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Somatic Mutations from Whole Exome Sequencing Analysis of the Patients with Biliary Tract Cancer

Article information

Genomics Inform. 2018;16.e35
Publication date (electronic) : 2018 December 28
doi : https://doi.org/10.5808/GI.2018.16.4.e35
Kyong-Ah Yoon1orcid_icon, Sang Myung Woo2,3,orcid_icon, Yun-Hee Kim3orcid_icon, Sun-Young Kong3,4orcid_icon, Sung-Sik Han2orcid_icon, Sang-Jae Park2orcid_icon, Woo Jin Lee2orcid_icon
1College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea
2Center for Liver Cancer, National Cancer Center, Goyang 10408, Korea
3Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang 10408, Korea
4Center for Diagnostic Oncology, National Cancer Center, Goyang 10408, Korea
*Corresponding author: Tel: +82-31-920-1733, Fax: +82-31-920-2798, E-mail: wsm@ncc.re.kr
Received 2018 December 10; Revised 2018 December 18; Accepted 2018 December 19.

Abstract

Biliary tract cancer (BTC) is a rare cancer and is associated with a poor prognosis. To understand the genetic characteristics of BTC, we analyzed whole-exome sequencing data and identified somatic mutations in patients with BTC. Tumors and matched blood or normal samples were obtained from seven patients with cholangiocarcinoma who underwent surgical resection. We discovered inactivating mutations of tumor suppressor genes, including APC, TP53, and ARID1A, in three patients. Activating mutations of KRAS and NRAS were also identified. Our analyses identified somatic mutations in Korean patients with BTC.

Keywords: biliary tract neoplasms; cholangiocarcinoma; somatic mutations; whole-exome sequencing

Introduction

Biliary tract cancer (BTC) is a heterogeneous group of cancers, including gallbladder cancer and extrahepatic and intrahepatic cholangiocarcinoma. BTC has been known as a disease with a poor prognosis, with few treatment options, regardless of its low incidence. In Korea, in 2014, the crude incidence rate of BTC was 11.2 per 100,000 men, and the crude mortality rate was 7.7 per 100,000 in both men and women [1]. Most patients have been diagnosed at an advanced stage. Although surgical resection is a curative treatment, recurrence of disease has been a clinical issue for patients after surgery [2]. Combination treatment with cisplatin plus gemcitabine has been reported as an appropriate treatment for patients with advanced BTC [3].

The genomic characteristics of BTC have been revealed through several studies using high-throughput next-generation sequencing technologies [4–6]. Jiao et al. [5] reported exome sequencing results of 32 patients with intrahepatic cholangiocarcinoma. Inactivating mutations in chromatin remodeling genes, including BAP1, ARID1A, and PBRM1, were identified with frequent mutations in IDH1 and IDH2. The oncogenes KRAS, PIK3CA, NRAS, GNAS, and ERBB2 were also significantly mutated in BTC [6]. Genomic analyses need to be performed in more BTCs to understand their biology and develop therapeutic strategies.

Here, we reported the whole-exome sequencing (WES) data of seven patients with BTC and analyzed their somatic mutations to compare the genetic features between patients.

Methods

Patients and ppub of clinical data

All patients had been enrolled in a phase II clinical trial at the National Cancer Center of Korea, as approved by the institutional review board (IRB No. NCCCTC-09-411). Enrolled patients had undergone surgical resection for BTC and were then treated with gemcitabine (1,000 mg/m2) as an adjuvant chemotherapy. The participants voluntarily agreed to donate the materials by signing an informed consent form. Tumor samples were obtained from surgical specimens and blood from seven patients with BTC.

Whole-exome sequencing and data analysis

We extracted genomic DNA from tissue specimens and blood samples using the QIAamp DNA mini kit according to the manufacturer’s protocol (Qiagen, Valencia, CA, USA). The concentration and quality of DNA were assessed using a NanoDrop spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA). WES was performed using the SureSelect Human All Exon V5 Target Enrichment kit (Agilent Technologies, Santa Clara, CA, USA) and processed on the HiSeq 2500 platform (Illumina, San Diego, CA, USA). The size and quantity of the libraries were checked using a 2100 Bioanalyzer (Agilent Technologies).

Sequence reads were aligned to the human reference genome hg19 using the Burrows-Wheeler Aligner–MEM algorithm [7]. The alignments were refined using the Genome Analysis Tool Kit (Broad Institute), and duplicate or low-quality reads were excluded [8]. Somatic mutations were called using Mutect and Strelka with default settings by comparing the sequences of tumor samples with those of matched normal samples [9, 10]. Only mutations showing a total read depth of greater than 30 in normal samples were considered for further analysis.

Results and Discussion

The demographic and clinical characteristics of the patients with BTC, including age, sex, cancer stage, recurrence, and survival, are summarized in Table 1.

Demographic information for patients with BTC

The patients included three females and four males with an average age of 60 years. Among the seven patients, five patients were defined as experiencing recurrence of disease after surgery.

We analyzed whole-exome sequencing data of matched tumor and normal DNA from the patients. The mean coverage depth for all samples is demonstrated in Supplementary Table 1. In total, 274 somatic mutations in protein-coding regions were called by both callers, Strelka and Mutect. The average number of somatic mutations per case was 34, showing a range of 25 to 59 (Fig. 1). We found two patients harboring activating mutations in KRAS, such as G12V and G13D (Table 2). Missense mutations in codon 61 of the NRAS gene and codon 766 of the NTRK1 gene were also detected in two patients. A nonsense mutation in TP53 was found in a patient, and APC was inactivated by frameshift mutations in two patients. A patient harbored a frameshift mutation that was caused by a deletion of G in the ARID1A gene. Detailed information on the somatic mutations is provided in Supplementary Table 2.

Fig. 1

Somatic mutation count for patients with biliary tract cancer.

Somatic mutations that were annotated with cancer gene census

This study analyzed somatic mutations using WES in a limited number of patients with BTC. To understand the genetic features of BTC, more data need to be analyzed from more patients.

SUPPLEMENTARY INFORMATION

Supplementary data including two tables can be found with this article online at https://doi.org/10.5808/GI.2018.16.4.e35.

Coverage Information

Detailed information on total somatic mutations

Acknowledgments

This work was supported by a National Cancer Center Research Grant 1510690 to W.G. Lee.

Notes

Conflicts of Interest

No potential conflicts of interest relevant to this article was reported.

Authors’ contribution

Conceptualization: KAY, SMW, WJL

Data curation: KAY, SMW

Formal analysis: KAY, SMW, YHK, SYK, WJL

Funding acquisition: SMW, WJL

Investigation: KAY, SMW, SSH, SJP, WJL

Methodology: KAY, SMW, YHK, SYK

Project administration: KAY, SMW, WJL

Software: KAY

Supervision: KAY, SMW, SSH, SJP, WJL

Validation: KAY, SMW, YHK, SYK, WJL

Visualization: K.-A,Y., S.M.W.

Writing – original draft: K.-A,Y., S.M.W

Writing – review and editing: KAY, SMW, YHK, SYK, SSH, SJP, WJL

References

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3. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273–1281.
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5. Jiao Y, Pawlik TM, Anders RA, Selaru FM, Streppel MM, Lucas DJ, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet 2013;45:1470–1473.
6. Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, et al. Genomic spectra of biliary tract cancer. Nat Genet 2015;47:1003–1010.
7. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009;25:1754–1760.
8. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010;20:1297–1303.
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Article information Continued

Copyright © 2018 by the Korea Genome Organization

It is identical to the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/).

Supplementary Table 1.

Coverage Information

Sample X1 X5 X10 X15 X20 X25 X30 X50 Total bases aligned(bases) Mean coverage depth
BTC_1N 99.96% 99.77% 99.22% 98.14% 96.33% 93.69% 90.19% 69.94% 6,034,974,927 80.99
BTC_1T 99.97% 99.90% 99.71% 99.38% 98.84% 98.03% 96.92% 89.02% 9,863,779,665 132.38
BTC_2N 99.86% 99.66% 99.15% 98.17% 96.48% 93.95% 90.45% 69.62% 5,978,637,815 80.24
BTC_2T 99.88% 99.79% 99.63% 99.38% 99.00% 98.46% 97.71% 92.10% 11,086,728,430 148.79
BTC_4N 99.97% 99.80% 99.30% 98.32% 96.67% 94.26% 91.07% 72.14% 6,345,622,329 85.16
BTC_4T 99.98% 99.90% 99.72% 99.43% 98.98% 98.33% 97.44% 91.14% 10,760,737,151 144.41
BTC_5N 99.86% 99.62% 98.95% 97.66% 95.53% 92.44% 88.40% 66.57% 5,823,253,443 78.15
BTC_5T 99.87% 99.78% 99.57% 99.21% 98.65% 97.88% 96.83% 89.50% 10,599,020,827 142.24
BTC_6N 99.87% 99.67% 99.16% 98.14% 96.43% 93.80% 90.22% 69.15% 5,968,127,744 80.09
BTC_6T 99.88% 99.79% 99.63% 99.37% 98.99% 98.43% 97.66% 91.94% 10,923,830,027 146.60
BTC_7N 99.97% 99.78% 99.25% 98.21% 96.48% 93.96% 90.63% 71.11% 6,186,543,991 83.03
BTC_7T 99.98% 99.88% 99.66% 99.27% 98.66% 97.75% 96.48% 87.79% 9,956,458,889 133.62
BTC_8N 99.97% 99.76% 99.17% 97.97% 95.96% 93.09% 89.35% 68.81% 5,998,051,912 80.50
BTC_8T 99.98% 99.89% 99.68% 99.34% 98.82% 98.06% 97.01% 89.49% 10,131,605,777 135.97

Supplementary Table 2

Detailed information on total somatic mutations

Patient ID Hugo_Sym Entrez_Gen Chromoso Start_position End_position Variant_Classification Reference_ Tumor_Seq cDNA_Change Codon_ChaProtein_Ch Description
BTC-1 APC 324 5 112174759 112174760 Frame_Shift_Del AG - c.3468_3469delAG c.(3466-34p.EE1156fs adenomatous polyposis coli
BTC-1 KRTAP19-6 337973 21 31914024 31914024 Nonsense_Mutation G T c.129C>A c.(127-129)p.C43* keratin associated protein 19-6
BTC-1 PABPC4L 132430 4 135121319 135121319 Nonsense_Mutation G A c.856C>T c.(856-858)p.R286* poly(A) binding protein, cytoplasmic 4-like
BTC-1 APC 324 5 112175951 112175951 Nonsense_Mutation G T c.4660G>T c.(4660-46p.E1554* adenomatous polyposis coli
BTC-1 C6orf222 389384 6 36290159 36290159 Nonsense_Mutation G C c.1532C>G c.(1531-15p.S511* chromosome 6 open reading frame 222
BTC-1 ABCA1 19 9 107553269 107553269 Nonsense_Mutation G C c.5861C>G c.(5860-58p.S1954* ATP-binding cassette, sub-family A (ABC1), member 1
BTC-1 AMER1 139285X 63412530 63412530 Nonsense_Mutation G A c.637C>T c.(637-639)p.Q213* APC membrane recruitment protein 1
BTC-1 MFAP2 4237 1 17302995 17302995 Splice_Site C A c.e5+1 microfibrillar-associated protein 2
BTC-1 HIF3A 64344 19 46825222 46825222 Splice_Site C T c.1334C>T c.(1333-13p.S445L hypoxia inducible factor 3, alpha subunit
BTC-1 MAP3K13 9175 3 185155234 185155234 Splice_Site G C c.e3-1 mitogen-activated protein kinase kinase kinase 13
BTC-1 DAB2IP 153090 9 124329507 124329507 Splice_Site G A c.40G>A c.(40-42)Gap.E14K DAB2 interacting protein
BTC-1 ABCC2 1244 10 101591752 101591752 Missense_Mutation C T c.3122C>T c.(3121-31p.A1041V ATP-binding cassette, sub-family C (CFTR/MRP), member 2
BTC-1 ACE 1636 17 61570945 61570945 Missense_Mutation G A c.1339G>A c.(1339-134p.V447M angiotensin I converting enzyme
BTC-1 ACTN2 88 1 236899007 236899007 Missense_Mutation C T c.770C>T c.(769-771)p.A257V actinin, alpha 2
BTC-1 ACTN4 81 19 39207832 39207832 Missense_Mutation G A c.1019G>A c.(1018-10p.R340H actinin, alpha 4
BTC-1 ACVR1B 91 12 52379016 52379016 Missense_Mutation C A c.864C>A c.(862-864)p.N288K activin A receptor, type IB
BTC-1 ADCY5 111 3 123166420 123166420 Missense_Mutation C T c.973G>A c.(973-975)p.A325T adenylate cyclase 5
BTC-1 ADCY8 114 8 131949376 131949376 Missense_Mutation C T c.1424G>A c.(1423-14p.R475H adenylate cyclase 8 (brain)
BTC-1 ANO3 63982 11 26463533 26463533 Missense_Mutation T C c.115T>C c.(115-117)p.C39R anoctamin 3
BTC-1 APC2 10297 19 1457029 1457029 Missense_Mutation G A c.994G>A c.(994-996)p.A332T adenomatosis polyposis coli 2
BTC-1 AQPEP 0 5 115298621 115298621 Missense_Mutation G A c.307G>A c.(307-309)p.V103M
BTC-1 AUTS2 26053 7 69364311 69364311 Missense_Mutation C T c.349C>T c.(349-351)p.R117C autism susceptibility candidate 2
BTC-1 C11orf63 79864 11 122775018 122775018 Missense_Mutation C T c.730C>T c.(730-732)p.R244C chromosome 11 open reading frame 63
BTC-1 C5orf42 65250 5 37153858 37153858 Missense_Mutation T A c.8195A>T c.(8194-81p.D2732V chromosome 5 open reading frame 42
BTC-1 CDH2 1000 18 25572711 25572711 Missense_Mutation C T c.1159G>A c.(1159-11p.A387T cadherin 2, type 1, N-cadherin (neuronal)
BTC-1 CHST9 83539 18 24628462 24628462 Missense_Mutation C T c.127G>A c.(127-129)p.V43M carbohydrate (N-acetylgalactosamine 4-0) sulfotransferase 9
BTC-1 CYP11B1 1584 8 143956558 143956558 Missense_Mutation C T c.1426G>A c.(1426-14p.V476M cytochrome P450, family 11, subfamily B, polypeptide 1
BTC-1 DNAH10 196385 12 124341718 124341718 Missense_Mutation G A c.6200G>A c.(6199-62p.R2067H dynein, axonemal, heavy chain 10
BTC-1 DSCAM 1826 21 41559851 41559851 Missense_Mutation C T c.2617G>A c.(2617-26p.E873K Down syndrome cell adhesion molecule
BTC-1 ELF3 1999 1 201983140 201983140 Missense_Mutation G A c.989G>A c.(988-990)p.S330N E74-like factor 3 (ets domain transcription factor, epithelial-specific )
BTC-1 FGD3 89846 9 95738639 95738639 Missense_Mutation C T c.101C>T c.(100-102)p.A34V FYVE, RhoGEF and PH domain containing 3
BTC-1 FUBP3 8939 9 133493210 133493210 Missense_Mutation G A c.594G>A c.(592-594)p.M198I far upstream element (FUSE) binding protein 3
BTC-1 HAND1 9421 5 153855452 153855452 Missense_Mutation G T c.562C>A c.(562-564)p.P188T heart and neural crest derivatives expressed 1
BTC-1 KCNS2 3788 8 99440299 99440299 Missense_Mutation G A c.92G>A c.(91-93)cGp.R31H potassium voltage-gated channel, delayed-rectifier, subfamily S, member 2
BTC-1 KIAA1429 25962 8 95503865 95503865 Missense_Mutation C G c.5081G>C c.(5080-50p.R1694T KIAA1429
BTC-1 KRTAP19-1 337882 21 31852374 31852374 Missense_Mutation C T c.263G>A c.(262-264)p.G88D keratin associated protein 19-1
BTC-1 LRP1B 53353 2 141004693 141004693 Missense_Mutation G T c.13286C>A c.(13285-1p.P4429Q low density lipoprotein receptor-related protein 1B
BTC-1 LRRK2 120892 12 40689336 40689336 Missense_Mutation G T c.2986G>T c.(2986-29p.D996Y leucine-rich repeat kinase 2
BTC-1 MAP2K1 5604 15 66727455 66727455 Missense_Mutation G C c.171G>C c.(169-171)p.K57N mitogen-activated protein kinase kinase 1
BTC-1 MBTD1 54799 17 49296318 49296318 Missense_Mutation A C c.376T>G c.(376-378)p.L126V mbt domain containing 1
BTC-1 MUC19 283463 12 40820354 40820354 Missense_Mutation G A c.332G>A c.(331-333)p.R111H mucin 19, oligomeric
BTC-1 MYLK2 85366 20 30419645 30419645 Missense_Mutation G A c.1564G>A c.(1564-15p.V522I myosin light chain kinase 2
BTC-1 PCDH17 27253 13 58207860 58207860 Missense_Mutation G A c.1180G>A c.(1180-11p.G394R protocadherin 17
BTC-1 PLIN4 729359 19 4510530 4510530 Missense_Mutation G A c.3400C>T c.(3400-34p.R1134C perilipin 4
BTC-1 PRRC2B 84726 9 134322013 134322013 Missense_Mutation A G c.839A>G c.(838-840)p.D280G proline-rich coiled-coil 2B
BTC-1 RBM15 64783 1 110883546 110883546 Missense_Mutation T G c.1519T>G c.(1519-15p.W507G RNA binding motif protein 15
BTC-1 RP1-139D8 0 6 42123292 42123292 Missense_Mutation G T c.14G>T c.(13-15)aGp.S5I
BTC-1 SDK1 221935 7 4273010 4273010 Missense_Mutation C T c.5891C>T c.(5890-58p.A1964V sidekick cell adhesion molecule 1
BTC-1 SPRY2 10253 13 80911584 80911584 Missense_Mutation G C c.257C>G c.(256-258)p.P86R sprouty homolog 2 (Drosophila)
BTC-1 ST6GALNA 81849 1 77509964 77509964 Missense_Mutation C A c.337C>A c.(337-339)p.Q113K ST6 (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 5
BTC-1 SYT3 84258 19 51135883 51135883 Missense_Mutation C T c.334G>A c.(334-336)p.G112R synaptotagmin III
BTC-1 TADA2A 6871 17 35837062 35837062 Missense_Mutation G C c.1307G>C c.(1306-13p.R436T transcriptional adaptor 2A
BTC-1 TGM2 7052 20 36793594 36793594 Missense_Mutation C T c.7G>A c.(7-9)Gagp.E3K transglutaminase 2
BTC-1 TMEM184B 25829 22 38643871 38643871 Missense_Mutation T C c.97A>G c.(97-99)Acp.T33A transmembrane protein 184B
BTC-1 TRPC1 7220 3 142499703 142499703 Missense_Mutation A T c.792A>T c.(790-792)p.Q264H transient receptor potential cation channel, subfamily C, member 1
BTC-1 TSHZ3 57616 19 31770589 31770589 Missense_Mutation G C c.110C>G c.(109-111)p.A37G teashirt zinc finger homeobox 3
BTC-1 TSPAN14 81619 10 82271948 82271948 Missense_Mutation T G c.499T>G c.(499-501)p.Y167D tetraspanin 14
BTC-1 ZFR 51663 5 32395347 32395347 Missense_Mutation C T c.1897G>A c.(1897-18p.E633K zinc finger RNA binding protein
BTC-1 ZFYVE26 23503 14 68264958 68264958 Missense_Mutation C A c.2021G>T c.(2020-20p.G674V zinc finger, FYVE domain containing 26
BTC-2 EPHA2 1969 1 16464447 16464447 Frame_Shift_Del G - c.1213delC c.(1213-12p.H405fs EPH receptor A2
BTC-2 LGI4 163175 19 35617610 35617610 Nonsense_Mutation C T c.863G>A c.(862-864)p.W288* leucine-rich repeat LGI family, member 4
BTC-2 EPHA2 1969 1 16456720 16456720 Splice_Site C T c.e15+1 EPH receptor A2
BTC-2 C17orf97 400566 17 260315 260315 Missense_Mutation G T c.182G>T c.(181-183)p.G61V chromosome 17 open reading frame 97
BTC-2 CAMK2N1 55450 1 20810156 20810156 Missense_Mutation G A c.223C>T c.(223-225)p.P75S calcium/calmodulin-dependent protein kinase II inhibitor 1
BTC-2 CNBD1 168975 8 88249206 88249206 Missense_Mutation G A c.637G>A c.(637-639)p.V213M cyclic nucleotide binding domain containing 1
BTC-2 COL14A1 7373 8 121292323 121292323 Missense_Mutation G A c.3631G>A c.(3631-36p.E1211K collagen, type XIV, alpha 1
BTC-2 FBN3 84467 19 8201283 8201283 Missense_Mutation C T c.1334G>A c.(1333-13p.G445D fibrillin 3
BTC-2 FIGN 55137 2 164467285 164467285 Missense_Mutation C A c.1057G>T c.(1057-10p.D353Y fidgetin
BTC-2 FLNB 2317 3 58118580 58118580 Missense_Mutation A G c.4529A>G c.(4528-45p.H1510R filamin B, beta
BTC-2 INO80D 54891 2 206884534 206884534 Missense_Mutation G A c.1334C>T c.(1333-13p.A445V INO80 complex subunit D
BTC-2 INTS1 26173 7 1544069 1544069 Missense_Mutation C G c.233G>C c.(232-234)p.C78S integrator complex subunit 1
BTC-2 KCNIP1 30820 5 170145809 170145809 Missense_Mutation G A c.109G>A c.(109-111)p.E37K Kv channel interacting protein 1
BTC-2 KIAA1549 57670 7 138603864 138603864 Missense_Mutation G A c.508C>T c.(508-510)p.R170W KIAA1549
BTC-2 LGALS9 3965 17 25975970 25975970 Missense_Mutation G A c.934G>A c.(934-936)p.V312M lectin, galactoside-binding, soluble, 9
BTC-2 PLEKHG1 57480 6 151152904 151152904 Missense_Mutation G A c.2657G>A c.(2656-26p.R886H pleckstrin homology domain containing, family G (with RhoGef domain) member 1
BTC-2 PNCK 139728X 152937421 152937421 Missense_Mutation C G c.328G>C c.(328-330)p.E110Q pregnancy up-regulated nonubiquitous CaM kinase
BTC-2 PPDPF 79144 20 62152924 62152924 Missense_Mutation G A c.115G>A c.(115-117)p.A39T pancreatic progenitor cell differentiation and proliferation factor
BTC-2 PROKR2 128674 20 5282783 5282783 Missense_Mutation C T c.1058G>A c.(1057-10p.R353H prokineticin receptor 2
BTC-2 RP11-429E 0 20 60294088 60294088 Missense_Mutation G A c.139C>T c.(139-141)p.L47F
BTC-2 SCN5A 6331 3 38645514 38645514 Missense_Mutation C T c.1579G>A c.(1579-15p.G527R sodium channel, voltage-gated, type V, alpha subunit
BTC-2 SLC35F1 222553 6 118556702 118556702 Missense_Mutation G A c.380G>A c.(379-381)p.R127Q solute carrier family 35, member F1
BTC-2 SLC9A6 10479X 135067950 135067950 Missense_Mutation C T c.289C>T c.(289-291)p.R97C solute carrier family 9, subfamily A (NHE6, cation proton antiporter 6), member 6
BTC-2 SPARC 6678 5 151047056 151047056 Missense_Mutation T C c.557A>G c.(556-558)p.N186S secreted protein, acidic, cysteine-rich (osteonectin)
BTC-2 TLL2 7093 10 98144434 98144434 Missense_Mutation C G c.2104G>C c.(2104-21p.V702L tolloid-like 2
BTC-2 TRIM58 25893 1 248028097 248028097 Missense_Mutation C T c.607C>T c.(607-609)p.R203W tripartite motif containing 58
BTC-2 TSPAN16 26526 19 11408947 11408947 Missense_Mutation A G c.199A>G c.(199-201)p.I67V tetraspanin 16
BTC-2 TSSK2 23617 22 19119034 19119034 Missense_Mutation A C c.122A>C c.(121-123)p.K41T testis-specific serine kinase 2
BTC-2 VAV2 7410 9 136635595 136635595 Missense_Mutation G A c.2222C>T c.(2221-22p.S741L vav 2 guanine nucleotide exchange factor
BTC-2 ZC2HC1B 153918 6 144224199 144224199 Missense_Mutation C T c.508C>T c.(508-510)p.P170S zinc finger, C2HC-type containing 1B
BTC-2 ZFP69B 65243 1 40928270 40928270 Missense_Mutation G A c.614G>A c.(613-615)p.G205D ZFP69 zinc finger protein B
BTC-2 ZNF423 23090 16 49669726 49669726 Missense_Mutation C T c.3337G>A c.(3337-33p.A1113T zinc finger protein 423
BTC-4 ARID1A 8289 1 27023831 27023831 Frame_Shift_Del G - c.937delG c.(937-939)p.G314fs AT rich interactive domain 1A (SWI-like)
BTC-4 TULP1 7287 6 35480415 35480415 Splice_Site C G c.e2+1 tubby like protein 1
BTC-4 ACOXL 55289 2 111850501 111850501 Missense_Mutation T A c.1590T>A c.(1588-15p.H530Q acyl-CoA oxidase-like
BTC-4 CACNA1H 8912 16 1270626 1270626 Missense_Mutation C A c.6676C>A c.(6676-66p.L2226M calcium channel, voltage-dependent, T type, alpha 1H subunit
BTC-4 CATSPERB 79820 14 92174496 92174496 Missense_Mutation T A c.455A>T c.(454-456)p.D152V catsper channel auxiliary subunit beta
BTC-4 CDKN2A 1029 9 21971035 21971035 Missense_Mutation T C c.170A>G c.(169-171)p.D57G cyclin-dependent kinase inhibitor 2A
BTC-4 CES3 23491 16 67006620 67006620 Missense_Mutation G A c.408G>A c.(406-408)p.M136I carboxylesterase 3
BTC-4 CLCNKA 1187 1 16349137 16349137 Missense_Mutation G A c.23G>A c.(22-24)cGp.R8H chloride channel, voltage-sensitive Ka
BTC-4 COL22A1 169044 8 139890232 139890232 Missense_Mutation C T c.419G>A c.(418-420)p.R140H collagen, type XXII, alpha 1
BTC-4 CRISPLD1 83690 8 75941665 75941665 Missense_Mutation G A c.1364G>A c.(1363-13p.R455Q cysteine-rich secretory protein LCCL domain containing 1
BTC-4 DAW1 164781 2 228767727 228767727 Missense_Mutation T C c.550T>C c.(550-552)p.S184P dynein assembly factor with WDR repeat domains 1
BTC-4 DYSF 8291 2 71797023 71797023 Missense_Mutation G A c.2938G>A c.(2938-294p.G980R dysferlin
BTC-4 ELN 2006 7 73461047 73461047 Missense_Mutation C T c.593C>T c.(592-594)p.P198L elastin
BTC-4 FAM135B 51059 8 139165339 139165339 Missense_Mutation A G c.1379T>C c.(1378-13p.L460P family with sequence similarity 135, member B
BTC-4 FAM208B 54906 10 5803432 5803432 Missense_Mutation C A c.7172C>A c.(7171-71p.T2391K family with sequence similarity 208, member B
BTC-4 GPR65 8477 14 88478153 88478153 Missense_Mutation G A c.962G>A c.(961-963)p.R321H G protein-coupled receptor 65
BTC-4 GUCY1A3 2982 4 156643206 156643206 Missense_Mutation A T c.1733A>T c.(1732-17p.H578L guanylate cyclase 1, soluble, alpha 3
BTC-4 HID1 283987 17 72959068 72959068 Missense_Mutation T A c.496A>T c.(496-498)p.S166C HID1 domain containing
BTC-4 HIP1 3092 7 75189111 75189111 Missense_Mutation G A c.1300C>T c.(1300-13p.R434W huntingtin interacting protein 1
BTC-4 IRF3 3661 19 50167939 50167939 Missense_Mutation T C c.157A>G c.(157-159)p.I53V interferon regulatory factor 3
BTC-4 KCNB1 3745 20 48098906 48098906 Missense_Mutation C T c.112G>A c.(112-114)p.G38R potassium voltage-gated channel, Shab-related subfamily, member 1
BTC-4 KCNT1 57582 9 138664603 138664603 Missense_Mutation C T c.2051C>T c.(2050-20p.T684M potassium channel, subfamily T, member 1
BTC-4 LLGL1 3996 17 18143990 18143990 Missense_Mutation C T c.2305C>T c.(2305-23p.R769W lethal giant larvae homolog 1 (Drosophila)
BTC-4 LPHN1 22859 19 14294398 14294398 Missense_Mutation G A c.17C>T c.(16-18)gCp.A6V latrophilin 1
BTC-4 MARS 4141 12 57906626 57906626 Missense_Mutation A T c.1846A>T c.(1846-184p.I616F methionyl-tRNA synthetase
BTC-4 MBTPS1 8720 16 84093019 84093019 Missense_Mutation G A c.2719C>T c.(2719-27p.R907W membrane-bound transcription factor peptidase, site 1
BTC-4 PDC 5132 1 186413572 186413572 Missense_Mutation G A c.280C>T c.(280-282)p.R94C phosducin
BTC-4 PTTG1IP 754 21 46285352 46285352 Missense_Mutation C G c.126G>C c.(124-126)p.Q42H pituitary tumor-transforming 1 interacting protein
BTC-4 RBBP6 5930 16 24581304 24581304 Missense_Mutation A T c.3293A>T c.(3292-32p.E1098V retinoblastoma binding protein 6
BTC-4 RBBP7 5931X 16871823 16871823 Missense_Mutation T A c.872A>T c.(871-873)p.D291V retinoblastoma binding protein 7
BTC-4 RDH10 157506 8 74234976 74234976 Missense_Mutation A G c.833A>G c.(832-834)p.K278R retinol dehydrogenase 10 (all-trans)
BTC-4 RFX8 731220 2 102018971 102018971 Missense_Mutation C T c.1172G>A c.(1171-11p.R391Q RFX family member 8, lacking RFX DNA binding domain
BTC-4 SEMA6D 80031 15 48058143 48058143 Missense_Mutation C T c.1505C>T c.(1504-15p.A502V sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6D
BTC-4 SLC6A17 388662 1 110734682 110734682 Missense_Mutation C A c.953C>A c.(952-954)p.A318D solute carrier family 6 (neutral amino acid transporter), member 17
BTC-4 TMEM205 374882 19 11455971 11455971 Missense_Mutation G A c.221C>T c.(220-222)p.S74L transmembrane protein 205
BTC-4 TRIM4 89122 7 99506284 99506284 Missense_Mutation T C c.719A>G c.(718-720)p.N240S tripartite motif containing 4
BTC-5 HMCN1 83872 1 186057081 186057084 Frame_Shift_Del GTAT - c.9381_9384delGT c.(9379-93p.QY3127fs hemicentin 1
BTC-5 UPP2 151531 2 158977957 158977958 Frame_Shift_Ins - T c.491_492insT c.(490-495)p.V165fs uridine phosphorylase 2
BTC-5 FNTB 2342 14 65511053 65511053 Nonsense_Mutation C T c.847C>T c.(847-849)p.R283* farnesyltransferase, CAAX box, beta
BTC-5 ACSM2A 123876 16 20482871 20482871 Nonsense_Mutation C T c.754C>T c.(754-756)p.Q252* acyl-CoA synthetase medium-chain family member 2A
BTC-5 PSD3 23362 8 18430175 18430175 Nonsense_Mutation C A c.2647G>T c.(2647-264p.E883* pleckstrin and Sec7 domain containing 3
BTC-5 COL11A1 1301 1 103467527 103467527 Splice_Site T C c.e24-2 collagen, type XI, alpha 1
BTC-5 AC007405. 0 2 171570595 171570595 Missense_Mutation G C c.359C>G c.(358-360)p.A120G
BTC-5 AC009365. 0 7 132412557 132412557 Missense_Mutation G A c.409G>A c.(409-411)p.V137I
BTC-5 ADAM21 8747 14 70924614 70924614 Missense_Mutation G T c.398G>T c.(397-399)p.R133L ADAM metallopeptidase domain 21
BTC-5 APOOL 139322X 84329077 84329077 Missense_Mutation G C c.560G>C c.(559-561)p.S187T apolipoprotein O-like
BTC-5 ASPM 259266 1 197074062 197074062 Missense_Mutation T C c.4319A>G c.(4318-43p.Q1440R asp (abnormal spindle) homolog, microcephaly associated (Drosophila)
BTC-5 ATP7A 538X 77301051 77301051 Missense_Mutation C A c.4208C>A c.(4207-42p.S1403Y ATPase, Cu++ transporting, alpha polypeptide
BTC-5 ATP8B4 79895 15 50288883 50288883 Missense_Mutation C G c.580G>C c.(580-582)p.G194R ATPase, class I, type 8B, member 4
BTC-5 CACNA1A 773 19 13616812 13616812 Missense_Mutation C A c.227G>T c.(226-228)p.R76L calcium channel, voltage-dependent, P/Q type, alpha 1A subunit
BTC-5 CCDC175 729665 14 60031860 60031860 Missense_Mutation T C c.625A>G c.(625-627)p.I209V coiled-coil domain containing 175
BTC-5 CCL18 6362 17 34398340 34398340 Missense_Mutation G A c.209G>A c.(208-210)p.C70Y chemokine (C-C motif) ligand 18 (pulmonary and activation-regulated)
BTC-5 CD163 9332 12 7651580 7651580 Missense_Mutation A G c.662T>C c.(661-663)p.I221T CD163 molecule
BTC-5 COL21A1 81578 6 55922544 55922544 Missense_Mutation G T c.2785C>A c.(2785-27p.Q929K collagen, type XXI, alpha 1
BTC-5 CSMD3 114788 8 113697935 113697935 Missense_Mutation G C c.2182C>G c.(2182-21p.P728A CUB and Sushi multiple domains 3
BTC-5 CXorf28 1E+08X 3189922 3189922 Missense_Mutation C T c.49C>T c.(49-51)Ccp.P17S chromosome X open reading frame 28
BTC-5 DMXL2 23312 15 51791693 51791693 Missense_Mutation T A c.3728A>T c.(3727-37p.D1243V Dmx-like 2
BTC-5 GAS2 2620 11 22747946 22747946 Missense_Mutation G A c.376G>A c.(376-378)p.D126N growth arrest-specific 2
BTC-5 GPR98 84059 5 89939702 89939702 Missense_Mutation C T c.2636C>T c.(2635-26p.T879M G protein-coupled receptor 98
BTC-5 HOXA4 3201 7 27170310 27170310 Missense_Mutation G T c.43C>A c.(43-45)Ccp.P15T homeobox A4
BTC-5 HP 3240 16 72090131 72090131 Missense_Mutation C T c.77C>T c.(76-78)aCp.T26M haptoglobin
BTC-5 ICAM5 7087 19 10405259 10405259 Missense_Mutation T C c.2173T>C c.(2173-21p.C725R intercellular adhesion molecule 5, telencephalin
BTC-5 KIAA1244 57221 6 138576619 138576619 Missense_Mutation C T c.817C>T c.(817-819)p.H273Y KIAA1244
BTC-5 KIF21B 23046 1 200948693 200948693 Missense_Mutation C T c.4130G>A c.(4129-41p.R1377Q kinesin family member 21B
BTC-5 KRTAP21-1 337977 21 32127554 32127554 Missense_Mutation C A c.143G>T c.(142-144)p.C48F keratin associated protein 21-1
BTC-5 LCA10 0X 153152431 153152431 Missense_Mutation G T c.311G>T c.(310-312)p.R104L
BTC-5 MAP1B 4131 5 71490888 71490888 Missense_Mutation C G c.1706C>G c.(1705-17p.T569R microtubule-associated protein 1B
BTC-5 MLK4 0 1 233518335 233518335 Missense_Mutation C T c.2989C>T c.(2989-29p.P997S
BTC-5 NBEAL2 23218 3 47041430 47041430 Missense_Mutation C A c.3841C>A c.(3841-384p.Q1281K neurobeachin-like 2
BTC-5 NFATC2 4773 20 50140482 50140482 Missense_Mutation C T c.298G>A c.(298-300)p.A100T nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2
BTC-5 NRAS 4893 1 115256529 115256529 Missense_Mutation T C c.182A>G c.(181-183)p.Q61R neuroblastoma RAS viral (v-ras) oncogene homolog
BTC-5 OLFML2B 25903 1 161967939 161967939 Missense_Mutation T A c.1153A>T c.(1153-11p.S385C olfactomedin-like 2B
BTC-5 OSBPL5 114879 11 3143583 3143583 Missense_Mutation G A c.295C>T c.(295-297)p.L99F oxysterol binding protein-like 5
BTC-5 PCDHB1 29930 5 140432385 140432385 Missense_Mutation G A c.1330G>A c.(1330-13p.D444N protocadherin beta 1
BTC-5 PCSK5 5125 9 78936474 78936474 Missense_Mutation G A c.3940G>A c.(3940-394p.E1314K proprotein convertase subtilisin/kexin type 5
BTC-5 PGR 5241 11 100998706 100998706 Missense_Mutation C T c.1096G>A c.(1096-10p.D366N progesterone receptor
BTC-5 PHIP 55023 6 79695085 79695085 Missense_Mutation T G c.2521A>C c.(2521-25p.S841R pleckstrin homology domain interacting protein
BTC-5 PIK3C2G 5288 12 18435656 18435656 Missense_Mutation C A c.641C>A c.(640-642)p.P214H phosphatidylinositol-4-phosphate 3-kinase, catalytic subunit type 2 gamma
BTC-5 PRKCD 5580 3 53219710 53219710 Missense_Mutation A T c.979A>T c.(979-981)p.M327L protein kinase C, delta
BTC-5 SEC14L2 23541 22 30802345 30802345 Missense_Mutation C G c.145C>G c.(145-147)p.L49V SEC14-like 2 (S. cerevisiae)
BTC-5 SEMA6A 57556 5 115782872 115782872 Missense_Mutation C T c.2530G>A c.(2530-25p.E844K sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6A
BTC-5 SKIV2L2 23517 5 54635888 54635888 Missense_Mutation G T c.566G>T c.(565-567)p.S189I superkiller viralicidic activity 2-like 2 (S. cerevisiae)
BTC-5 TAF1L 138474 9 32631848 32631848 Missense_Mutation G A c.3730C>T c.(3730-37p.R1244W TAF1 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 210kDa-like
BTC-5 TEX15 56154 8 30702546 30702546 Missense_Mutation T G c.3988A>C c.(3988-39p.K1330Q testis expressed 15
BTC-5 TLR8 51311X 12939230 12939230 Missense_Mutation G C c.2125G>C c.(2125-21p.E709Q toll-like receptor 8
BTC-5 TMEM200A 114801 6 130762039 130762039 Missense_Mutation A G c.472A>G c.(472-474)p.I158V transmembrane protein 200A
BTC-5 TMEM80 283232 11 703112 703112 Missense_Mutation G T c.469G>T c.(469-471)p.V157F transmembrane protein 80
BTC-5 TRPM6 140803 9 77377993 77377993 Missense_Mutation C A c.3594G>T c.(3592-35p.K1198N transient receptor potential cation channel, subfamily M, member 6
BTC-5 TSPYL5 85453 8 98290039 98290039 Missense_Mutation G A c.34C>T c.(34-36)Cgp.R12C TSPY-like 5
BTC-6 AMIGO2 347902 12 47471598 47471598 Missense_Mutation A C c.1188T>G c.(1186-11p.F396L adhesion molecule with Ig-like domain 2
BTC-6 BIRC6 57448 2 32712788 32712788 Missense_Mutation A T c.7888A>T c.(7888-78p.I2630F baculoviral IAP repeat containing 6
BTC-6 BZW1 9689 2 201680210 201680210 Missense_Mutation T G c.211T>G c.(211-213)p.F71V basic leucine zipper and W2 domains 1
BTC-6 CD200R1 131450 3 112648303 112648303 Missense_Mutation G A c.185C>T c.(184-186)p.P62L CD200 receptor 1
BTC-6 CRYBG3 131544 3 97593426 97593426 Missense_Mutation G T c.3388G>T c.(3388-33p.G1130W beta-gamma crystallin domain containing 3
BTC-6 DEAF1 10522 11 694992 694992 Missense_Mutation A G c.56T>C c.(55-57)gTp.V19A DEAF1 transcription factor
BTC-6 EFCAB5 374786 17 28295933 28295933 Missense_Mutation A T c.315A>T c.(313-315)p.E105D EF-hand calcium binding domain 5
BTC-6 FSIP2 401024 2 186671383 186671383 Missense_Mutation G A c.17350G>A c.(17350-1p.A5784T fibrous sheath interacting protein 2
BTC-6 GAPVD1 26130 9 128064438 128064438 Missense_Mutation A T c.362A>T c.(361-363)p.N121I GTPase activating protein and VPS9 domains 1
BTC-6 IQSEC2 23096X 53349985 53349985 Missense_Mutation C T c.337G>A c.(337-339)p.D113N IQ motif and Sec7 domain 2
BTC-6 KDM5A 5927 12 427378 427378 Missense_Mutation C T c.2791G>A c.(2791-27p.G931R lysine (K)-specific demethylase 5A
BTC-6 LPAR3 23566 1 85279695 85279695 Missense_Mutation T C c.896A>G c.(895-897)p.D299G lysophosphatidic acid receptor 3
BTC-6 NLRP1 22861 17 5462767 5462767 Missense_Mutation A G c.1249T>C c.(1249-12p.W417R NLR family, pyrin domain containing 1
BTC-6 OR6B3 150681 2 240984973 240984973 Missense_Mutation C A c.517G>T c.(517-519)p.V173F olfactory receptor, family 6, subfamily B, member 3
BTC-6 OTUD6A 139562X 69282627 69282627 Missense_Mutation G C c.253G>C c.(253-255)p.E85Q OTU deubiquitinase 6A
BTC-6 PTPRH 5794 19 55715264 55715264 Missense_Mutation T C c.772A>G c.(772-774)p.T258A protein tyrosine phosphatase, receptor type, H
BTC-6 RAD50 10111 5 131927660 131927660 Missense_Mutation T G c.1727T>G c.(1726-17p.L576R RAD50 homolog (S. cerevisiae)
BTC-6 RB1 5925 13 49039417 49039417 Missense_Mutation G C c.2402G>C c.(2401-24p.G801A retinoblastoma 1
BTC-6 SAMD9L 219285 7 92763376 92763376 Missense_Mutation C T c.1909G>A c.(1909-19p.A637T sterile alpha motif domain containing 9-like
BTC-6 SERINC5 256987 5 79454696 79454696 Missense_Mutation C G c.949G>C c.(949-951)p.G317R serine incorporator 5
BTC-6 ST6GALNA 81849 1 77515950 77515950 Missense_Mutation T A c.679T>A c.(679-681)p.S227T ST6 (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 5
BTC-6 TMEM47 83604X 34657486 34657486 Missense_Mutation A G c.245T>C c.(244-246)p.L82P transmembrane protein 47
BTC-6 TRIM41 90933 5 180651595 180651595 Missense_Mutation T C c.596T>C c.(595-597)p.L199P tripartite motif containing 41
BTC-6 WDSUB1 151525 2 160139525 160139525 Missense_Mutation G A c.56C>T c.(55-57)gCp.A19V WD repeat, sterile alpha motif and U-box domain containing 1
BTC-6 ZC3H13 23091 13 46616352 46616352 Missense_Mutation C T c.286G>A c.(286-288)p.V96M zinc finger CCCH-type containing 13
BTC-7 CCDC18 343099 1 93705341 93705341 Nonsense_Mutation G T c.2866G>T c.(2866-28p.E956* coiled-coil domain containing 18
BTC-7 KANSL1 284058 17 44115975 44115975 Nonsense_Mutation G A c.2281C>T c.(2281-22p.R761* KAT8 regulatory NSL complex subunit 1
BTC-7 PLEKHG2 64857 19 39912773 39912773 Nonsense_Mutation G T c.1522G>T c.(1522-15p.E508* pleckstrin homology domain containing, family G (with RhoGef domain) member 2
BTC-7 ZNF546 339327 19 40520465 40520465 Nonsense_Mutation C T c.1288C>T c.(1288-12p.R430* zinc finger protein 546
BTC-7 SI 6476 3 164760855 164760855 Nonsense_Mutation C A c.1996G>T c.(1996-19p.G666* sucrase-isomaltase (alpha-glucosidase)
BTC-7 SLITRK2 84631X 144904042 144904042 Nonsense_Mutation T A c.99T>A c.(97-99)tgp.C33* SLIT and NTRK-like family, member 2
BTC-7 CNTNAP5 129684 2 125367471 125367471 Missense_Mutation C T c.1847C>T c.(1846-184p.P616L contactin associated protein-like 5
BTC-7 DNMT3A 1788 2 25467461 25467461 Missense_Mutation T C c.946A>G c.(946-948)p.I316V DNA (cytosine-5-)-methyltransferase 3 alpha
BTC-7 DSG4 147409 18 28971077 28971077 Missense_Mutation G A c.721G>A c.(721-723)p.D241N desmoglein 4
BTC-7 EPC1 80314 10 32560813 32560813 Missense_Mutation T C c.2038A>G c.(2038-204p.T680A enhancer of polycomb homolog 1 (Drosophila)
BTC-7 ESM1 11082 5 54277867 54277867 Missense_Mutation A T c.409T>A c.(409-411)p.Y137N endothelial cell-specific molecule 1
BTC-7 F13A1 2162 6 6266956 6266956 Missense_Mutation C A c.406G>T c.(406-408)p.V136F coagulation factor XIII, A1 polypeptide
BTC-7 FCRL3 115352 1 157665154 157665154 Missense_Mutation G A c.1376C>T c.(1375-13p.A459V Fc receptor-like 3
BTC-7 FUT1 2523 19 49254093 49254093 Missense_Mutation C A c.446G>T c.(445-447)p.W149L fucosyltransferase 1 (galactoside 2-alpha-L-fucosyltransferase, H blood group)
BTC-7 GLI3 2737 7 42005951 42005951 Missense_Mutation C A c.2720G>T c.(2719-27p.S907I GLI family zinc finger 3
BTC-7 HEATR1 55127 1 236721708 236721708 Missense_Mutation C T c.5033G>A c.(5032-50p.C1678Y HEAT repeat containing 1
BTC-7 KLHL24 54800 3 183368493 183368493 Missense_Mutation A G c.349A>G c.(349-351)p.M117V kelch-like family member 24
BTC-7 KLHL9 55958 9 21333179 21333179 Missense_Mutation C G c.1680G>C c.(1678-16p.M560I kelch-like family member 9
BTC-7 KMT2A 4297 11 118392628 118392628 Missense_Mutation T A c.11660T>A c.(11659-1p.M3887K lysine (K)-specific methyltransferase 2A
BTC-7 KRAS 3845 12 25398284 25398284 Missense_Mutation C A c.35G>T c.(34-36)gGp.G12V Kirsten rat sarcoma viral oncogene homolog
BTC-7 LPP 4026 3 188326976 188326976 Missense_Mutation C T c.457C>T c.(457-459)p.P153S LIM domain containing preferred translocation partner in lipoma
BTC-7 LRP1B 53353 2 141707920 141707920 Missense_Mutation A G c.3020T>C c.(3019-30p.F1007S low density lipoprotein receptor-related protein 1B
BTC-7 MSH3 4437 5 79950739 79950739 Missense_Mutation G A c.193G>A c.(193-195)p.A65T mutS homolog 3
BTC-7 NCOR1 9611 17 16049747 16049747 Missense_Mutation T C c.1025A>G c.(1024-10p.Y342C nuclear receptor corepressor 1
BTC-7 NIPBL 25836 5 37064917 37064917 Missense_Mutation A G c.8338A>G c.(8338-834p.S2780G Nipped-B homolog (Drosophila)
BTC-7 NTRK1 4914 1 156851340 156851340 Missense_Mutation G A c.2297G>A c.(2296-22p.R766Q neurotrophic tyrosine kinase, receptor, type 1
BTC-7 PELP1 27043 17 4575146 4575146 Missense_Mutation C T c.3140G>A c.(3139-314p.G1047E proline, glutamate and leucine rich protein 1
BTC-7 RELN 5649 7 103183183 103183183 Missense_Mutation A T c.6666T>A c.(6664-66p.H2222Q reelin
BTC-7 SPTBN1 6711 2 54871578 54871578 Missense_Mutation G A c.4124G>A c.(4123-41p.R1375Q spectrin, beta, non-erythrocytic 1
BTC-7 SUSD2 56241 22 24583685 24583685 Missense_Mutation G T c.2038G>T c.(2038-204p.A680S sushi domain containing 2
BTC-7 ZNF14 7561 19 19822422 19822422 Missense_Mutation C A c.1668G>T c.(1666-16p.E556D zinc finger protein 14
BTC-8 APC 324 5 112175952 112175952 Frame_Shift_Del A - c.4661delA c.(4660-46p.E1554fs adenomatous polyposis coli
BTC-8 LMO7 4008 13 76408475 76408475 Nonsense_Mutation C T c.2479C>T c.(2479-24p.Q827* LIM domain 7
BTC-8 TP53 7157 17 7574003 7574003 Nonsense_Mutation G A c.1024C>T c.(1024-10p.R342* tumor protein p53
BTC-8 DUXA 503835 19 57670637 57670637 Nonsense_Mutation G A c.190C>T c.(190-192)p.Q64* double homeobox A
BTC-8 MMS22L 253714 6 97676947 97676947 Nonsense_Mutation C T c.1862G>A c.(1861-18p.W621* MMS22-like, DNA repair protein
BTC-8 KIF15 56992 3 44843467 44843467 Splice_Site G C c.e13+1 kinesin family member 15
BTC-8 ABCA9 10350 17 67025361 67025361 Missense_Mutation T G c.1453A>C c.(1453-14p.N485H ATP-binding cassette, sub-family A (ABC1), member 9
BTC-8 ACSS1 84532 20 25004233 25004233 Missense_Mutation C T c.676G>A c.(676-678)p.G226R acyl-CoA synthetase short-chain family member 1
BTC-8 ADAMTS6 11174 5 64595872 64595872 Missense_Mutation G A c.1310C>T c.(1309-13p.A437V ADAM metallopeptidase with thrombospondin type 1 motif, 6
BTC-8 ADORA1 134 1 203098180 203098180 Missense_Mutation A G c.211A>G c.(211-213)p.I71V adenosine A1 receptor
BTC-8 AOC3 8639 17 41006705 41006705 Missense_Mutation C T c.1841C>T c.(1840-184p.P614L amine oxidase, copper containing 3
BTC-8 CPZ 8532 4 8603105 8603105 Missense_Mutation G A c.344G>A c.(343-345)p.R115Q carboxypeptidase Z
BTC-8 DACT3 147906 19 47151783 47151783 Missense_Mutation G C c.1846C>G c.(1846-184p.L616V dishevelled-binding antagonist of beta-catenin 3
BTC-8 ENPP2 5168 8 120577135 120577135 Missense_Mutation A C c.1097T>G c.(1096-10p.V366G ectonucleotide pyrophosphatase/phosphodiesterase 2
BTC-8 INO80D 54891 2 206870153 206870153 Missense_Mutation C A c.2023G>T c.(2023-20p.A675S INO80 complex subunit D
BTC-8 IRX3 79191 16 54319378 54319378 Missense_Mutation T C c.415A>G c.(415-417)p.T139A iroquois homeobox 3
BTC-8 KRAS 3845 12 25398281 25398281 Missense_Mutation C T c.38G>A c.(37-39)gGp.G13D Kirsten rat sarcoma viral oncogene homolog
BTC-8 KRT73 319101 12 53004589 53004589 Missense_Mutation C T c.1141G>A c.(1141-114p.A381T keratin 73
BTC-8 LAX1 54900 1 203743063 203743063 Missense_Mutation G A c.451G>A c.(451-453)p.A151T lymphocyte transmembrane adaptor 1
BTC-8 MATN4 8785 20 43927089 43927089 Missense_Mutation G A c.1147C>T c.(1147-114p.R383W matrilin 4
BTC-8 NAB1 4664 2 191524551 191524551 Missense_Mutation G A c.649G>A c.(649-651)p.E217K NGFI-A binding protein 1 (EGR1 binding protein 1)
BTC-8 NPR3 4883 5 32712527 32712527 Missense_Mutation C A c.645C>A c.(643-645)p.F215L natriuretic peptide receptor 3
BTC-8 OTOG 340990 11 17655819 17655819 Missense_Mutation A G c.7288A>G c.(7288-72p.T2430A otogelin
BTC-8 PCDHGB6 56100 5 140788665 140788665 Missense_Mutation G A c.896G>A c.(895-897)p.G299D protocadherin gamma subfamily B, 6
BTC-8 POLA1 5422X 24906154 24906154 Missense_Mutation G A c.4061G>A c.(4060-40p.R1354H polymerase (DNA directed), alpha 1, catalytic subunit
BTC-8 RALGAPA1 253959 14 36096402 36096402 Missense_Mutation T A c.5272A>T c.(5272-52p.M1758L Ral GTPase activating protein, alpha subunit 1 (catalytic)
BTC-8 RIPK2 8767 8 90792331 90792331 Missense_Mutation G C c.882G>C c.(880-882)p.L294F receptor-interacting serine-threonine kinase 2
BTC-8 ROBO1 6091 3 78710287 78710287 Missense_Mutation A G c.2213T>C c.(2212-22p.I738T roundabout, axon guidance receptor, homolog 1 (Drosophila)
BTC-8 ROBO2 6092 3 77657029 77657029 Missense_Mutation C A c.3217C>A c.(3217-32p.P1073T roundabout, axon guidance receptor, homolog 2 (Drosophila)
BTC-8 SHISA8 440829 22 42310285 42310285 Missense_Mutation C A c.286G>T c.(286-288)p.A96S shisa family member 8
BTC-8 SMARCA2 6595 9 2104152 2104152 Missense_Mutation T C c.3275T>C c.(3274-32p.L1092P SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2
BTC-8 SSTR1 6751 14 38678956 38678956 Missense_Mutation G A c.362G>A c.(361-363)p.R121H somatostatin receptor 1
BTC-8 SYN3 8224 22 33265027 33265027 Missense_Mutation C T c.547G>A c.(547-549)p.G183S synapsin III
BTC-8 TROVE2 6738 1 193046115 193046115 Missense_Mutation C G c.1021C>G c.(1021-10p.L341V TROVE domain family, member 2
BTC-8 USH2A 7399 1 215844423 215844423 Missense_Mutation C T c.14024G>A c.(14023-14p.R4675K Usher syndrome 2A (autosomal recessive, mild)
BTC-8 USH2A 7399 1 216062042 216062042 Missense_Mutation G C c.7949C>G c.(7948-79p.P2650R Usher syndrome 2A (autosomal recessive, mild)
BTC-8 XCR1 2829 3 46062623 46062623 Missense_Mutation G A c.817C>T c.(817-819)p.R273C chemokine (C motif) receptor 1
BTC-8 ZSCAN20 7579 1 33960845 33960845 Missense_Mutation C A c.2901C>A c.(2899-29p.F967L zinc finger and SCAN domain containing 20

Fig. 1

Fig. 1

Somatic mutation count for patients with biliary tract cancer.

Table 1

Demographic information for patients with BTC

Patient ID Sex Age (y) Histologic type RFS duration (mo) OS duration (mo) Total No. of somatic mutations
BTC-1 Male 57 Cholangiocarcinoma 58.2 58.6 59
BTC-2 Female 70 Cholangiocarcinoma 4.1 50.1 32
BTC-4 Male 51 Cholangiocarcinoma 1.9 6.1 36
BTC-5 Female 68 Cholangiocarcinoma 39.8 39.8 53
BTC-6 Female 69 Cholangiocarcinoma 18 38.5 25
BTC-7 Male 55 Cholangiocarcinoma 8.4 23.3 31
BTC-8 Male 55 Cholangiocarcinoma 8.9 15.8 38

BTC, biliary tract cancer; RFS, recurrence-free survival; OS, overall survival.

Table 2

Somatic mutations that were annotated with cancer gene census

Hugo_Symbol Sample ID Variant classification cDNA change Protein change
APC BTC-1 Nonsense c.4660G>T p.E1554*
APC BTC-8 Frameshift c.4661delA p.E1554fs
ARID1A BTC-4 Frameshift c.937delG p.G314fs
DNMT3A BTC-7 Missense c.946A>G p.I316V
ELN BTC-4 Missense c.593C>T p.P198L
HIP1 BTC-4 Missense c.1300C>T p.R434W
KDM5A BTC-6 Missense c.2791G>A p.G931R
KIAA1549 BTC-2 Missense c.508C>T p.R170W
KRAS BTC-7 Missense c.35G>T p.G12V
KRAS BTC-8 Missense c.38G>A p.G13D
LPP BTC-7 Missense c.457C>T p.P153S
NRAS BTC-5 Missense c.182A>G p.Q61R
NTRK1 BTC-7 Missense c.2297G>A p.R766Q
RB1 BTC-6 Missense c.2402G>C p.G801A
RBM15 BTC-1 Missense c.1519T>G p.W507G
TP53 BTC-8 Nonsense c.1024C>T p.R342*