Mutation frequencies in representative cancer-associated genes in colorectal cancers with or without APC and other WNT/β-catenin pathway alterations from the Cancer Genome Atlas (TCGA)
Gene
Entire cohort (n = 534)
Quadruple altered (n = 95)
APC only altered (n = 300)
Triple altered (n = 44)
Quadruple wild type (n = 95)
P
EGFR
19 (3.6)
6 (6.3)
5 (1.7)
2 (4.5)
2 (2.1)
0.09
ERBB2
20 (3.7)
8 (8.4)
8 (2.7)
3 (6.8)
1 (1.1)
0.02
ERBB3
32 (6.0)
15 (15.8)
8 (2.7)
3 (6.8)
3 (3.2)
0.00001
ERBB4
62 (11.6)
19 (20)
18 (6)
8 (18.2)
4 (4.2)
0.00002
FGFR2
22 (4.1)
5 (5.3)
4 (1.3)
3 (6.8)
4 (4.2)
0.06
FGFR3
18 (3.4)
10 (10.5)
3 (1)
3 (6.8)
1 (1.1)
0.00002
RET
30 (5.6)
11 (11.6)
9 (3)
6 (13.6)
2 (2.1)
0.0003
ALK
41 (7.7)
16 (16.8)
8 (2.7)
4 (9.1)
4 (4.2)
< 0.00001
NTRK3
29 (5.4)
8 (8.4)
7 (2.3)
4 (9.1)
3 (3.2)
0.02
NF1
43 (8.1)
15 (15.8)
8 (2.7)
6 (13.6)
2 (2.1)
< 0.00001
RASA1
29 (5.4)
9 (9.5)
6 (2)
3 (6.8)
2 (2.1)
0.004
PIK3CB
16 (3.0)
6 (6.3)
2 (0.7)
3 (6.8)
0
0.001
PIK3R1
38 (7.1)
15 (15.8)
9 (3)
3 (6.8)
5 (5.3)
0.0001
PTEN
48 (9.0)
10 (10.5)
10 (3.3)
10 (22.7)
4 (4.2)
< 0.00001
PPP2R1A
15 (2.8)
7 (7.4)
3 (1)
3 (6.8)
1 (1.1)
0.001
TSC1
21 (3.9)
9 (9.5)
4 (1.3)
4 (9.1)
1 (1.1)
0.0001
MTOR
46 (8.6)
15 (15.8)
11 (3.7)
6 (13.6)
9 (9.5)
0.0003
MSH2
27 (5.1)
15 (15.8)
3 (1)
3 (6.8)
0
< 0.00001
MSH6
29 (5.4)
14 (14.7)
3 (1)
3 (6.8)
4 (4.2)
< 0.00001
PMS2
16 (3.0)
8 (8.4)
4 (1.3)
2 (4.5)
0
0.001
MLH1
24 (4.5)
7 (7.4)
5 (1.7)
7 (15.9)
3 (3.2)
0.00004
POLE
50 (9.4)
24 (25.3)
6 (2)
3 (6.8)
3 (3.2)
< 0.00001
BRCA1
19 (3.6)
9 (9.5)
3 (1)
3 (6.8)
1 (1.1)
0.00009
BRCA2
69 (12.9)
19 (20)
12 (4)
6 (13.6)
1 (1.1)
< 0.00001
ATM
107 (20.0)
23 (24.2)
25 (8.3)
12 (27.2)
10 (10.5)
0.00002
BRIP1
25 (4.7)
11 (11.6)
3 (1)
0
4 (4.2)
0.00002
CDK12
42 (7.9)
13 (13.7)
7 (2.3)
8 (18.2)
3 (3.2)
< 0.00001
LRP1B
190 (35.6)
29 (30.5)
41 (13.7)
11 (25)
13 (13.7)
0.0007
AMER1
72 (13.5)
22 (23.2)
32 (10.7)
6 (13.6)
7 (7.4)
0.004
AXIN2
36 (6.7)
10 (10.5)
7 (2.3)
7 (15.9)
5 (5.3)
0.0001
FAT1
99 (18.5)
26 (27.4)
13 (4.3)
12 (27.3)
5 (5.3)
< 0.00001
FAT4
124 (23.2)
35 (36.8)
54 (18)
21 (47.7)
14 (14.7)
< 0.00001
Percentages are shown in parentheses. APC: adenomatous polyposis coli
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References
Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024.CA Cancer J Clin. 2024;74:12–49.Erratum in: CA Cancer J Clin. 2024;74:203. [DOI] [PubMed]
Arnold M, Abnet CC, Neale RE, Vignat J, Giovannucci EL, McGlynn KA, et al. Global Burden of 5 Major Types of Gastrointestinal Cancer.Gastroenterology. 2020;159:335–49.e15. [DOI] [PubMed] [PMC]
Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, et al. Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.J Natl Compr Canc Netw. 2021;19:329–59. [DOI] [PubMed]
André T, Shiu K, Kim TW, Jensen BV, Jensen LH, Punt C, et al.; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer.N Engl J Med. 2020;383:2207–18. [DOI] [PubMed]
Kopetz S, Grothey A, Yaeger R, Cutsem EV, Desai J, Yoshino T, et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer.N Engl J Med. 2019;381:1632–43. [DOI] [PubMed]
Siena S, Bartolomeo MD, Raghav K, Masuishi T, Loupakis F, Kawakami H, et al.; DESTINY-CRC01 investigators. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial.Lancet Oncol. 2021;22:779–89. [DOI] [PubMed]
Yaeger R, Weiss J, Pelster MS, Spira AI, Barve M, Ou SI, et al. Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C.N Engl J Med. 2023;388:44–54. [DOI] [PubMed] [PMC]
Pathak PS, Chan G, Deming DA, Chee CE. State-of-the-Art Management of Colorectal Cancer: Treatment Advances and Innovation.Am Soc Clin Oncol Educ Book. 2024;44:e438466. [DOI] [PubMed]
Voutsadakis IA. KRAS mutated colorectal cancers with or without PIK3CA mutations: Clinical and molecular profiles inform current and future therapeutics.Crit Rev Oncol Hematol. 2023;186:103987. [DOI] [PubMed]
Fasano M, Pirozzi M, Miceli CC, Cocule M, Caraglia M, Boccellino M, et al. TGF-β Modulated Pathways in Colorectal Cancer: New Potential Therapeutic Opportunities.Int J Mol Sci. 2024;25:7400. [DOI] [PubMed] [PMC]
Fujita M, Demizu Y. Advances in the development of Wnt/β-catenin signaling inhibitors. [Epub ahead of print]. 2024 [cited 2024 Nov 02]. [DOI] [PubMed] [PMC]
Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer.Nature. 2012;487:330–7. [DOI] [PubMed] [PMC]
Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Nishihara R, et al. Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma.Cell Rep. 2016;15:857–65.Erratum in: Cell Rep. 2016;17:1206. [DOI] [PubMed] [PMC]
Voutsadakis IA. The ubiquitin-proteasome system in colorectal cancer.Biochim Biophys Acta. 2008;1782:800–8. [DOI] [PubMed]
Hankey W, Frankel WL, Groden J. Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting.Cancer Metastasis Rev. 2018;37:159–72. [DOI] [PubMed] [PMC]
Ellrott K, Bailey MH, Saksena G, Covington KR, Kandoth C, Stewart C, et al.; MC3 Working Group; Cancer Genome Atlas Research Network. Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines.Cell Syst. 2018;6:271–81.e7. [DOI] [PubMed] [PMC]
Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers.Genome Biol. 2011;12:R41. [DOI] [PubMed] [PMC]
Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T, et al. Absolute quantification of somatic DNA alterations in human cancer.Nat Biotechnol. 2012;30:413–21. [DOI] [PubMed] [PMC]
Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity.Nature. 2012;483:603–7.Erratum in: Nature. 2012;492:290. Erratum in: Nature. 2019;565:E5–6. [DOI] [PubMed] [PMC]
Iorio F, Knijnenburg TA, Vis DJ, Bignell GR, Menden MP, Schubert M, et al. A Landscape of Pharmacogenomic Interactions in Cancer.Cell. 2016;166:740–54. [DOI] [PubMed] [PMC]
Behan FM, Iorio F, Picco G, Gonçalves E, Beaver CM, Migliardi G, et al. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens.Nature. 2019;568:511–6. [DOI] [PubMed]
Boehm JS, Garnett MJ, Adams DJ, Francies HE, Golub TR, Hahn WC, et al. Cancer research needs a better map.Nature. 2021;589:514–6. [DOI] [PubMed]
van der Meer D, Barthorpe S, Yang W, Lightfoot H, Hall C, Gilbert J, et al. Cell Model Passports-a hub for clinical, genetic and functional datasets of preclinical cancer models.Nucleic Acids Res. 2019;47:D923–9. [DOI] [PubMed] [PMC]
Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al. Defining a Cancer Dependency Map.Cell. 2017;170:564–76.e16. [DOI] [PubMed] [PMC]
Marcotte R, Sayad A, Brown KR, Sanchez-Garcia F, Reimand J, Haider M, et al. Functional Genomic Landscape of Human Breast Cancer Drivers, Vulnerabilities, and Resistance.Cell. 2016;164:293–309. [DOI] [PubMed] [PMC]
Dwane L, Behan FM, Gonçalves E, Lightfoot H, Yang W, van der Meer D, et al. Project Score database: a resource for investigating cancer cell dependencies and prioritizing therapeutic targets.Nucleic Acids Res. 2021;49:D1365–72. [DOI] [PubMed] [PMC]
Meyers RM, Bryan JG, McFarland JM, Weir BA, Sizemore AE, Xu H, et al. Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells.Nat Genet. 2017;49:1779–84. [DOI] [PubMed] [PMC]
Dempster JM, Boyle I, Vazquez F, Root DE, Boehm JS, Hahn WC, et al. Chronos: a cell population dynamics model of CRISPR experiments that improves inference of gene fitness effects.Genome Biol. 2021;22:343. [DOI] [PubMed] [PMC]
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.Cancer Discov. 2012;2:401–4.Erratum in: Cancer Discov. 2012;2:960. [DOI] [PubMed] [PMC]
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.Sci Signal. 2013;6:pl1. [DOI] [PubMed] [PMC]
Baulies A, Angelis N, Li VSW. Hallmarks of intestinal stem cells.Development. 2020;147:dev182675. [DOI] [PubMed]
Basak O, Beumer J, Wiebrands K, Seno H, Oudenaarden Av, Clevers H. Induced Quiescence of Lgr5+ Stem Cells in Intestinal Organoids Enables Differentiation of Hormone-Producing Enteroendocrine Cells.Cell Stem Cell. 2017;20:177–90.e4. [DOI] [PubMed]
Zhang C, Jin Y, Marchetti M, Lewis MR, Hammouda OT, Edgar BA. EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation.Curr Biol. 2022;32:3704–19.e7. [DOI] [PubMed] [PMC]
Voutsadakis IA. Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome system and Cox-2.J Cell Mol Med. 2007;11:252–85. [DOI] [PubMed] [PMC]
Perochon J, Carroll LR, Cordero JB. Wnt Signalling in Intestinal Stem Cells: Lessons from Mice and Flies.Genes (Basel). 2018;9:138. [DOI] [PubMed] [PMC]
Voutsadakis IA. Molecular Alterations and Putative Therapeutic Targeting of Planar Cell Polarity Proteins in Breast Cancer.J Clin Med. 2023;12:411. [DOI] [PubMed] [PMC]
Tabernero J, Cutsem EV, Garralda E, Tai D, Braud FD, Geva R, et al. A Phase Ib/II Study of WNT974 + Encorafenib + Cetuximab in Patients With BRAFV600E-Mutant KRAS Wild-Type Metastatic Colorectal Cancer.Oncologist. 2023;28:230–8. [DOI] [PubMed] [PMC]
Lung H, Wentworth KL, Moody T, Zamarioli A, Ram A, Ganesh G, et al. Wnt pathway inhibition with the porcupine inhibitor LGK974 decreases trabecular bone but not fibrosis in a murine model with fibrotic bone.JBMR Plus. 2024;8:ziae011. [DOI] [PubMed] [PMC]
Kim MK. Novel insight into the function of tankyrase.Oncol Lett. 2018;16:6895–902. [DOI] [PubMed] [PMC]
Klement K, Brückner M, Bernkopf DB. Phosphorylation of axin within biomolecular condensates counteracts its tankyrase-mediated degradation.J Cell Sci. 2023;136:jcs261214. [DOI] [PubMed] [PMC]
Fearon ER. PARsing the phrase “all in for Axin” - Wnt pathway targets in cancer.Cancer Cell. 2009;16:366–8. [DOI] [PubMed]
Huang SA, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.Nature. 2009;461:614–20. [DOI] [PubMed]
Masuda M, Sawa M, Yamada T. Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer.Pharmacol Ther. 2015;156:1–9. [DOI] [PubMed]
Shitashige M, Satow R, Jigami T, Aoki K, Honda K, Shibata T, et al. Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth.Cancer Res. 2010;70:5024–33. [DOI] [PubMed]
Yamamoto D, Oshima H, Wang D, Takeda H, Kita K, Lei X, et al. Characterization of RNF43 frameshift mutations that drive Wnt ligand- and R-spondin-dependent colon cancer.J Pathol. 2022;257:39–52. [DOI] [PubMed] [PMC]
Stefanski CD, Prosperi JR. Wnt-Independent and Wnt-Dependent Effects of APC Loss on the Chemotherapeutic Response.Int J Mol Sci. 2020;21:7844. [DOI] [PubMed] [PMC]
Lessey LR, Robinson SC, Chaudhary R, Daniel JM. Adherens junction proteins on the move-From the membrane to the nucleus in intestinal diseases.Front Cell Dev Biol. 2022;10:998373. [DOI] [PubMed] [PMC]
