. 2015 Dec 21:8:83.

doi: 10.1186/s12920-015-0160-7.

Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas

Berta Luzón-Toro^{1

2}, Marta Bleda^{3

4

5}, Elena Navarro^{6

7}, Luz García-Alonso^{8

9}, Macarena Ruiz-Ferrer^{10

11}, Ignacio Medina^{12

13}, Marta Martín-Sánchez^{14

15}, Cristina Y Gonzalez^{16

17}, Raquel M Fernández^{18

19}, Ana Torroglosa^{20

21}, Guillermo Antiñolo^{22

23}, Joaquin Dopazo^{24

25

26}, Salud Borrego^{27

28}

Affiliations

¹ Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. berta.luzon.exts@juntadeandalucia.es.
² Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. berta.luzon.exts@juntadeandalucia.es.
³ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. mb2033@cam.ac.uk.
⁴ Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), C/Eduardo Primo Yúfera, 3, 46012, Valencia, Spain. mb2033@cam.ac.uk.
⁵ Present Address: Department of Medicine, University of Cambridge, School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, UK. mb2033@cam.ac.uk.
⁶ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. elena.navarro.sspa@juntadeandalucia.es.
⁷ Department of Endocrinology, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. elena.navarro.sspa@juntadeandalucia.es.
⁸ Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), C/Eduardo Primo Yúfera, 3, 46012, Valencia, Spain. luzgaral@ebi.ac.uk.
⁹ Present Address: European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. luzgaral@ebi.ac.uk.
¹⁰ Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. mm.ruiz.exts@juntadeandalucia.es.
¹¹ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. mm.ruiz.exts@juntadeandalucia.es.
¹² Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), C/Eduardo Primo Yúfera, 3, 46012, Valencia, Spain. im411@cam.ac.uk.
¹³ Present Address: HPC Services, University of Cambridge, Cambridge, UK. im411@cam.ac.uk.
¹⁴ Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. martamartin-ibis@us.es.
¹⁵ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. martamartin-ibis@us.es.
¹⁶ Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), C/Eduardo Primo Yúfera, 3, 46012, Valencia, Spain. cyenyxe@ebi.ac.uk.
¹⁷ Present Address: European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. cyenyxe@ebi.ac.uk.
¹⁸ Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. raquelm.fernandez.sspa@juntadeandalucia.es.
¹⁹ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. raquelm.fernandez.sspa@juntadeandalucia.es.
²⁰ Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. ana.torroglosa.exts@juntadeandalucia.es.
²¹ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. ana.torroglosa.exts@juntadeandalucia.es.
²² Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. guillermo.antinolo.sspa@juntadeandalucia.es.
²³ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. guillermo.antinolo.sspa@juntadeandalucia.es.
²⁴ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. jdopazo@cipf.es.
²⁵ Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), C/Eduardo Primo Yúfera, 3, 46012, Valencia, Spain. jdopazo@cipf.es.
²⁶ Functional Genomics Node, (INB) at CIPF, Valencia, Spain. jdopazo@cipf.es.
²⁷ Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. salud.borrego.sspa@juntadeandalucia.es.
²⁸ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. salud.borrego.sspa@juntadeandalucia.es.

PMID: 26690675
PMCID: PMC4685628
DOI: 10.1186/s12920-015-0160-7

Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas

Berta Luzón-Toro et al. BMC Med Genomics. 2015.

. 2015 Dec 21:8:83.

doi: 10.1186/s12920-015-0160-7.

Authors

Affiliations

¹ Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. berta.luzon.exts@juntadeandalucia.es.
² Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. berta.luzon.exts@juntadeandalucia.es.
³ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. mb2033@cam.ac.uk.
⁴ Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), C/Eduardo Primo Yúfera, 3, 46012, Valencia, Spain. mb2033@cam.ac.uk.
⁵ Present Address: Department of Medicine, University of Cambridge, School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, UK. mb2033@cam.ac.uk.
⁶ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. elena.navarro.sspa@juntadeandalucia.es.
⁷ Department of Endocrinology, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. elena.navarro.sspa@juntadeandalucia.es.
⁸ Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), C/Eduardo Primo Yúfera, 3, 46012, Valencia, Spain. luzgaral@ebi.ac.uk.
⁹ Present Address: European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. luzgaral@ebi.ac.uk.
¹⁰ Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. mm.ruiz.exts@juntadeandalucia.es.
¹¹ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. mm.ruiz.exts@juntadeandalucia.es.
¹² Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), C/Eduardo Primo Yúfera, 3, 46012, Valencia, Spain. im411@cam.ac.uk.
¹³ Present Address: HPC Services, University of Cambridge, Cambridge, UK. im411@cam.ac.uk.
¹⁴ Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. martamartin-ibis@us.es.
¹⁵ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. martamartin-ibis@us.es.
¹⁶ Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), C/Eduardo Primo Yúfera, 3, 46012, Valencia, Spain. cyenyxe@ebi.ac.uk.
¹⁷ Present Address: European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. cyenyxe@ebi.ac.uk.
¹⁸ Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. raquelm.fernandez.sspa@juntadeandalucia.es.
¹⁹ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. raquelm.fernandez.sspa@juntadeandalucia.es.
²⁰ Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. ana.torroglosa.exts@juntadeandalucia.es.
²¹ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. ana.torroglosa.exts@juntadeandalucia.es.
²² Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. guillermo.antinolo.sspa@juntadeandalucia.es.
²³ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. guillermo.antinolo.sspa@juntadeandalucia.es.
²⁴ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. jdopazo@cipf.es.
²⁵ Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), C/Eduardo Primo Yúfera, 3, 46012, Valencia, Spain. jdopazo@cipf.es.
²⁶ Functional Genomics Node, (INB) at CIPF, Valencia, Spain. jdopazo@cipf.es.
²⁷ Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain. salud.borrego.sspa@juntadeandalucia.es.
²⁸ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain. salud.borrego.sspa@juntadeandalucia.es.

PMID: 26690675
PMCID: PMC4685628
DOI: 10.1186/s12920-015-0160-7

Abstract

Background: The molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk.

Methods: We carried out the first screening for epistasis by Multifactor-Dimensionality Reduction (MDR) in genome-wide association study (GWAS) on sMTC and juvenile PTC, to identify the potential simultaneous involvement of pairs of variants in the disease.

Results: We have identified two significant epistatic gene interactions in sMTC (CHFR-AC016582.2 and C8orf37-RNU1-55P) and three in juvenile PTC (RP11-648k4.2-DIO1, RP11-648k4.2-DMGDH and RP11-648k4.2-LOXL1). Interestingly, each interacting gene pair included a non-coding RNA, providing thus support to the relevance that these elements are increasingly gaining to explain carcinoma development and progression.

Conclusions: Overall, this study contributes to the understanding of the genetic basis of thyroid carcinoma susceptibility in two different case scenarios such as sMTC and juvenile PTC.

PubMed Disclaimer

Figures

**Fig. 1**
Gene-gene interactions obtained in sMTC patients by MDR analyses. a a total of 29 GxG interactions were obtained, (b) from which three were significant based on cross-validation value (>0.5)

**Fig. 2**
Gene-gene interactions obtained in jPTC patients by MDR analyses. a a total of 259 GxG interactions were obtained, (b) from which 133 were significant based on cross-validation value (>0.5)

**Fig. 3**
Expression profiling for arrays in 18 PTC samples (a) *DIO1,* (b) *DMGD* and (c) *LOXL1* genes. Figures adapted from GeoDataSets

See this image and copyright information in PMC

Cited by

Germline mutations predisposing to diffuse large B-cell lymphoma.
Leeksma OC, de Miranda NF, Veelken H. Leeksma OC, et al. Blood Cancer J. 2017 Feb 17;7(2):e532. doi: 10.1038/bcj.2017.15. Blood Cancer J. 2017. PMID: 28211887 Free PMC article. Review.
Eigen-Epistasis for detecting gene-gene interactions.
Stanislas V, Dalmasso C, Ambroise C. Stanislas V, et al. BMC Bioinformatics. 2017 Jan 23;18(1):54. doi: 10.1186/s12859-017-1488-0. BMC Bioinformatics. 2017. PMID: 28114904 Free PMC article.
Harnessing deep learning for SNP-based disease prediction in genomics.
Alme C, Pirim H, Mishkatur Rahman M. Alme C, et al. Int J Inf Technol. 2024 Jul 4:10.1007/s41870-025-02624-8. doi: 10.1007/s41870-025-02624-8. Online ahead of print. Int J Inf Technol. 2024. PMID: 40822924 Free PMC article.
Artificial Intelligence in Epigenetic Studies: Shedding Light on Rare Diseases.
Brasil S, Neves CJ, Rijoff T, Falcão M, Valadão G, Videira PA, Dos Reis Ferreira V. Brasil S, et al. Front Mol Biosci. 2021 May 5;8:648012. doi: 10.3389/fmolb.2021.648012. eCollection 2021. Front Mol Biosci. 2021. PMID: 34026829 Free PMC article. Review.
Genetic expression profile-based screening of genes and pathways associated with papillary thyroid carcinoma.
Li S, Yin Y, Yu H. Li S, et al. Oncol Lett. 2018 Nov;16(5):5723-5732. doi: 10.3892/ol.2018.9342. Epub 2018 Aug 21. Oncol Lett. 2018. PMID: 30344727 Free PMC article.

See all "Cited by" articles

References

1. Figge JJ. Epidemiology of thyroid cancer. In: Wartofsky LVND, editor. Thyroid Cancer: A Comprehensive Guide to Clinical Management. Totowa: Human Press; 1999.
1. Randolph GW, Maniar D. Medullary carcinoma of the thyroid. Cancer Control. 2000;7(3):253–261. - PubMed
1. Moline J EC: Multiple Endocrine Neoplasia Type 2. In: SourceGeneReviews® [Internet]. Edited by Pagon RA AM, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K, editors. Seattle: University of Washington, Seattle; 2005.
1. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. Jama. 1996;276(19):1575–1579. doi: 10.1001/jama.1996.03540190047028. - DOI - PubMed
1. Fernandez RM, Pecina A, Antinolo G, Navarro E, Borrego S. Analysis of RET polymorphisms and haplotypes in the context of sporadic medullary thyroid carcinoma. Thyroid. 2006;16(4):411–417. doi: 10.1089/thy.2006.16.411. - DOI - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Supplementary concepts

Actions

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- NIAID Data Ecosystem - Find datasets on Infectious and Immune-mediated Diseases

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas

Affiliations

Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas

Authors

Affiliations

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Supplementary concepts

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Supplementary concepts

Related information

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases