Forward and reverse mutations in stages of cancer development

Abstract

Cancer has been recognized as a disease of the genome. Using the next-generation sequencing (NGS) platform, large numbers of interstitial loss-of-heterozygosities (LOHs) along with gain-of-heterozygosities (GOHs) type of single-nucleotide-variations (SNVs) were found in cancers. Here multiple same-patient samples were analyzed using the AluScan platform to determine the interplay between GOHs and LOHs. Morphologically normal tissues > 2 cm away from and within 2 cm of tumors (T) were designated as ‘nontumor’ (N) and ‘paratumor’ (P) samples. Widespread GOHs enriched with CG-to-TG changes and associated with nearby CNVs, and LOHs enriched with TG-to-CG changes, were observed. Occurrences of GOH were 1.9-fold higher than LOH in ‘nontumor’ tissues, and a majority of these GOHs and LOHs were reversed in ‘paratumor’ tissues, forming forward-reverse mutation cycles. The revertant LOHs displayed strong lineage effects that pointed to a sequential development from ‘nontumor’ to ‘paratumor’ and onto tumor cells, which was also supported by the relative frequencies of 26 distinct classes of CNVs between these three types of cell populations. They have also been demonstrated in whole-genome-sequencing and whole-exome-sequencing data. The results suggest that N, P and T represent successive ‘Stage-Specific Populations’ (SSP) in cancer cell development. The SSP model suggests that widespread genomic alterations in N- and P-stages provide the mutations required for carcinogenesis, and substantial reversions of these mutations are necessary to reduce mutation-load and facilitate cancer growth. An understanding of forward-reverse mutation cycles in cancer development could provide a genomic basis for improved early diagnosis, staging, and treatment of cancers.

Date of Award	2018
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology