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Article: Forward and reverse mutations in stages of cancer development

TitleForward and reverse mutations in stages of cancer development
Authors
KeywordsClonal evolution
Copy number variation
Interstitial loss of heterozygosity
Precancer mutations
Single-nucleotide variation
Issue Date2018
PublisherBioMed Central Ltd. The Journal's web site is located at http://www.humgenomics.com
Citation
Human Genomics, 2018, v. 12, p. article no. 40 How to Cite?
AbstractBACKGROUND: 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.
Persistent Identifierhttp://hdl.handle.net/10722/272986
ISSN
2019 Impact Factor: 3.351
2015 SCImago Journal Rankings: 1.632
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorHu, T-
dc.contributor.authorKumar, Y-
dc.contributor.authorShazia, I-
dc.contributor.authorDuan, SJ-
dc.contributor.authorLi, Y-
dc.contributor.authorChen, L-
dc.contributor.authorChen, JF-
dc.contributor.authorYin, R-
dc.contributor.authorKwong, A-
dc.contributor.authorLeung, GKK-
dc.contributor.authorMat, WK-
dc.contributor.authorWu, Z-
dc.contributor.authorLong, X-
dc.contributor.authorChan, CH-
dc.contributor.authorChen, S-
dc.contributor.authorLee, P-
dc.contributor.authorNg, SK-
dc.contributor.authorHo, TYC-
dc.contributor.authorYang, J-
dc.contributor.authorDing, X-
dc.contributor.authorTsang, SY-
dc.contributor.authorZhou, X-
dc.contributor.authorZhang, DH-
dc.contributor.authorThe International Cancer Genome Consortium-
dc.contributor.authorZhou, EX-
dc.contributor.authorXu, L-
dc.contributor.authorPoon, WS-
dc.contributor.authorWang, HY-
dc.contributor.authorXue, H-
dc.date.accessioned2019-08-06T09:20:26Z-
dc.date.available2019-08-06T09:20:26Z-
dc.date.issued2018-
dc.identifier.citationHuman Genomics, 2018, v. 12, p. article no. 40-
dc.identifier.issn1473-9542-
dc.identifier.urihttp://hdl.handle.net/10722/272986-
dc.description.abstractBACKGROUND: 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.-
dc.languageeng-
dc.publisherBioMed Central Ltd. The Journal's web site is located at http://www.humgenomics.com-
dc.relation.ispartofHuman Genomics-
dc.rightsHuman Genomics. Copyright © BioMed Central Ltd.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectClonal evolution-
dc.subjectCopy number variation-
dc.subjectInterstitial loss of heterozygosity-
dc.subjectPrecancer mutations-
dc.subjectSingle-nucleotide variation-
dc.titleForward and reverse mutations in stages of cancer development-
dc.typeArticle-
dc.identifier.emailKwong, A: avakwong@hku.hk-
dc.identifier.emailLeung, GKK: gkkleung@hku.hk-
dc.identifier.authorityKwong, A=rp01734-
dc.identifier.authorityLeung, GKK=rp00522-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/s40246-018-0170-6-
dc.identifier.pmid30134973-
dc.identifier.pmcidPMC6104001-
dc.identifier.scopuseid_2-s2.0-85055615685-
dc.identifier.hkuros300026-
dc.identifier.hkuros301053-
dc.identifier.volume12-
dc.identifier.spagearticle no. 40-
dc.identifier.epagearticle no. 40-
dc.publisher.placeUnited Kingdom-

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