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Hum Genomics. 2018 Aug 22;12(1):40. doi: 10.1186/s40246-018-0170-6.

Forward and reverse mutations in stages of cancer development.

Author information

1
Division of Life Science, Applied Genomics Centre and Centre for Statistical Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
2
Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
3
Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
4
Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
5
Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
6
Jiangsu Key Laboratory of Cancer Molecular Biology and Translational Medicine, Jiangsu Cancer Hospital, Nanjing, China.
7
Division of Neurosurgery, Department of Surgery, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong, China.
8
Division of Life Science, Applied Genomics Centre and Centre for Statistical Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. hxue@ust.hk.
9
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. hxue@ust.hk.

Abstract

BACKGROUND:

Massive occurrences of interstitial loss of heterozygosity (LOH) likely resulting from gene conversions were found by us in different cancers as a type of single-nucleotide variations (SNVs), comparable in abundance to the commonly investigated gain of heterozygosity (GOH) type of SNVs, raising the question of the relationships between these two opposing types of cancer mutations.

METHODS:

In the present study, SNVs in 12 tetra sample and 17 trio sample sets from four cancer types along with copy number variations (CNVs) were analyzed by AluScan sequencing, comparing tumor with white blood cells as well as tissues vicinal to the tumor. Four published "nontumor"-tumor metastasis trios and 246 pan-cancer pairs analyzed by whole-genome sequencing (WGS) and 67 trios by whole-exome sequencing (WES) were also examined.

RESULTS:

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 more than 2 cm away from the tumors, and a majority of these GOHs and LOHs were reversed in "paratumor" tissues within 2 cm of the tumors, forming forward-reverse mutation cycles where the revertant LOHs displayed strong lineage effects that pointed to a sequential instead of parallel 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.

CONCLUSIONS:

These findings suggest that developing cancer cells undergo sequential changes that enable the "nontumor" cells to acquire a wide range of forward mutations including ones that are essential for oncogenicity, followed by revertant mutations in the "paratumor" cells to avoid growth retardation by excessive mutation load. Such utilization of forward-reverse mutation cycles as an adaptive mechanism was also observed in cultured HeLa cells upon successive replatings. An understanding of forward-reverse mutation cycles in cancer development could provide a genomic basis for improved early diagnosis, staging, and treatment of cancers.

KEYWORDS:

Clonal evolution; Copy number variation; Interstitial loss of heterozygosity; Precancer mutations; Single-nucleotide variation

PMID:
30134973
PMCID:
PMC6104001
DOI:
10.1186/s40246-018-0170-6
[Indexed for MEDLINE]
Free PMC Article

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