Abstract:
Introduction: Hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant disorder characterized
by the development of multiple cancer types. Molecular diagnosis of HNPCC requires the precise identification of
pathogenic germline variants in DNA mismatch repair (MMR) genes. Next Generation Sequencing (NGS) is now
the gold standard test in practice, to identify these variants. However, large genomic rearrangements (LGR) in cancer
predisposing genes (CPGs) are missed by NGS. This may lead to underestimation of the frequency of the variants,
misleading the genetic diagnosis and delaying intervention in high risk individuals. Hence this study was aimed at
identifying the presence of large genomic alterations that could explain the missing heritable risk of colon cancer in
affected patients with family history strongly suggestive of hereditary colorectal cancer in Sri Lanka. Methods: A
cohort of six patients affected with hereditary colorectal cancer who tested negative for pathogenic variants in next
generation sequencing studies was investigated using Sure Print G3 Human CGH 4x180K microarray platform. Agilent
Genomic-Workbench-v7.0.4.0 software was used to identify the Copy Number Variants (CNV). Four healthy individuals
(>55years) were used as controls. Annotations of the CNV regions which were observed were done using the database
of Genomic Variants. Results: We identified 150 CNVs including regions of both genomic gains and losses in the
patient cohort. There was no difference in the average number or the average genomic burden of CNVs identified in
the patients versus the controls. CNVs were residing on the positions of 1q21.2, 2q37.3, 2p11.2-p11.1, 5q13.2, 6p12.3,
7q31.33, 7p14.1, 14q32.33, 15q11.1-11.2, 16p11.2, 22q11.22, 22q13.1 that were assessed by the array platform used
in the study. CNVs in any of the well-known common CPG s or CNVs that reside on or in close proximity to genes
corresponding to MMR pathway were not identified. We found several distinct pathways that have previously been
identified as having a direct association with the progression of HNPCC. Conclusion: This study shows that CNVs
are likely contributors to the colorectal cancer predisposition in a small but significant proportion of patients affected
with hereditary colorectal cancer in this cohort. Further studies have to perform to get a better understanding on the
contribution of CNVs to the cancer predisposition in this cohort of patients in the Sri Lankan population.
