heterozygous NM_000245: MET chr7:116415034 c.3128C>T p.S1061F missense . heterozygous NM_000245: MET chr7:116339474 c.336G>C p.W112C missense . heterozygous NM_005933: MLL chr11:118375181c,8565G>C p.K2855N missense . heterozygous NM_001042492: NF1 chr17:29556403 c.2770G>A p.E924K missense . heterozygous NM_001042492: NF1 chr17:29559852 c.3449C>G p.S1150* nonsense rs1555614972 heterozygous NM_001042492: NF1 chr17:29679408 c.7591C>T p.Q2531* nonsense rs1555536372 heterozygous NM_001042492: NF1 chr17:29560050 c.3527G>C p.R1176T missense . heterozygous NM_001042492: NF1 chr17:29588817 c.4666G>A p.D1556N missense . heterozygous NM_001042492: NF1 chr17:29486049 c.226G>A p.E76K missense . heterozygous NM_001042492: NF1 chr17:29548880 c.1654C>G p.L552V missense . heterozygous NM_002646： PIK3C2B chr1:204416682 c.2371G>C p.D791H missense . heterozygous NM_006218: PIK3CA chr3:178928079 c.1357G>A p.E453K missense rs1057519925 heterozygous NM_006218: PIK3CA chr3:178936095 c.1637A>G p.Q546R missense rs397517201 heterozygous NM_006218: PIK3CA chr3:178938934 c.2176G>A p.E726K missense rs867262025 heterozygous NM_006218: PIK3CA chr3:178952074 c.3129G>A p.M1043I missense rs121913283 heterozygous NM_006218: PIK3CA chr3:178951957 c.3012G>A p.M1004I missense COSM1420933 heterozygous NM_006218: PIK3CA chr3:178951994 c.3049G>A p.D1017N missense . heterozygous NM_006218: PIK3CA chr3:178919248 c.733G>C p.E245Q missense . heterozygous NM_006218: PIK3CA chr3:178916728 c.115G>C p.E39Q missense . heterozygous NM_002649: PIK3CG chr7:106513269 c.2173G>A p.G725S missense COSM5609846 heterozygous NM_005027: PIK3R2 chr19:18279980 c.2063C>A p.S688* nonsense . heterozygous NM_002661: PLCG2 chr16:81953243 c.2209C>A p.P737T missense . heterozygous NM_001083603: PTCH1 chr9:98232147 c.1795G>C p.D599H missense . heterozygous NM_000314: PTEN chr10:89717661 c.686C>A p.S229* nonsense COSM6955728 heterozygous NM_000314: PTEN chr10:89717734 c.759C>G p.I253M missense .