Clinical presentation. Duration (Month)

Transcription

1 Supplementary information, Table S1A: Clinical information for 125 PAs. No. Subtype Gender (M/F) Age at diagnosis (year) Clinical presentation Duration (Month) Maximal adenoma diameter(cm) Tumor invasion* MIB-1 (Ki-67) 1 ACTH F 36 Hypertension NO ND 2 ACTH F 38 Amenorrhea NO <1% 3 ACTH F 43 Fatigue NO 2% 4 ACTH F 32 Weight gain NO <1% 5 ACTH F 36 Peripheral edema NO 1% 6 ACTH F 43 Weight gain NO 1% 7 ACTH F 41 Acne 12 1 NO 3% 8 ACTH F 15 Amenorrhea NO 2% 9 ACTH M 25 Weight gain NO <1% 10 ACTH F 36 Weight gain 72 1 NO <1% 11 ACTH F 45 Weight gain NO 1% 12 ACTH F 46 Weight gain NO 1% 13 ACTH F 40 Moon facies 55 5 YES 1% 14 ACTH F 36 Visual loss YES 4% 15 ACTH F 34 Weight gain NO 1% 16 ACTH M 36 Weight gain NO <1% 17 ACTH M 56 Fatigue NO 2% 18 ACTH M 25 Acne NO 1% 19 ACTH F 53 Hypertension NO 1% 20 ACTH F 46 Weight gain 6 4 YES <1 21 (GH+ACTH) F 62 Peripheral edema NO 4% 22 (GH+TSH) M 33 Visual loss YES <1% 23 M 23 Acromegaly YES 2% 24 (GH+TSH) M 42 Peripheral edema YES <1% 25 F 62 Acromegaly NO 1% 26 M 46 Acromegaly NO 1% 27 M 53 Acromegaly NO <1% 28 M 47 Acromegaly NO 1% 29 F 28 Acromegaly NO 1% 30 M 60 Acromegaly NO <1% 31 F 65 Acromegaly YES 1% 32 M 32 Acromegaly YES 2% 33 (GH+ACTH) F 46 Amenorrhea YES <1% 34 M 20 Acromegaly YES <1%

2 35 M 35 Acromegaly YES <1% 36 GH M 49 Acromegaly NO 2% 37 GH M 38 Acromegaly NO <1% 38 GH F 51 Acromegaly NO <1% 39 GH M 34 Acromegaly NO ND 40 GH F 50 Acromegaly NO <1% 41 GH M 45 Acromegaly NO ND 42 GH F 41 Acromegaly 48 3 NO <1% 43 GH M 49 Diabetes mellitus NO ND 44 GH M 27 Acromegaly YES <1% 45 GH F 60 Acromegaly NO 1% 46 GH F 33 Acromegaly NO ND 47 GH F 14 Headache NO 8% 48 GH F 31 Acromegaly NO ND 49 GH F 28 Acromegaly NO ND 50 GH F 18 Amenorrhea YES 2% 51 GH M 23 Acromegaly YES <1% 52 GH F 47 Acromegaly YES 1% 53 GH M 62 Acromegaly YES 2% 54 GH F 50 Acromegaly NO 1% 55 GH M 34 Acromegaly YES 4% 56 PRL M 30 Sexual dysfunction NO 2% 57 PRL M 45 Visual loss YES ND 58 PRL M 12 Headache NO <1% 59 PRL M 60 Headache 10 2 NO <1% 60 PRL M 53 Mammoplasia NO 1% 61 PRL M 68 Epistaxis YES 1% 62 PRL F 39 Amenorrhea 48 1 NO ND 63 PRL F 13 Amenorrhea NO <1% 64 PRL M 64 Visual loss NO 1% 65 PRL M 23 Visual loss 24 5 YES 3% 66 PRL F 15 Visual loss YES 5% 67 PRL M 30 Visual loss YES <1% 68 PRL M 25 Headache 24 4 YES 3% 69 PRL M 29 Sexual dysfunction YES <1% 70 PRL F 16 Amenorrhea NO 1% 71 PRL F 27 Amenorrhea NO 2% 72 PRL F 26 Amenorrhea NO 3% 73 PRL F 24 Amenorrhea NO 1% 74 PRL F 47 Visual loss YES <1% 75 PRL F 28 Amenorrhea NO 2% 76 M 28 Visual loss YES 2% 77 M 58 Headache NO 2% 78 F 48 Visual loss YES <1% 79 F 40 Amenorrhea YES <1% 80 M 48 Visual loss YES 1%

3 81 F 60 Visual loss YES <1% 82 M 44 Visual loss YES <1% 83 M 13 Visual loss YES 2% 84 M 31 Visual loss YES <1% 85 M 25 Visual loss YES 3% 86 M 34 Visual loss YES 3% 87 F 53 Visual loss YES <1% 88 F 22 Visual loss YES 2% 89 M 70 Fatigue NO 1% 90 M 57 Headache NO 2% 91 M 47 Visual loss YES 2% 92 M 59 Dizzy NO <1% 93 M 60 Dizzy NO <1% 94 M 25 Visual loss YES 2% 95 F 28 Amenorrhea YES 2% 96 GT M 52 Visual loss YES 1% 97 GT M 38 Visual loss YES ND 98 GT M 46 Visual loss YES <1% 99 GT M 40 Visual loss YES 2% 100 GT M 29 Visual loss YES <1% 101 GT M 71 Visual loss YES <1% 102 GT M 77 Visual loss 2 4 YES 1% 103 GT M 67 Visual loss YES 2% 104 GT M 34 Visual loss NO 1% 105 GT M 56 Fatigue NO <1% 106 GT M 38 Visual loss NO <1% 107 GT M 40 Visual loss 3 3 NO 2% 108 GT M 60 Headache NO ND 109 GT M 32 Visual loss NO 1% 110 GT M 24 Visual loss YES 2% 111 GT M 72 Visual loss NO 2% 112 GT M 62 Headache NO <1% 113 GT M 57 Visual loss NO 1% 114 GT M 47 Dizzy NO <1% 115 GT M 64 Headache NO <1% 116 TSH M 27 Fatigue YES <1% 117 TSH M 32 Palpitations YES 1% 118 TSH M 48 Visual loss NO <1% 119 TSH M 48 Palpitations NO 1% 120 TSH M 57 Palpitations NO 1% 121 TSH F 16 Amenorrhea NO <1%

4 122 TSH F 28 Thyromegaly NO <1% 123 TSH F 26 Thyromegaly 4 1 NO <1% 124 TSH M 27 Palpitations NO 1% 125 TSH M 63 Palpitations NO <1% * Invasive adenomas were defined as fulfilling 1 of 2 conditions: (1) Hardy s modified classification grade III, IV and/or stage C, D and E; (2) Knosp classification grade III and IV.

5 Supplementary information, Table S1B: 412 mutations identified in exome sequencing of 125 PAs. No. Subtype 1* ACTH Function Gene symbol Genomic position Transcript Exon CDS level Protein level ANKS3 chr16:g _ NM_ exon4 c.288_306del p.a96fs 2GGCCAGCATCCGGGCTGTG>- 2* ACTH 3* ACTH 4* ACTH 5* ACTH 6* 7* ACTH ACTH 8* ACTH 9 ACTH 10 ACTH FGF4 chr11:g c>a NM_ exon1 c.g277t p.g93c nonsense IGSF10 chr3:g g>c NM_ exon4 c.c3767g p.s1256x IL18RAP chr2:g g>t NM_ exon9 c.g1006t p.v336f STAG2 chrx:g g>c NM_ exon14 c.g1363c p.g455r USP29 chr19:g a>g NM_ exon4 c.a1354g p.n452d non chr15:g _50782 USP8 NM_ CTC>exon14 c.2151_2153del p.s718del nonsense ADGRV1 chr5:g c>t NM_ exon46 c.c9877t p.r3293x CCDC159 chr19:g >c NM_ exon5 c.311dupc p.a104fs ORC4 chr2:g t>c NM_ exon7 c.a524g p.d175g PPFIA3 chr19:g g>t NM_ exon21 c.g2731t p.a911s USP8 chr15:g c>g NM_ exon14 c.c2159g p.p720r VWF chr12:g g>c NM_ exon20 c.c2634g p.f878l chr19:g _11658 non CNN1 649GAAAGGAAACAAGGTGAAC NM_ GTGGGAGTGAA>exon5 c.399_428del p.133_143del CPM chr12:g t>c NM_ exon3 c.a254g p.d85g GTF3C3 chr2:g a>g NM_ exon13 c.t1729c p.s577p NME5 chr5:g g>a NM_ exon2 c.c19t p.p7s NRP2 chr2:g g>t NM_ exon3 c.g379t p.d127y nonsense OBSL1 chr2:g g>a NM_ exon14 c.c4390t p.q1464x PRKAA2 chr1:g t>g NM_ exon7 c.t1183g p.l395v UGT8 chr4:g t>c NM_ exon1 c.t50c p.i17t URGCP chr7:g c>t NM_ exon5 c.g1279a p.g427r USP8 chr15:g t>c NM_ exon14 c.t2152c p.s718p DYNC1H1 chr14:g a>g NM_ exon12 c.a3047g p.e1016g USP8 chr15:g c>g NM_ exon14 c.c2159g p.p720r APBB1 chr11:g a>t NM_ exon11 c.t1109a p.l370h GABRE chrx:g c>a NM_ exon9 c.g1228t p.v410f USP8 chr15:g t>c NM_ exon14 c.t2152c p.s718p ZNF846 chr19:g g>c NM_ exon3 c.c139g p.l47v NRAP chr10:g a>t NM_ exon26 c.t2904a p.h968q OR7A5 chr19:g >t NM_ exon1 c.933dupa p.g312fs OR7A5 chr19:g c>g NM_ exon1 c.g930c p.m310i USP8 chr15:g t>c NM_ exon14 c.t2152c p.s718p HIST1H1B chr6:g g>t NM_ exon1 c.c225a p.d75e splicing KIR2DL5A, chr19_gl000209_random: NM_ KIR2DL5B g.95373g>a exon7 c.858+1g>a PLCL2 chr3:g g>a NM_ exon2 c.g2218a p.g740r SIPA1 chr11:g t>a NM_ exon10 c.t2442a p.d814e USP8 chr15:g t>c NM_ exon14 c.t2152c p.s718p LY75,LY75 -CD302 chr2:g c>t NM_ exon31 c.g4387a p.e1463k NUFIP1 chr13:g t>g NM_ exon3 c.a518c p.h173p SLC24A2 chr9:g g>a NM_ exon5 c.c1286t p.a429v SOX4 chr6:g a>g NM_ exon1 c.a377g p.y126c non chr15:g _50782 USP8 NM_ CTC>exon14 c.2151_2153del p.718del USP8 chr15:g c>a NM_ exon14 c.c2159a p.p720q USH2A chr1:g t>c NM_ exon13 c.a2279g p.n760s CCDC178 chr18:g g>a NM_ exon22 c.c2531t p.s844f USP8 chr15:g t>c NM_ exon14 c.t2152c p.s718p RBM12 chr20:g a>- NM_ exon2 c.831delt p.l277fs

6 11 ACTH ACTH 20* ACTH 13* ACTH 14* ACTH 15* ACTH 16 ACTH 17 ACTH 18 ACTH ACTH (GH+ACTH) (GH+TSH) HIST1H2BA chr6:g g>a NM_ exon1 c.g202a p.v68i USP8 chr15:g c>a NM_ exon14 c.c2159a p.p720q chr2:g _23065 TRIP ACATGGCCCGTGAGCTGC NM_ CG>exon31 c.4017_4036del p.l1339fs TRIP12 chr2:g a>g NM_ exon31 c.t4016c p.l1339p MBLAC2 chr5:g a>g NM_ exon2 c.t794c p.l265p ANXA9 chr1:g a>g NM_ exon13 c.a866g p.n289s DCAF15 chr19:g c>t NM_ exon7 c.c1034t p.a345v non chr12:g _176575c IQSEC3 NM_ TCCGCCCTCGG>exon1 c.516_527del p.172_176del USP48 chr1:g c>t NM_ exon10 c.g1245a p.m415i TICRR chr15:g c>t NM_ exon20 c.c3328t p.h1110y WNK3 chrx:g a>g NM_ exon7 c.t1199c p.l400s ABCC12 chr16:g g>c NM_ exon27 c.c3787g p.q1263e BCOR chrx:g c>t NM_ exon4 c.g283a p.g95r DDX5 chr17:g t>c NM_ exon13 c.a1769g p.q590r LARP6 chr15:g c>g NM_ exon3 c.g310c p.a104p LGI1 chr10:g g>a NM_ exon4 c.g409a p.g137r MXRA5 chrx:g g>a NM_ exon4 c.c452t p.t151m POLR3B chr12:g c>- NM_ exon25 c.2787delc p.d929fs nonsense NR3C1 chr5:g g>a NM_ exon7 c.c1894t p.q632x chr5:g _14268 NR3C1 NM_ GATTTTCAGA>exon5 c.1534_1543del p.s512fs BRAF chr7:g a>t NM_ exon15 c.t1799a p.v600e FLG chr1:g c>g NM_ exon3 c.g1418c p.s473t KHDRBS2 chr6:g g>c NM_ exon6 c.c740g p.a247g NDUFV1 chr11:g a>g NM_ exon7 c.a911g p.n304s chr4:g _ YIPF7 NM_ AGGCTGCT>exon3 c.203_210del p.e68fs MAGEB10 chrx:g g>t NM_ exon3 c.g958t p.a320s HADHA chr2:g g>c NM_ exon8 c.c692g p.p231r IFT140 chr16:g >g NM_ exon19 c.2254dupc p.q752fs PHKB chr16:g c>a NM_ exon29 c.c2941a p.l981i PLIN2 chr9:g c>t NM_ exon5 c.g391a p.a131t splicing UPF1 chr19:g a>c NM_ exon11 c a>c non chrx:g _ FGD1 NM_ TCC>exon4 c.1044_1046del p.348_349del GPRIN3 chr4:g c>a NM_ exon2 c.g1828t p.d610y TAF5 chr10:g c>g NM_ exon2 c.c690g p.d230e UNKL chr16:g c>t NM_ exon3 c.g316a p.d106n AKNAD1 chr1:g a>g NM_ exon7 c.t1490c p.v497a CHD2 chr15:g a>g NM_ exon30 c.a3883g p.k1295e NR3C1 chr5:g c>g NM_ exon8 c.g2141c p.r714p non chr5:g _14267 NR3C1 NM_ ATT>exon6 c.1888_1890del p.630_630del RAP1GAP2 chr17:g g>c NM_ exon11 c.g869c p.g290a SETD2 chr3:g a>c NM_ exon4 c.t4562g p.l1521r TEDDM1 chr1:g g>c NM_ exon1 c.c813g p.s271r TADA2A chr17:g c>a NM_ exon11 c.c909a p.f303l non chr13:g _1144 GRK1 NM_ CTT>exon6 c.1275_1277del p.425_426del KIF14 chr1:g g>a NM_ exon30 c.c4615t p.r1539c MRPS9 chr2:g c>g NM_ exon2 c.c287g p.p96r SLCO1C1 chr12:g t>a NM_ exon12 c.t1594a p.c532s CCBL1 chr9:g t>c NM_ exon3 c.a104g p.q35r MAST4 chr5:g t>g NM_ exon5 c.t340g p.s114a nonsense PRAMEF19 chr1:g g>a NM_ exon3 c.c1021t p.r341x splicing SP100 chr2:g g>a NM_ exon28 c g>a SRF chr6:g g>a NM_ exon1 c.g338a p.g113e STX19 chr3:g a>t NM_ exon2 c.t530a p.m177k WDR33 chr2:g t>c NM_ exon16 c.a1834g p.m612v HNF1A chr12:g c>t NM_ exon7 c.c1424t p.p475l DYSF chr2:g g>a NM_ exon46 c.g5251a p.v1751m

7 (GH+TSH) (GH+ACTH) nonsense NEK8 chr17:g c>t NM_ exon9 c.c1297t p.q433x non PEG3 splicing USP7 chr16:g c>t NM_ exon6 c.563+1g>a ZNHIT2 chr11:g g>a NM_ exon1 c.c160t p.l54f ADRBK1 chr11:g a>c NM_ exon18 c.a1505c p.d502a ADRBK1 chr11:g a>c NM_ exon18 c.a1559c p.e520a ALDH5A1 chr6:g c>a NM_ exon6 c.c935a p.p312q nonsense CLASP2 chr3:g g>c NM_ exon15 c.c1289g p.s430x COL7A1 chr3:g c>g NM_ exon67 c.g5624c p.g1875a ENDOD1 chr11:g a>c NM_ exon2 c.a1120c p.s374r HDAC9 chr7:g g>a NM_ exon17 c.g2329a p.v777m HK2 chr2:g c>t NM_ exon12 c.c1789t p.p597s ICE1 chr5:g g>a NM_ exon13 c.g3274a p.g1092s MSANTD4 chr11:g c>t NM_ exon3 c.g472a p.e158k TCL1A chr14:g g>a NM_ exon2 c.c277t p.r93c non chr1:g _ TRNAU1AP NM_ CTT>exon2 c.51_53del p.17_18del CACNA1B chr9:g a>g NM_ exon7 c.a967g p.t323a CCDC155 chr19:g c>a NM_ exon14 c.c1060a p.l354i FOXN2 chr2:g a>g NM_ exon7 c.a1100g p.y367c IDS chrx:g g>- NM_ exon6 c.782delc p.p261fs nonsense MEN1 chr11:g c>t NM_ exon3 c.g608a p.w203x non chr7:g _ PEG10 NM_ AAA>exon2 c.27_29del p.9_10del RNF123 chr3:g g>a NM_ exon28 c.g2704a p.a902t LTBP1 chr2:g g>a NM_ exon17 c.g2296a p.g766r chr11:g _64577 MEN1 NM_ GCGGGTC>exon2 c.208_214del p.d70fs unknown KCP chr7:g c>t PAK1IP1 chr6:g t>c NM_ exon2 c.t218c p.i73t PLXNB2 chr22:g a>t NM_ exon34 c.t5219a p.l1740q SP100 chr2:g c>g NM_ exon28 c.c2532g p.h844q TBL1X chrx:g a>g NM_ exon14 c.a1216g p.i406v GNAS chr20:g a>t NM_ exon8 c.a680t p.q227l MED1 chr17:g t>c NM_ exon13 c.a1084g p.r362g MYO18B chr22:g g>a NM_ exon21 c.g3803a p.r1268h PITPNM2 chr12:g c>t NM_ exon12 c.g1684a p.v562i SOCS3 chr17:g g>a NM_ exon2 c.c491t p.a164v ADAMTSL4 chr1:g g>a NM_ exon18 c.g3047a p.r1016k DOCK8 chr9:g g>t NM_ exon12 c.g1297t p.v433f GNAS chr20:g a>t NM_ exon8 c.a680t p.q227l NFKB1 chr4:g a>g NM_ exon3 c.a73g p.i25v nonsense SLC25A48 chr5:g c>t NM_ exon4 c.c394t p.q132x GLB1L3 chr11:g t>c NM_ exon11 c.t979c p.s327p LMNTD1 chr12:g c>t NM_ exon5 c.g653a p.r218h MYH10 chr17:g t>g NM_ exon14 c.a1747c p.k583q non chr20:g _60640 TAF4 NM_ GGGCGCGGG>exon1 c.748_756del p.250_252del DESI2 chr1:g a>g NM_ exon3 c.a154g p.i52v GNAS chr20:g g>a NM_ exon8 c.g601a p.r201h MARK1 chr1:g g>t NM_ exon10 c.g1002t p.q334h MYH11 chr16:g g>a NM_ exon18 c.c2198t p.a733v OMG chr17:g c>g NM_ exon2 c.g411c p.k137n THOC6 chr16:g a>t NM_ exon6 c.a385t p.i129f XIRP2 chr2:g g>a NM_ exon7 c.g6385a p.v2129i splicing CREBBP chr16:g c>t NM_ exon23 c g>a c.4254_4255insg chr19:g >TGGCTCAGCAGCCTCCACTTC NM_ exon7 p.n1419delins AAGTGGAGGCTGCTG EVEAAEPN AGCCA RUFY2 chr10:g g>c NM_ exon18 c.c1889g p.a630g SLC9A3R1 chr17:g g>a NM_ exon3 c.g691a p.v231m

8 34 35 GNAS chr20:g g>a NM_ exon2 c.g145a p.g49r 36 GH SKIDA1 chr10:g >g NM_ exon4 c.1088dupc p.p363fs U2AF2 chr19:g c>g NM_ exon5 c.c439g p.q147e ZBP1 chr20:g a>g NM_ exon7 c.t905c p.f302s 37 GH 38 GH ADAM15 chr1:g c>t NM_ exon19 c.c2309t p.s770f 39 GH HAVCR2 chr5:g c>t NM_ exon2 c.g151a p.v51i JMJD4 chr1:g c>t NM_ exon5 c.g1036a p.e346k MGA chr15:g a>g NM_ exon19 c.a6691g p.r2231g TTC4 chr1:g t>c NM_ exon7 c.t836c p.l279p GNAS chr20:g a>t NM_ exon8 c.a680t p.q227l VPS37D chr7:g g>a NM_ exon2 c.g187a p.a63t 40 GH ZNF507 chr19:g a>- NM_ exon2 c.1775dela p.e592fs ARSD chrx:g c>t NM_ exon10 c.g1759a p.e587k 41 GH LAMA1 chr18:g c>t NM_ exon16 c.g2188a p.v730m AHCTF1 chr1:g t>c NM_ exon25 c.a3197g p.n1066s FFAR2 chr19:g g>a NM_ exon1 c.g89a p.r30q 42 GH MUC16 chr19:g g>a NM_ exon5 c.c32402t p.a10801v PARPBP chr12:g t>a NM_ exon3 c.t245a p.m82k SNX16 chr8:g g>c NM_ exon5 c.c600g p.f200l ACSS2 chr20:g a>g NM_ exon9 c.a722g p.y241c GH1 chr17:g g>- NM_ exon4 c.487delc p.l163fs 43 GH GRB10 chr7:g g>a NM_ exon10 c.c1069t p.l357f ITIH5 chr10:g g>a NM_ exon5 c.c610t p.p204s LRP10 chr14:g a>g NM_ exon5 c.a1208g p.n403s OR1S2 chr11:g g>a NM_ exon1 c.c538t p.l180f OR4A16 chr11:g g>a NM_ exon1 c.g149a p.s50n 44 GH GRB10 chr7:g t>a NM_ exon4 c.a463t p.t155s LTBP2 chr14:g c>a NM_ exon22 c.g3334t p.a1112s BCL11A chr2:g a>c NM_ exon4 c.t2323g p.c775g chr11:g _14497 COPB1 NM_ TTCT>exon13 c.1485_1488del p.k495fs ERC2 chr3:g g>a NM_ exon4 c.c1112t p.a371v LRRC7 chr1:g c>t NM_ exon19 c.c2390t p.s797l 45 GH PTPRS chr19:g c>t NM_ exon26 c.g4048a p.e1350k RAPSN chr11:g c>a NM_ exon2 c.g341t p.g114v RFX7 chr15:g >g NM_ exon9 c.3045dupc p.s1016fs SNUPN chr15:g c>t NM_ exon3 c.g202a p.d68n WIPI1 chr17:g c>t NM_ exon2 c.g133a p.v45m LXN chr3:g g>c NM_ exon5 c.c563g p.a188g 46 GH PIK3C2G chr12:g g>a NM_ exon3 c.g709a p.v237i nonsense ZNF417 chr19:g g>a NM_ exon3 c.c850t p.q284x 47 GH HECTD4 chr12:g c>t NM_ exon59 c.g8779a p.a2927t CSMD3 chr8:g a>g NM_ exon1 c.t2c p.m1t DGKZ chr11:g c>t NM_ exon5 c.c454t p.r152c 48 GH SLC22A6 chr11:g a>g NM_ exon4 c.t703c p.f235l GPN1 chr2:g g>a NM_ exon1 c.g67a p.e23k NPEPL1 chr20:g c>t NM_ exon1 c.c62t p.p21l ZNF578 chr19:g g>t NM_ exon6 c.g1116t p.k372n CASP8AP2 chr6:g t>- NM_ exon8 c.3234delt p.s1078fs 49 GH CLDN17 chr21:g a>g NM_ exon1 c.t392c p.i131t unknown SELT chr3:g a>g 50 GH MALT1 chr18:g c>g NM_ exon16 c.c2307g p.s769r MYH4 chr17:g t>c NM_ exon20 c.a2240g p.e747g

9 51 GH CLASP1 chr2:g g>a NM_ exon13 c.c1220t p.a407v 52 GH SLC13A1 chr7:g a>g NM_ exon4 c.t383c p.m128t STAP2 chr19:g c>t NM_ exon10 c.g943a p.g315r 53 GH FRMD6 chr14:g c>t NM_ exon7 c.c649t p.l217f 54 GH CCDC160 chrx:g c>g NM_ exon2 c.c290g p.s97c 55 GH RPS3 chr11:g c>g NM_ exon2 c.c128g p.p43r 56 PRL C11orf84 chr11:g t>c NM_ exon5 c.t767c p.f256s ABCA4 chr1:g g>c NM_ exon12 c.c1660g p.p554a GABRG2 chr5:g g>t NM_ exon9 c.g1223t p.c408f 57 PRL RBL1 chr20:g c>t NM_ exon22 c.g3092a p.r1031q UPRT chrx:g g>a NM_ exon7 c.g905a p.g302e USP40 chr2:g a>t NM_ exon30 c.t3548a p.i1183n UBFD1 chr16:g g>a NM_ exon3 c.g544a p.e182k 59 PRL MGP chr12:g c>t NM_ exon4 c.g182a p.r61h LRP2 chr2:g g>a NM_ exon8 c.c803t p.p268l non BBS10 chr12:g >agc NM_ exon1 c.137_138insgct p.l46delinsll 60 PRL BRCA1 chr17:g t>c NM_ exon9 c.a3013g p.n1005d IDE chr10:g a>t NM_ exon6 c.t826a p.s276t AP2M1 chr3:g g>t NM_ exon11 c.g1274t p.r425l GORAB chr1:g c>a NM_ exon5 c.c1109a p.s370y 61 PRL IARS chr9:g c>a NM_ exon30 c.g3215t p.g1072v MAP10 chr1:g t>c NM_ exon1 c.t2279c p.v760a USP11 chrx:g a>g NM_ exon2 c.a323g p.h108r COG7 chr16:g g>t NM_ exon17 c.c2191a p.r731s FLG2 chr1:g a>c NM_ exon3 c.t6552g p.s2184r 62 PRL KIF5A chr12:g c>t NM_ exon25 c.c2813t p.t938i TLDC2 chr20:g g>c NM_ exon3 c.g259c p.g87r ZCCHC24 chr10:g g>a NM_ exon3 c.c493t p.r165c 63 PRL TBX4 chr17:g t>c NM_ exon8 c.t1594c p.y532h splicing DFNB59 chr2:g a>g NM_ exon4 c.408-2a>g 64 PRL FAM120A chr9:g g>a NM_ exon9 c.g1559a p.s520n unknown PCSK6 chr15:g g>a SLC25A16 chr10:g t>c NM_ exon7 c.a718g p.t240a 65 PRL SCN10A chr3:g c>t NM_ exon14 c.g2156a p.r719q 66 PRL ZNF674 chrx:g t>c NM_ exon6 c.a553g p.n185d PRL PRL CAMSAP3 ADAMTSL1 chr19:g c>t chr9:g g>a NM_ NM_ exon11 exon2 c.c2032t c.g95a p.r678w p.r32q TBX5 ENKD1 chr12:g g>a chr16:g g>t NM_ NM_ exon8 exon4 c.c913t c.c557a p.r305c p.t186n ECE2 chr3:g a>g NM_ exon14 c.a1612g p.t538a 69 PRL nonsense IFT52 chr20:g g>t NM_ exon14 c.g1288t p.e430x SIDT2 chr11:g c>t NM_ exon24 c.c2285t p.a762v 71 PRL nonsense NDST1 chr5:g c>t NM_ exon14 c.c2452t p.r818x unknown FOXD1 chr5:g _ GCGGCGGCGGCCTGC> 72 PRL KCTD19 chr16:g c>t NM_ exon9 c.g1337a p.r446q NLGN4X chrx:g t>a NM_ exon6 c.a2026t p.s676c TAF1 chrx:g t>c NM_ exon15 c.t2471c p.i824t 73 PRL RBFOX1 chr16:g c>g NM_ exon8 c.c763g p.q255e AGT chr1:g c>t NM_ exon5 c.g1432a p.v478m 74 PRL 75 PRL 76 HDAC4 chr2:g c>t NM_ exon4 c.g271a p.a91t HGF chr7:g c>a NM_ exon16 c.g1774t p.d592y SEC24B chr4:g t>c NM_ exon2 c.t464c p.f155s TTN chr2:g t>g NM_ exon162 c.a62084c p.y20695s FAM131A chr3:g c>a NM_ exon6 c.c715a p.p239t unknown FAM58A chrx:g c>t SYK chr9:g a>g NM_ exon4 c.a716g p.q239r TTN chr2:g g>a NM_ exon154 c.c47029t p.r15677c ALS2 chr2:g a>c NM_ exon4 c.t715g p.l239v BRIP1 chr17:g a>t NM_ exon19 c.t2726a p.l909h C17orf96 chr17:g a>g NM_ exon1 c.t2c p.m1t COL12A1 chr6:g a>g NM_ exon38 c.t4666c p.c1556r FAM170B chr10:g c>g NM_ exon2 c.g130c p.g44r HRH1 chr3:g g>c NM_ exon2 c.g214c p.a72p HRH1 chr3:g g>c NM_ exon2 c.g222c p.l74f

10 SLCO1B1 chr12:g g>a NM_ exon3 c.g173a p.r58k GNA15 chr19:g g>a NM_ exon4 c.g557a p.r186h TMEM169 chr2:g a>t NM_ exon2 c.a188t p.d63v ADAM2 chr8:g c>t NM_ exon17 c.g1874a p.c625y EBPL chr13:g a>c NM_ exon2 c.t193g p.s65a SSPO chr7:g c>t NM_ exon55 c.c8165t p.s2722f BSN chr3:g c>a NM_ exon5 c.c3703a p.r1235s SPEG chr2:g g>t NM_ exon41 c.g9740t p.r3247l 95 UHRF1BP1 chr6:g >a NM_ exon14 c.2362dupa p.l787fs BTG1 chr12:g t>c NM_ exon1 c.a43g p.i15v CFAP46 chr10:g t>c NM_ exon7 c.a668g p.h223r 96 GT KIF5A chr12:g a>g NM_ exon20 c.a2246g p.y749c SCN1A chr2:g g>a NM_ exon20 c.c3950t p.t1317i TMX1 chr14:g c>t NM_ exon1 c.c29t p.p10l 97 GT C3 chr19:g c>t NM_ exon24 c.g3125a p.r1042q CTNND1 chr11:g c>a NM_ exon2 c.c127a p.r43s FRRS1 chr1:g >t NM_ exon5 c.357_358insa p.a120fs KRT83 chr12:g g>a NM_ exon1 c.c196t p.r66c RECK chr9:g t>g NM_ exon2 c.t106g p.l36v RYR1 chr19:g g>a NM_ exon17 c.g1841a p.r614h PPAPDC1B chr8:g g>t NM_ exon1 c.c68a p.a23d TTLL11 chr9:g c>t NM_ exon1 c.g361a p.e121k ARL5A chr2:g a>c NM_ exon4 c.t161g p.v54g C20orf194 chr20:g g>a NM_ exon24 c.c2099t p.a700v DLGAP5 chr14:g t>g NM_ exon10 c.a1260c p.e420d JAGN1 chr3:g a>g NM_ exon2 c.a200g p.q67r PRMT9 chr4:g t>a NM_ exon2 c.a247t p.i83l RAD21L1 chr20:g t>c NM_ exon12 c.t1348c p.s450p TSPAN6 chrx:g g>t NM_ exon1 c.c35a p.p12q ZDBF2 chr2:g a>g NM_ exon5 c.a6637g p.i2213v ARMC8 chr3:g a>g NM_ exon16 c.a1426g p.m476v GSG2 chr17:g c>a NM_ exon1 c.c1286a p.t429k RNF216 chr7:g t>a NM_ exon7 c.a1285t p.i429f UROC1 chr3:g g>a NM_ exon14 c.c1343t p.p448l ZMYM2 chr13:g c>a NM_ exon3 c.c6a p.d2e TRIP11 chr14:g t>a NM_ exon13 c.a4778t p.d1593v TUBGCP6 chr22:g g>a NM_ exon21 c.c4744t p.l1582f OPHN1 chrx:g a>c NM_ exon5 c.t346g p.l116v COL4A3 chr2:g g>c NM_ exon25 c.g1593c p.q531h KLHL35 chr11:g c>t NM_ exon4 c.g1333a p.v445m LRP1 chr12:g g>a NM_ exon24 c.g3928a p.a1310t nonsense MAGEA3 chrx:g g>a NM_ exon3 c.c373t p.r125x OR5D16 chr11:g t>a NM_ exon1 c.t295a p.c99s SLC9A8 chr20:g g>c NM_ exon1 c.g3c p.m1i ATXN7 chr3:g a>g NM_ exon8 c.a1273g p.t425a C9orf172 chr9:g g>a NM_ exon1 c.g2242a p.g748s CAPN1 chr11:g g>a NM_ exon14 c.g1588a p.a530t FAM208A chr3:g c>t NM_ exon1 c.g155a p.s52n nonsense GPR182 chr12:g g>a NM_ exon2 c.g236a p.w79x ILF3 chr19:g a>g NM_ exon5 c.a538g p.m180v PROM2 chr2:g g>a NM_ exon2 c.g280a p.v94m RUNX2 chr6:g c>t NM_ exon6 c.c1319t p.t440i GPR132 chr14:g g>a NM_ exon3 c.c134t p.t45m PJA2 chr5:g c>t NM_ exon4 c.g1246a p.g416r RNMTL1 chr17:g t>- NM_ exon4 c.1122delt p.g374fs TRAPPC6A chr19:g g>a NM_ exon2 c.c191t p.p64l TRIP12 chr2:g g>a NM_ exon19 c.c2237t p.s746l TUBGCP5 chr15:g g>c NM_ exon6 c.g541c p.d181h ZNF334 chr20:g c>t NM_ exon5 c.g1313a p.c438y IARS chr9:g c>t NM_ exon23 c.g2423a p.r808h NOS3 chr7:g c>a NM_ exon21 c.c2521a p.p841t PEX13 chr2:g c>- NM_ exon1 c.22delc p.p8fs

11 98 GT 99 GT 100 GT 101 GT 102 GT DOCK7 chr1:g g>c NM_ exon14 c.c1667g p.p556r LPCAT2 chr16:g t>c NM_ exon5 c.t653c p.f218s UTRN chr6:g t>c NM_ exon8 c.t745c p.s249p ASH1L chr1:g c>a NM_ exon11 c.g6365t p.c2122f CCDC134 chr22:g c>t NM_ exon5 c.c476t p.s159l KIAA0368 chr9:g t>c NM_ exon43 c.a4903g p.i1635v UBASH3B chr11:g g>a NM_ exon13 c.g1703a p.g568e MAP3K6 chr1:g >g NM_ exon1 c.104dupc p.p35fs RASSF9 chr12:g c>t NM_ exon2 c.g215a p.g72e EIF4E1B chr5:g a>g NM_ exon7 c.a362g p.d121g GOLM1 chr9:g a>g NM_ exon3 c.t242c p.l81p KCNH2 chr7:g c>t NM_ exon2 c.g235a p.a79t LRFN5 chr14:g a>t NM_ exon3 c.a218t p.n73i non SKIDA1 chr10:g >ggc NM_ exon4 c.678_679insgcc p.a227delinsa A DLG1 chr3:g t>a NM_ exon12 c.a1518t p.e506d EED chr11:g t>a NM_ exon11 c.t1148a p.v383d MCOLN1 chr19:g c>g NM_ exon5 c.c631g p.l211v INPP4A chr2:g a>g NM_ exon13 c.a1097g p.h366r non chr10:g _1261 LHPP NM_ GT 77069TTC>exon3 c.390_392del p.130_131del TMEM68 chr8:g t>c NM_ exon4 c.a358g p.m120v PNMAL1 chr19:g c>t NM_ exon2 c.g1292a p.r431h 105 GT TOR1B chr9:g g>c NM_ exon2 c.g232c p.g78r GT GT GDF9 ANKRD65 chr5:g g>t chr1:g c>t NM_ NM_ exon2 exon2 c.c877a c.g34a p.q293k p.e12k OASL FAM133A chr12:g a>t chrx:g g>t NM_ NM_ exon4 exon3 c.t818a c.g5t p.i273n p.g2v 109 GT CHMP7 chr8:g a>g NM_ exon3 c.a412g p.m138v 110 GT nonsense EXOSC2 chr9:g c>t NM_ exon3 c.c259t p.r87x KLHL41 chr2:g g>c NM_ exon1 c.g668c p.r223p C2orf54 chr2:g c>g NM_ exon2 c.g703c p.g235r splicing IMPACT chr18:g a>g NM_ exon7 c.491-2a>g MAP2 chr2:g a>g NM_ exon7 c.a2083g p.i695v 111 GT nonsense NLRP11 chr19:g g>a NM_ exon4 c.c265t p.r89x RRP12 chr10:g c>a NM_ exon22 c.g2635t p.a879s WNK1 chr12:g a>g NM_ exon1 c.a266g p.n89s ZAK chr2:g g>a NM_ exon20 c.g2347a p.a783t ZNF616 chr19:g t>c NM_ exon4 c.a2330g p.n777s CFAP74 chr1:g t>- NM_ exon13 c.1445dela p.k482fs 112 GT COPRS chr17:g t>g NM_ exon4 c.a549c p.e183d TPP2 chr13:g a>g NM_ exon22 c.a2630g p.y877c 113 GT CLPB chr11:g g>a NM_ exon4 c.c604t p.r202c OR4B1 chr11:g g>a NM_ exon1 c.g771a p.m257i ACACA chr17:g t>c NM_ exon12 c.a1426g p.n476d 114 GT BRPF3 chr6:g a>g NM_ exon11 c.a3247g p.k1083e GAS2L2 chr17:g a>g NM_ exon3 c.t674c p.m225t ZFHX2 chr14:g g>a NM_ exon9 c.c5984t p.p1995l 115 GT CHRNE chr17:g c>a NM_ exon10 c.g1112t p.r371l 117 TSH ABHD17B chr9:g g>a NM_ exon4 c.c691t p.h231y 118 TSH MRPS26 chr20:g g>t NM_ exon1 c.g52t p.a18s 119 TSH C1QTNF2 chr5:g c>a NM_ exon2 c.g238t p.v80f SYNPO2 chr4:g c>a NM_ exon4 c.c2117a p.p706q GLCE chr15:g g>a NM_ exon3 c.g52a p.a18t 120 TSH PSTPIP2 chr18:g a>t NM_ exon1 c.t30a p.f10l CCDC62 chr12:g t>g NM_ exon9 c.t986g p.m329r 121 TSH nonsense MAP7D3 chrx:g a>t NM_ exon5 c.t423a p.y141x SLC33A1 chr3:g t>c NM_ exon5 c.a1294g p.i432v 122 TSH WASF2 chr1:g t>c NM_ exon8 c.a985g p.m329v 123 TSH FAM98A chr2:g g>c NM_ exon3 c.c284g p.s95c SPTA1 chr1:g a>g NM_ exon52 c.t7160c p.f2387s ADCK3 chr1:g g>a NM_ exon15 c.g1810a p.e604k 125 TSH KBTBD13 chr15:g c>- NM_ exon1 c.684delc p.g228fs SF3B6 chr2:g t>c NM_ exon4 c.a307g p.t103a * indicates the ACTH-PAs samples included in our prior study

12 Supplementary information, Table S1C: Potential Drugs in 125 PAs Accession Number Target gene Type Status DB00398 BRAF small molecule FDA approved,investigational DB08881 BRAF small molecule FDA approved DB08896 BRAF small molecule FDA approved DB08912 BRAF small molecule FDA approved DB06999 BRAF small molecule experimental DB07000 BRAF small molecule experimental DB08553 BRAF small molecule experimental DB00381 CACNA1B small molecule FDA approved DB00661 CACNA1B small molecule FDA approved DB00996 CACNA1B small molecule FDA approved,investigational DB01202 CACNA1B small molecule FDA approved,investigational DB08838 CACNA1B small molecule experimental,investigational DB00686 FGF4 small molecule FDA approved DB06176 HDAC4 small molecule FDA approved,investigational DB07879 HDAC4 small molecule experimental DB08613 HDAC4 biotech experimental DB00013 LRP2 biotech FDA approved,investigational,withdrawn DB00030 LRP2 biotech FDA approved,experimental,investigational DB00071 LRP2 small molecule FDA approved DB00798 LRP2 small molecule FDA approved DB00945 NFKB1 small molecule FDA approved DB01041 NFKB1 small molecule FDA approved,investigational,withdrawn DB01411 NFKB1 small molecule FDA approved DB08814 NFKB1 small molecule FDA approved DB00360 NOS3 small molecule FDA approved,investigational DB01110 NOS3 small molecule FDA approved,investigational DB02044 NOS3 small molecule experimental DB02141 NOS3 small molecule experimental DB02911 NOS3 small molecule experimental DB03065 NOS3 small molecule experimental DB03707 NOS3 small molecule experimental DB03910 NOS3 small molecule experimental DB04559 NOS3 small molecule experimental DB07001 NOS3 small molecule experimental DB07244 NOS3 small molecule experimental DB07388 NOS3 small molecule experimental DB08018 NOS3 small molecule experimental DB08019 NOS3 small molecule experimental DB00025 VWF small molecule FDA approved,investigational DB08655 CREBBP small molecule experimental DB02587 GNAS small molecule experimental DB06843 GNAS small molecule experimental DB08696 MED1 small molecule experimental DB06834 SYK small molecule experimental DB07159 SYK small molecule experimental DB07194 SYK small molecule experimental DB08361 SYK small molecule experimental DB08846 SYK biotech investigational