Targeted next generation sequencing reveals a common genetic pathway for colorectal cancers with chromosomal instability and those with microsatellite and chromosome stability

• Published in: Pathology, research and practice Vol. 215; no. 7; p. 152445
• Main Authors: Ham-Karim, Hersh A., Ebili, Henry O., Bradshaw, Kirsty, Richman, Susan D., Fadhil, Wakkas, Domingo, Enric, Tomlinson, Ian, Ilyas, Mohammad
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.07.2019
• Subjects: Alleles; Chromosomal Instability; colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Gene Frequency; genomic instability; High-Throughput Nucleotide Sequencing; Humans; Microsatellite and chromosomal stable; Microsatellite Instability; Mutation; Next-generation sequencing; tumour ploidy; colorectal cancer; Next-generation sequencing; tumour ploidy; Chromosomal instability; Microsatellite and chromosomal stable; genomic instability
• ISSN: 0344-0338; 1618-0631
• DOI: 10.1016/j.prp.2019.152445

Microsatellite stable sporadic colorectal cancers (CRCs) can be classified as either tumours with chromosomal instability (CIN+) or tumours that are ‘Microsatellite and Chromosomal Stable’ (MACS). The CIN + tumours are aneuploid whilst MACS are near-diploid; little else is known about their differences. We compared the mutation profiles of CIN + and MACS CRCs. Targeted Next Generation Sequencing for mutation in 26 driver genes (TruSight-26 kit) was undertaken in 46 CIN + and 35 MACSCRCs. Tumours were compared for mutation frequency, allelic imbalance and clonal heterogeneity. Mutations were detected in 58% genes and, overall, mutation in driver genes was at expected frequencies. Comparison of classes revealed similar mutation frequencies in most genes and allelic imbalance atAPC and TP53. Differences were seen in mutation frequency in KRAS (41% CIN+ vs 68% MACS, p = 0.015) and GNAS (0% CIN+ vs 12% MACS, p = 0.032). Twenty percent CIN + CRCs harboured mutations only in TP53 - a profile not seen in the MACS tumours (p = 0.009). None of the differences were significant after multiple testing corrections. The mutation profiles of CIN and MACS CRCs are similar. The events allowing aneuploidy (or forcing retention of diploidy) remain unknown.