Whole-Genome Profiles of Malay Colorectal Cancer Patients with Intact MMR Proteins.

Wan Khairunnisa Wan Juhari,Khairul Bariah Ahmad Amin Noordin,Wan Faiziah Wan Abdul Rahman,Muhammad Radzi Abu Hassan,Andee Dzulkarnaen Zakaria,Ahmad Shanwani Mohammed Sidek,Wan Muhamad Mokhzani Wan Muhamad Mokhter,Bin Alwi Zilfalil

doi:10.3390/genes12091448

Abstract

Background: This study aimed to identify new genes associated with CRC in patients with normal mismatch repair (MMR) protein expression. Method: Whole-genome sequencing (WGS) was performed in seven early-age-onset Malay CRC patients. Potential germline genetic variants, including single-nucleotide variations and insertions and deletions (indels), were prioritized using functional and predictive algorithms. Results: An average of 3.2 million single-nucleotide variations (SNVs) and over 800 indels were identified. Three potential candidate variants in three genes—IFNE, PTCH2 and SEMA3D—which were predicted to affect protein function, were identified in three Malay CRC patients. In addition, 19 candidate genes—ANKDD1B, CENPM, CLDN5, MAGEB16, MAP3K14, MOB3C, MS4A12, MUC19, OR2L8, OR51Q1, OR51AR1, PDE4DIP, PKD1L3, PRIM2, PRM3, SEC22B, TPTE, USP29 and ZNF117—harbouring nonsense variants were prioritised. These genes are suggested to play a role in cancer predisposition and to be associated with cancer risk. Pathway enrichment analysis indicated significant enrichment in the olfactory signalling pathway. Conclusion: This study provides a new spectrum of insights into the potential genes, variants and pathways associated with CRC in Malay patients.

Highlights

IntroductionPotential germline genetic variants, including single-nucleotide variations and insertions and deletions (indels), were prioritized using functional and predictive algorithms
The resulting variants in Mismatch repair (MMR) genes were mostly discovered in intronic regions, suggesting that the variants may have no effect on protein expression
The whole-genome sample data of the studied patients were filtered and prioritized to fully characterize the high- and low-risk loci that may be associated with Colorectal cancer (CRC) in Malay patients fulfilling the Bethesda criteria

Summary

Introduction

Potential germline genetic variants, including single-nucleotide variations and insertions and deletions (indels), were prioritized using functional and predictive algorithms. Three potential candidate variants in three genes—IFNE, PTCH2 and SEMA3D—which were predicted to affect protein function, were identified in three. 19 candidate genes—ANKDD1B, CENPM, CLDN5, MAGEB16, MAP3K14, MOB3C, MS4A12, MUC19, OR2L8, OR51Q1, OR51AR1, PDE4DIP, PKD1L3, PRIM2, PRM3, SEC22B, TPTE, USP29 and ZNF117—harbouring nonsense variants were prioritised. These genes are suggested to play a role in cancer predisposition and to be associated with cancer risk. Conclusion: This study provides a new spectrum of insights into the potential genes, variants and pathways associated with CRC in Malay patients

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Conclusion