Germline mutations in predisposition genes account for only 20% of all familial colorectal cancers (CRC) and the remaining genetic burden may be due to rare high- to moderate-penetrance germline variants that are not explored. With the aim of identifying such potential cancer-predisposing variants, we performed whole exome sequencing on three CRC cases and three unaffected members of a Polish family and identified two novel heterozygous variants: a coding variant in APC downregulated 1 gene (APCDD1, p.R299H) and a non-coding variant in the 5' untranslated region (UTR) of histone deacetylase 5 gene (HDAC5). Sanger sequencing confirmed the variants segregating with the disease and Taqman assays revealed 8 additional APCDD1 variants in a cohort of 1705 familial CRC patients and no further HDAC5 variants. Proliferation assays indicated an insignificant proliferative impact for the APCDD1 variant. Luciferase reporter assays using the HDAC5 variant resulted in an enhanced promoter activity. Targeting of transcription factor binding sites of SNAI-2 and TCF4 interrupted by the HDAC5 variant showed a significant impact of TCF4 on promoter activity of mutated HDAC5. Our findings contribute not only to the identification of unrecognized genetic causes of familial CRC but also underline the importance of 5'UTR variants affecting transcriptional regulation and the pathogenesis of complex disorders.

Bioinformatics and Omics Data Analytics German Cancer Research Center 69120 Heidelberg Germany

Biomedical Center Faculty of Medicine in Pilsen Charles University Prague 30605 Pilsen Czech Republic

Cancer Epidemiology German Cancer Research Center 69120 Heidelberg Germany

Computational Oncology Molecular Diagnostics Program National Center for Tumor Diseases 69120 Heidelberg Germany

Department of Genetics and Pathology Pomeranian Medical University 71252 Szczecin Poland

Division of Pediatric Neurooncology German Cancer Research Center 69120 Heidelberg Germany

Hopp Children's Cancer Center 69120 Heidelberg Germany

Institute of Bioinformatics International Technology Park Bangalore 560066 India

Manipal Academy of Higher Education Manipal 576104 India

Medical Faculty Heidelberg University 69120 Heidelberg Germany

Molecular Genetic Epidemiology German Cancer Research Center 69120 Heidelberg Germany

Zobrazit více v PubMed

Lichtenstein P., Holm N.V., Verkasalo P.K., Iliadou A., Kaprio J., Koskenvuo M., Pukkala E., Skytthe A., Hemminki K. Environmental and Heritable Factors in the Causation of Cancer—Analyses of Cohorts of Twins from Sweden, Denmark, and Finland. N. Engl. J. Med. 2000;343:78–85. doi: 10.1056/NEJM200007133430201. PubMed DOI

Jasperson K.W., Tuohy T.M., Neklason D.W., Burt R.W. Hereditary and Familial Colon Cancer. Gastroenterology. 2010;138:2044–2058. doi: 10.1053/j.gastro.2010.01.054. PubMed DOI PMC

Da Silva F.C., Wernhoff P., Dominguez-Barrera C., Dominguez-Valentin M. Update on Hereditary Colorectal Cancer. Anticancer. Res. 2016;36:4399–4406. doi: 10.21873/anticanres.10983. PubMed DOI

Wei C., Peng B., Han Y., Chen W.V., Rother J., Tomlinson G.E., Boland C.R., Chaussabel M., Frazier M.L., Amos C.I. Mutations of HNRNPA0 and WIF1 predispose members of a large family to multiple cancers. Fam. Cancer. 2015;14:297–306. doi: 10.1007/s10689-014-9758-8. PubMed DOI PMC

Kuiper R.P., Hoogerbrugge N. NTHL1 defines novel cancer syndrome. Oncotarget. 2015;6:34069–34070. doi: 10.18632/oncotarget.5864. PubMed DOI PMC

Weren R.D., Ligtenberg M.J., Kets C.M., De Voer R.M., Verwiel E.T., Spruijt L., van Zelst-Stams W.A., Jongmans M.C., Gilissen C., Hehir-Kwa J.Y., et al. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat. Genet. 2015;47:668–671. doi: 10.1038/ng.3287. PubMed DOI

Briggs S., Tomlinson I. Germline and somatic polymerase epsilon and delta mutations define a new class of hypermutated colorectal and endometrial cancers. J. Pathol. 2013;230:148–153. doi: 10.1002/path.4185. PubMed DOI PMC

Palles C., Cazier J.-B., Howarth K.M., Domingo E., Jones A.M., Broderick P., Kemp Z., Spain S.L., Guarino E., Salguero I., et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat. Genet. 2013;45:136–144. doi: 10.1038/ng.2503. PubMed DOI PMC

Lorans M., Dow E., Macrae F.A., Winship I.M., Buchanan D.D. Update on Hereditary Colorectal Cancer: Improving the Clinical Utility of Multigene Panel Testing. Clin. Color. Cancer. 2018;17:e293–e305. doi: 10.1016/j.clcc.2018.01.001. PubMed DOI

Gloss B.S., Dinger M.E. Realizing the significance of noncoding functionality in clinical genomics. Exp. Mol. Med. 2018;50:1–8. doi: 10.1038/s12276-018-0087-0. PubMed DOI PMC

Mucaki E.J., Caminsky N.G., Perri A.M., Lu R., Laederach A., Halvorsen M., Knoll J.H.M., Rogan P.K. A unified analytic framework for prioritization of non-coding variants of uncertain significance in heritable breast and ovarian cancer. BMC Med. Genom. 2016;9:19. doi: 10.1186/s12920-016-0178-5. PubMed DOI PMC

Alanazi I.O., Al Shehri Z.S., Ebrahimie E., Giahi H., Mohammadi-Dehcheshmeh M. Non-coding and coding genomic variants distinguish prostate cancer, castration-resistant prostate cancer, familial prostate cancer, and metastatic castration-resistant prostate cancer from each other. Mol. Carcinog. 2019;58:862–874. doi: 10.1002/mc.22975. PubMed DOI

Shabalina S.A., Spiridonov N.A. The mammalian transcriptome and the function of non-coding DNA sequences. Genome Biol. 2004;5:105. doi: 10.1186/gb-2004-5-4-105. PubMed DOI PMC

Kumar A., Bandapalli O.R., Paramasivam N., Giangiobbe S., Diquigiovanni C., Bonora E., Eils R., Schlesner M., Hemminki K., Försti A. Familial Cancer Variant Prioritization Pipeline version 2 (FCVPPv2) applied to a papillary thyroid cancer family. Sci. Rep. 2018;8:11635. doi: 10.1038/s41598-018-29952-z. PubMed DOI PMC

Bandapalli O.R., Paramasivam N., Giangiobbe S., Kumar A., Benisch W., Engert A., Witzens-Harig M., Schlesner M., Hemminki K., Försti A. Whole genome sequencing reveals DICER1 as a candidate predisposing gene in familial Hodgkin lymphoma. Int. J. Cancer. 2018;143:2076–2078. doi: 10.1002/ijc.31576. PubMed DOI

Srivastava A., Kumar A., Giangiobbe S., Bonora E., Hemminki K., Försti A., Bandapalli O.R. Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways. Biomolecules. 2019;9:605. doi: 10.3390/biom9100605. PubMed DOI PMC

Srivastava A., Giangiobbe S., Kumar A., Paramasivam N., Dymerska D., Behnisch W., Witzens-Harig M., Lubinski J., Hemminki K., Försti A., et al. Identification of Familial Hodgkin Lymphoma Predisposing Genes Using Whole Genome Sequencing. Front. Bioeng. Biotechnol. 2020;8:179. doi: 10.3389/fbioe.2020.00179. PubMed DOI PMC

Rentzsch P., Witten D., Cooper G.M., Shendure J., Kircher M. CADD: Predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47:D886–D894. doi: 10.1093/nar/gky1016. PubMed DOI PMC

Dayem Ullah A.Z., Oscanoa J., Wang J., Nagano A., Lemoine N.R., Chelala C. SNPnexus: Assessing the functional relevance of genetic variation to facilitate the promise of precision medicine. Nucleic Acids Res. 2018;46:W109–W113. doi: 10.1093/nar/gky399. PubMed DOI PMC

Stelzer G., Rosen N., Plaschkes I., Zimmerman S., Twik M., Fishilevich S., Stein T.I., Nudel R., Lieder I., Mazor Y., et al. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Curr. Protoc. Bioinform. 2016;54:1–30. doi: 10.1002/cpbi.5. PubMed DOI

Wang Z., Cummins J.M., Shen D., Cahill D.P., Jallepalli P.V., Wang T.-L., Parsons D.W., Traverso G., Awad M., Silliman N., et al. Three Classes of Genes Mutated In Colorectal Cancers with Chromosomal Instability. Cancer Res. 2004;64:2998–3001. doi: 10.1158/0008-5472.CAN-04-0587. PubMed DOI

Mitchell A.L., Attwood T.K., Babbitt P.C., Blum M., Bork P., Bridge A., Brown S.D., Chang H.-Y., El-Gebali S., Fraser M.I., et al. InterPro in 2019: Improving coverage, classification and access to protein sequence annotations. Nucleic Acids Res. 2019;47:D351–D360. doi: 10.1093/nar/gky1100. PubMed DOI PMC

El-Gebali S., Mistry J., Bateman A., Eddy S.R., Luciani A., Potter S.C., Qureshi M., Richardson L.J., Salazar G.A., Smart A., et al. The Pfam protein families database in 2019. Nucleic Acids Res. 2019;47:D427–D432. doi: 10.1093/nar/gky995. PubMed DOI PMC

Letunic I., Bork P. 20 years of the SMART protein domain annotation resource. Nucleic Acids Res. 2018;46:D493–D496. doi: 10.1093/nar/gkx922. PubMed DOI PMC

Takahashi M., Fujita M., Furukawa Y., Hamamoto R., Shimokawa T., Miwa N., Ogawa M., Nakamura Y. Isolation of a novel human gene, APCDD1, as a direct target of the beta-Catenin/T-cell factor 4 complex with probable involvement in colorectal carcinogenesis. Cancer Res. 2002;62:5651–5656. PubMed

Ernst J., Kellis M. ChromHMM: Automating chromatin-state discovery and characterization. Nat. Methods. 2012;9:215–216. doi: 10.1038/nmeth.1906. PubMed DOI PMC

Roadmap Epigenomics C., Kundaje A., Meuleman W., Ernst J., Bilenky M., Yen A., Heravi-Moussavi A., Kheradpour P., Zhang Z., Wang J., et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518:317–330. PubMed PMC

Hoffman M.M., Buske O.J., Wang J., Weng Z., Bilmes J.A., Noble W.S. Unsupervised pattern discovery in human chromatin structure through genomic segmentation. Nat. Methods. 2012;9:473–476. doi: 10.1038/nmeth.1937. PubMed DOI PMC

Fre S., Pallavi S.K., Huyghe M., Laé M., Janssen K.-P., Robine S., Artavanis-Tsakonas S., Louvard D. Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc. Natl. Acad. Sci. USA. 2009;106:6309–6314. doi: 10.1073/pnas.0900427106. PubMed DOI PMC

Badenes M., Trindade A., Pissarra H., Lopes-da-Costa L., Duarte A. Delta-like 4/Notch signaling promotes Apc (Min/+) tumor initiation through angiogenic and non-angiogenic related mechanisms. BMC Cancer. 2017;17:50. PubMed PMC

He P., Liang J., Shao T., Guo Y., Hou Y., Li Y. HDAC5 promotes colorectal cancer cell proliferation by up-regulating DLL4 expression. Int. J. Clin. Exp. Med. 2015;8:6510–6516. PubMed PMC

Stypula-Cyrus Y., Damania D., Kunte D.P., Cruz M.D., Subramanian H., Roy H.K., Backman V. HDAC Up-Regulation in Early Colon Field Carcinogenesis Is Involved in Cell Tumorigenicity through Regulation of Chromatin Structure. PLoS ONE. 2013;8:e64600. doi: 10.1371/journal.pone.0064600. PubMed DOI PMC

Shah M., Rennoll S.A., Raup-Konsavage W.M., Yochum G.S. A dynamic exchange of TCF3 and TCF4 transcription factors controls MYC expression in colorectal cancer cells. Cell Cycle. 2015;14:323–332. doi: 10.4161/15384101.2014.980643. PubMed DOI PMC

Findlay V.J., Wang C., Nogueira L.M., Hurst K., Quirk D., Ethier S.P., O’Carroll K.F.S., Watson D.K., Camp E.R. SNAI2 Modulates Colorectal Cancer 5-Fluorouracil Sensitivity through miR145 Repression. Mol. Cancer Ther. 2014;13:2713–2726. doi: 10.1158/1535-7163.MCT-14-0207. PubMed DOI PMC

de Sousa E.M.F., Colak S., Buikhuisen J., Koster J., Cameron K., de Jong J.H., Tuynman J.B., Prasetyanti P.R., Fessler E., van den Bergh S.P., et al. Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients. Cell Stem Cell. 2011;9:476–485. PubMed

Shimomura Y., Agalliu D., Vonica A., Luria V., Wajid M., Baumer A., Belli S., Petukhova L., Schinzel A., Brivanlou A.H., et al. APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex. Nature. 2010;464:1043–1047. doi: 10.1038/nature08875. PubMed DOI PMC

Ordóñez-Morán P., Dafflon C., Imajo M., Nishida E., Huelsken J. HOXA5 Counteracts Stem Cell Traits by Inhibiting Wnt Signaling in Colorectal Cancer. Cancer Cell. 2015;28:815–829. doi: 10.1016/j.ccell.2015.11.001. PubMed DOI

Marek L., Hamacher A., Hansen F.K., Kuna K., Gohlke H., Kassack M.U., Kurz T. Histone Deacetylase (HDAC) Inhibitors with a Novel Connecting Unit Linker Region Reveal a Selectivity Profile for HDAC4 and HDAC5 with Improved Activity against Chemoresistant Cancer Cells. J. Med. Chem. 2013;56:427–436. doi: 10.1021/jm301254q. PubMed DOI

Milde T., Oehme I., Korshunov A., Kopp-Schneider A., Remke M., Northcott P.A., Deubzer H.E., Lodrini M., Taylor M.D., Von Deimling A., et al. HDAC5 and HDAC9 in Medulloblastoma: Novel Markers for Risk Stratification and Role in Tumor Cell Growth. Clin. Cancer Res. 2010;16:3240–3252. doi: 10.1158/1078-0432.CCR-10-0395. PubMed DOI

Fan J., Lou B., Chen W., Zhang J., Lin S., Lv F.-F., Chen Y. Down-regulation of HDAC5 inhibits growth of human hepatocellular carcinoma by induction of apoptosis and cell cycle arrest. Tumor Biol. 2014;35:11523–11532. doi: 10.1007/s13277-014-2358-2. PubMed DOI

Lee H.-Y., Tsai A.-C., Chen M.-C., Shen P.-J., Cheng Y.-C., Kuo C.-C., Pan S.-L., Liu Y.-M., Liu J.-F., Yeh T.-K., et al. Azaindolylsulfonamides, with a More Selective Inhibitory Effect on Histone Deacetylase 6 Activity, Exhibit Antitumor Activity in Colorectal Cancer HCT116 Cells. J. Med. Chem. 2014;57:4009–4022. doi: 10.1021/jm401899x. PubMed DOI

Hrckulak D., Janeckova L., Lanikova L., Kriz V., Horazna M., Babosova O., Vojtechova M., Galuskova K., Sloncova E., Korinek V. Wnt Effector TCF4 Is Dispensable for Wnt Signaling in Human Cancer Cells. Genes. 2018;9:439. doi: 10.3390/genes9090439. PubMed DOI PMC

Korinek V., Barker N., Morin P.J., van Wichen D., de Weger R., Kinzler K.W., Vogelstein B., Clevers H. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science. 1997;275:1784–1787. doi: 10.1126/science.275.5307.1784. PubMed DOI

Bienz M., Clevers H. Linking colorectal cancer to Wnt signaling. Cell. 2000;103:311–320. doi: 10.1016/S0092-8674(00)00122-7. PubMed DOI

Smith D.R., Myint T., Goh H.S. Over-expression of the c-myc proto-oncogene in colorectal carcinoma. Br. J. Cancer. 1993;68:407–413. doi: 10.1038/bjc.1993.350. PubMed DOI PMC

Erisman M.D., Rothberg P.G., Diehl R.E., Morse C.C., Spandorfer J.M., Astrin S.M. Deregulation of c-myc gene expression in human colon carcinoma is not accompanied by amplification or rearrangement of the gene. Mol. Cell. Biol. 1985;5:1969–1976. doi: 10.1128/MCB.5.8.1969. PubMed DOI PMC

Rochlitz C.F., Herrmann R., De Kant E. Overexpression and Amplification of c-myc during Progression of Human Colorectal Cancer. Oncology. 1996;53:448–454. doi: 10.1159/000227619. PubMed DOI

Hatzis P., Van Der Flier L.G., Van Driel M.A., Guryev V., Nielsen F., Denissov S., Nijman I.J., Koster J., Santo E.E., Welboren W., et al. Genome-Wide Pattern of TCF7L2/TCF4 Chromatin Occupancy in Colorectal Cancer Cells. Mol. Cell. Biol. 2008;28:2732–2744. doi: 10.1128/MCB.02175-07. PubMed DOI PMC

Kriegl L., Horst D., Reiche J.A., Engel J., Kirchner T., Jung A. LEF-1 and TCF4 expression correlate inversely with survival in colorectal cancer. J. Transl. Med. 2010;8:123. doi: 10.1186/1479-5876-8-123. PubMed DOI PMC

Mao C.D., Byers S.W. Cell-context dependent TCF/LEF expression and function: Alternative tales of repression, de-repression and activation potentials. Crit. Rev. Eukaryot. Gene Expr. 2011;21:207–236. doi: 10.1615/CritRevEukarGeneExpr.v21.i3.10. PubMed DOI PMC

Hoverter N.P., Waterman M.L. A Wnt-fall for gene regulation: Repression. Sci. Signal. 2008;1:pe43. doi: 10.1126/scisignal.139pe43. PubMed DOI

Arce L., Yokoyama N.N., Waterman M.L. Diversity of LEF/TCF action in development and disease. Oncogene. 2006;25:7492–7504. doi: 10.1038/sj.onc.1210056. PubMed DOI

Cadigan K.M. TCFs and Wnt/beta-catenin signaling: More than one way to throw the switch. Curr. Top Dev. Biol. 2012;98:1–34. PubMed

Cadigan K.M., Waterman M.L. TCF/LEFs and Wnt Signaling in the Nucleus. Cold Spring Harb. Perspect. Biol. 2012;4:a007906. doi: 10.1101/cshperspect.a007906. PubMed DOI PMC

Brantjes H., Roose J., Van De Wetering M., Clevers H. All Tcf HMG box transcription factors interact with Groucho-related co-repressors. Nucleic Acids Res. 2001;29:1410–1419. doi: 10.1093/nar/29.7.1410. PubMed DOI PMC

Wang H., Matise M.P. Tcf7l2/Tcf4 Transcriptional Repressor Function Requires HDAC Activity in the Developing Vertebrate CNS. PLoS ONE. 2016;11:e0163267. doi: 10.1371/journal.pone.0163267. PubMed DOI PMC

Lahiri D.K., Schnabel B. DNA isolation by a rapid method from human blood samples: Effects of MgCl2, EDTA, storage time, and temperature on DNA yield and quality. Biochem. Genet. 1993;31:321–328. doi: 10.1007/BF00553174. PubMed DOI

Li H., Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–1760. doi: 10.1093/bioinformatics/btp324. PubMed DOI PMC

Li H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics. 2011;27:2987–2993. doi: 10.1093/bioinformatics/btr509. PubMed DOI PMC

Rimmer A., Phan H., Mathieson I., Iqbal Z., Twigg S.R., Consortium W.G.S., Wilkie A.O., McVean G., Lunter G. Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. Nat. Genet. 2014;46:912–918. doi: 10.1038/ng.3036. PubMed DOI PMC

Wang K., Li M., Hakonarson H. Annovar: Functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164. doi: 10.1093/nar/gkq603. PubMed DOI PMC

Genomes Project C., Auton A., Brooks L.D., Durbin R.M., Garrison E.P., Kang H.M., Korbel J.O., Marchini J.L., McCarthy S., McVean G.A., et al. A global reference for human genetic variation. Nature. 2015;526:68–74. PubMed PMC

Smigielski E.M., Sirotkin K., Ward M., Sherry S.T. dbSNP: A database of single nucleotide polymorphisms. Nucleic Acids Res. 2000;28:352–355. doi: 10.1093/nar/28.1.352. PubMed DOI PMC

Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., O’Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–291. doi: 10.1038/nature19057. PubMed DOI PMC

Steinke V., Engel C., Buttner R., Schackert H.K., Schmiegel W.H., Propping P. Hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome. Dtsch. Arztebl. Int. 2013;110:32–38. doi: 10.3238/arztebl.2013.0032. PubMed DOI PMC

Brandt A., Bermejo J.L., Sundquist J., Hemminki K. Age of onset in familial cancer. Ann. Oncol. 2008;19:2084–2088. doi: 10.1093/annonc/mdn527. PubMed DOI PMC

Kircher M., Witten D.M., Jain P., O’Roak B.J., Cooper G.M., Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 2014;46:310–315. doi: 10.1038/ng.2892. PubMed DOI PMC

Cooper G.M., Stone E.A., Asimenos G., Green E.D., Batzoglou S., Sidow A. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 2005;15:901–913. doi: 10.1101/gr.3577405. PubMed DOI PMC

Siepel A., Bejerano G., Pedersen J.S., Hinrichs A.S., Hou M., Rosenbloom K., Clawson H., Spieth J., Hillier L.W., Richards S., et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 2005;15:1034–1050. doi: 10.1101/gr.3715005. PubMed DOI PMC

Pollard K.S., Hubisz M.J., Rosenbloom K.R., Siepel A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 2009;20:110–121. doi: 10.1101/gr.097857.109. PubMed DOI PMC

Petrovski S., Wang Q., Heinzen E.L., Allen A.S., Goldstein D.B. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 2013;9:e1003709. doi: 10.1371/annotation/32c8d343-9e1d-46c6-bfd4-b0cd3fb7a97e. PubMed DOI PMC

Ward L.D., Kellis M. HaploReg: A resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40:D930–D934. doi: 10.1093/nar/gkr917. PubMed DOI PMC

Liu X., Wu C., Li C., Boerwinkle E. dbNSFP v3.0: A One-Stop Database of Functional Predictions and Annotations for Human Nonsynonymous and Splice-Site SNVs. Hum. Mutat. 2016;37:235–241. doi: 10.1002/humu.22932. PubMed DOI PMC

Tamborero D., Rubio-Perez C., Deu-Pons J., Schroeder M.P., Vivancos A., Rovira A., Tusquets I., Albanell J., Rodon J., Tabernero J., et al. Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterations. Genome Med. 2018;10:25. doi: 10.1186/s13073-018-0531-8. PubMed DOI PMC

Hecht M., Bromberg Y., Rost B. Better prediction of functional effects for sequence variants. BMC Genom. 2015;16(Suppl. 8):S1. doi: 10.1186/1471-2164-16-S8-S1. PubMed DOI PMC

Betel D., Koppal A., Agius P., Sander C., Leslie C. Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites. Genome Biol. 2010;11:R90. doi: 10.1186/gb-2010-11-8-r90. PubMed DOI PMC

Wei Y., Zhang S., Shang S., Zhang B., Li S., Wang X., Wang F., Su J., Wu Q., Liu H., et al. SEA: A super-enhancer archive. Nucleic Acids Res. 2016;44:D172–D179. doi: 10.1093/nar/gkv1243. PubMed DOI PMC

Agarwal V., Bell G.W., Nam J.-W., Bartel D.P. Predicting effective microRNA target sites in mammalian mRNAs. eLife. 2015;4:e05005. doi: 10.7554/eLife.05005. PubMed DOI PMC

Fornes O., Castro-Mondragon J.A., Khan A., Van Der Lee R., Zhang X., Richmond P.A., Modi B.P., Correard S., Gheorghe M., Baranašić D., et al. JASPAR 2020: Update of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 2019;48:D87–D92. doi: 10.1093/nar/gkz1001. PubMed DOI PMC

Robinson J.T., Thorvaldsdóttir H., Wenger A.M., Zehir A., Mesirov J.P. Variant Review with the Integrative Genomics Viewer. Cancer Res. 2017;77:e31–e34. doi: 10.1158/0008-5472.CAN-17-0337. PubMed DOI PMC

Rouillard A.D., Gundersen G.W., Fernandez N.F., Wang Z., Monteiro C.D., McDermott M.G., Ma’Ayan A. The harmonizome: A collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database. 2016;2016 doi: 10.1093/database/baw100. PubMed DOI PMC

Search for germline gene variants in colorectal cancer families presenting with multiple primary colorectal cancers

Whole exome sequencing identifies novel germline variants of SLC15A4 gene as potentially cancer predisposing in familial colorectal cancer