Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

Copy neutral loss of heterozygosity (cnLOH) patterns in synchronous colorectal cancer

European Journal of Human Genetics volume 29, pages 709–713 (2021)Cite this article

Subjects

Abstract

Copy neutral loss of heterozygosity (cnLOH) is a common event in several human malignancies—positing this as a mechanism of carcinogenesis. However, the role of cnLOH in synchronous colorectal cancer (SCRC), a unique CRC subtype, is not well understood. The aim of this study was to establish a cnLOH profile of SCRC using a single-nucleotide polymorphism array (SNP-A), and to explore associations between cnLOH and the genomic landscape of frequently mutated genes in SCRC. Among 74 paired SCRC cases, the most frequently altered regions were 16p11.2–p11.1 (59.5%) and 11p11.2–p11.12 (28.4%). Notably, the 6q11.21–q11.22 region altered by cnLOH was uniquely associated with polyclonal SCRCs (p = 0.038). Together, our analysis suggests that inactivation of tumor suppressor genes and cnLOH are rare events among SCRC cases. This study defines distinct patterns of cnLOH in SCRC, and provides initial evidence of a role for cnLOH in SCRC etiology.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Quantification of cnLOH events in SCRC groups.

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;1–31.

  2. Lam AKY, Chan SSY, Leung M, Lam AKY, Chan SSY, Leung M. Synchronous colorectal cancer: clinical, pathological and molecular implications. World J Gastroenterol. 2014;20:6815–20.

    Article  Google Scholar 

  3. Lochhead P, Chan AT, Nishihara R, Fuchs CS, Beck AH, Giovannucci E, et al. Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression. Mod Pathol. 2015;28:14–29.

    Article  Google Scholar 

  4. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J. et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463:899–905.

    Article  CAS  Google Scholar 

  5. Song F, Li X, Song F, Zhao Y, Li H, Zheng H. et al. Comparative genomic analysis reveals bilateral breast cancers are genetically independent. Oncotarget. 2015;6:31820–9.

    Article  Google Scholar 

  6. Perea J, García JL, Corchete L, Lumbreras E, Arriba M, Rueda D, et al. Redefining synchronous colorectal cancers based on tumor clonality. Int J Cancer. 2018;144:1596–608.

    Article  Google Scholar 

  7. Torabi K, Miró R, Fernández-Jiménez N, Quintanilla I, Ramos L, Prat E. et al. Patterns of somatic uniparental disomy identify novel tumor suppressor genes in colorectal cancer. Carcinogenesis. 2015;36:1103–10.

    Article  CAS  Google Scholar 

  8. Makishima H, Maciejewski JP. Pathogenesis and consequences of uniparental disomy in cancer. Clin Cancer Res. 2011;17:3913–23.

    Article  CAS  Google Scholar 

  9. Tuna M, Smid M, Zhu D, Martens JWM, Amos CI. Association between acquired uniparental disomy and homozygous mutations and HER2/ER/PR status in breast cancer. PLoS ONE. 2010;5:e15094.

  10. Torabi K, Erola P, Alvarez-Mora MI, Díaz-Gay M, Ferrer Q, Castells A, et al. Quantitative analysis of somatically acquired and constitutive uniparental disomy in gastrointestinal cancers. Int J Cancer. 2019;144:513–24.

    Article  CAS  Google Scholar 

  11. Andersen CL, Wiuf C, Kruhøffer M, Korsgaard M, Laurberg S, Ørntoft TF. Frequent occurrence of uniparental disomy in colorectal cancer. Carcinogenesis. 2007;28:38–48.

    Article  CAS  Google Scholar 

  12. Redaelli S, Maitz S, Crosti F, Sala E, Villa N, Spaccini L, et al. Refining the phenotype of recurrent rearrangements of chromosome 16. Int J Mol Sci. 2019;20:1–17.

    Article  Google Scholar 

  13. Bochukova EG, Huang N, Keogh J, Henning E, Purmann C, Blaszczyk K. et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature. 2010;463:666–70.

    Article  CAS  Google Scholar 

  14. Cheng Y, Duan C, Zhang C. New perspective on SH2B1: an accelerator of cancer progression. Biomed Pharmacother. 2020;121:109651.

    Article  CAS  Google Scholar 

  15. Maity G, Haque I, Ghosh A, Dhar G, Gupta V, Sarkar S, et al. The MAZ transcription factor is a downstream target of the oncoprotein Cyr61/CCN1 and promotes pancreatic cancer cell invasion via CRAF–ERK signaling. J Biol Chem. 2018;293:4334–49.

    Article  CAS  Google Scholar 

  16. Yang Q, Lang C, Wu Z, Dai Y, He S, Guo W, et al. MAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathway. J Exp Clin Cancer Res. 2019;38:1–17.

    Article  Google Scholar 

  17. Triner D, Castillo C, Hakim JB, Xue X, Greenson JK, Nuñez G, et al. Myc-associated zinc finger protein regulates the proinflammatory response in colitis and colon cancer via STAT3 signaling. Mol Cell Biol. 2018;38:1–15.

    Article  Google Scholar 

  18. Di J, Yang H, Jiang B, Wang Z, Ji J, Su X. Whole exome sequencing reveals intertumor heterogeneity and distinct genetic origins of sporadic synchronous colorectal cancer. Int J Cancer. 2018;142:927–39.

    Article  CAS  Google Scholar 

  19. Hänninen UA, Wirta EV, Katainen R, Tanskanen T, Hamberg J, Taipale M, et al. Exome and immune cell score analyses reveal great variation within synchronous primary colorectal cancers. Br J Cancer. 2019;120:922–30.

    Article  Google Scholar 

  20. Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S. et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature. 2009;460:904–8.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Tumor Registry of the Pathology Department of the 12 University Hospital, Madrid.

Funding

This work was funded by Projects PI16/01650 to JP, and PI16/01920 to RG-S, from the Spanish Ministry of Health and Consumer Affairs and FEDER, by Project 2012-0036 from the Mutua Madrileña Foundation. ANH was supported by the National Institutes of Health K12 HD043483 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Author information

Author notes

  1. These authors contributed equally: Sandra Tapial, Juan Luis García

Authors and Affiliations

  1. Digestive Cancer Research Unit, 12 de Octubre Research Institute, Madrid, Spain

    Sandra Tapial & Daniel Rueda

  2. Hereditary Cancer Laboratory, 12 de Octubre University Hospital, Madrid, Spain

    Sandra Tapial & Daniel Rueda

  3. Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca-USAL-CSIC, Salamanca, Spain

    Juan Luis García, Luis Corchete, Jessica Pérez & Rogelio González-Sarmiento

  4. Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain

    Juan Luis García, Luis Corchete, Jessica Pérez & Rogelio González-Sarmiento

  5. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Andreana N. Holowatyj

  6. Vanderbilt-Ingram Cancer Center, Nashville, TN, USA

    Andreana N. Holowatyj

  7. Familial Cancer Clinical Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Miguel Urioste

  8. Centre for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain

    Miguel Urioste

  9. Surgery Department, Fundación Jiménez Díaz University Hospital, Madrid, Spain

    José Perea

  10. Health Research Institute Fundación Jiménez Díaz, Madrid, Spain

    José Perea

Authors
  1. Sandra Tapial
    View author publications

    Search author on:PubMed Google Scholar

  2. Juan Luis García
    View author publications

    Search author on:PubMed Google Scholar

  3. Luis Corchete
    View author publications

    Search author on:PubMed Google Scholar

  4. Andreana N. Holowatyj
    View author publications

    Search author on:PubMed Google Scholar

  5. Jessica Pérez
    View author publications

    Search author on:PubMed Google Scholar

  6. Daniel Rueda
    View author publications

    Search author on:PubMed Google Scholar

  7. Miguel Urioste
    View author publications

    Search author on:PubMed Google Scholar

  8. Rogelio González-Sarmiento
    View author publications

    Search author on:PubMed Google Scholar

  9. José Perea
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to José Perea.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tapial, S., García, J.L., Corchete, L. et al. Copy neutral loss of heterozygosity (cnLOH) patterns in synchronous colorectal cancer. Eur J Hum Genet 29, 709–713 (2021). https://doi.org/10.1038/s41431-020-00774-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41431-020-00774-w

This article is cited by

Search

Advanced search

Quick links