Copy Number Variants (CNVs) and Small Insertions/Deletions (INDELs) in a Cohort of Colorectal Cancer Patients from Newfoundland

Salem Werdyani¹, Georgia Skardasi¹, Jingxiong Xu², Konstantin Shestopaloff³, Wei Xu^2,3, Elizabeth Dicks⁴, Jane Green¹, Patrick Parfrey⁴, Roger Green¹, Sevtap Savas^1,5

1. Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada; 2. Department of Biostatistics, Princess Margaret Hospital, Toronto, ON, Canada; 3. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada; 4. Clinical Epidemiology Unit, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada. 5Discipline of Oncology, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada

Introduction: Deleted or duplicated DNA segments larger than one kilobase (kb) are called copy number variations (CNVs), whereas the smaller ones are called insertions/deletions (INDELs). Recent studies reported important roles for these genetic variations in cancer susceptibility and outcome risk. This study aimed to computationally predict and identify the possible biological consequences of the INDELs/CNVs in 505 Caucasian colorectal cancer patients.

Methods: Patients (n=505) recruited to the Newfoundland Colorectal Cancer Registry (NFCCR) were included into this study. Their previously obtained genome-wide signal intensity data was processed and used to predict the INDELs/CNVs for each patient using the PennCNV and QuantiSNP algorithms. Stringent quality control criteria were applied to exclude low quality data. Information on the variations that were experimentally validated by others was retrieved from the Database of Genomic Variants (DGV) and compared with the predictions obtained. Ensembl database was utilized to identify the genes affected by the INDELs/CNVs. Biological pathways that may be affected by the INDELs/CNVs were then examined using the information in the PANTHER database. Duplex PCR was used to confirm homozygous deletions using DNA samples of 100 patients for five genic CNVs.

Results: The total number of distinct INDELs/CNVs identified was 3,349. The majority of these variations (83%) were rare occurring in less than 5% of the cohort. A set of INDELs/CNVs (63.3%) were detected to at least partially overlap with 1,589 different human genes. The biological pathway analysis returned information for 767 out of the 1,589 genes. These genes act in multiple pathways including signaling, immune system, and neurohormone/neurotransmitter-related pathways, which suggest that INDELs/CNVs may affect these biological processes in patients. Homozygous deletions were confirmed in ≥ 98% of the patients for five genic CNVs. These deletions are located within four cancer related genes and a gene with an unknown function.

Conclusion: This study is one of the most comprehensive studies that identified the genome-wide INDEL/CNV profiles in colorectal cancer. A significant portion of these variations are likely to affect genes and pathways that play roles in colorectal cancer development and prognosis. Further investigations focusing on the possible associations of these genetic variations with disease risk and prognosis are warranted.