Abstract
Purpose
A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called ‘missing heritability’. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset.
Methods/patients
We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter.
Results
We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis.
Conclusions
These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC.
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Acknowledgements
This work was supported by grants from the Fondo de Investigación Sanitaria/FEDER (11/00681, 11/00219), and COST Action BM1206 (EUCOLONGENE). AJB-F is supported by a contract from CIBERER (Centro de Investigacion Biomedica en Red de Enfermedades Raras). CIBERER is funded by the Instituto de Salud Carlos III. We are sincerely grateful to the patients who generously contributed to this study.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Brea-Fernandez, A.J., Fernandez-Rozadilla, C., Alvarez-Barona, M. et al. Candidate predisposing germline copy number variants in early onset colorectal cancer patients. Clin Transl Oncol 19, 625–632 (2017). https://doi.org/10.1007/s12094-016-1576-z
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DOI: https://doi.org/10.1007/s12094-016-1576-z