Abstract
BackgroundMassive 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.MethodsIn 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.ResultsWidespread 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.ConclusionsThese 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.
Highlights
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 Single-nucleotide variation (SNV), raising the question of the relationships between these two opposing types of cancer mutations
Genotypic changes in nontumor and paratumor tissues White blood cells (B), tumor tissue (T), paratumor tissue (P) immediately adjacent to the tumor, and more remote nontumor tissue (N) were collected in 12 same-patient tetra sample cases consisted of four breast carcinomas (BRCA), five stomach adenocarcinomas (STAD), and three hepatocellular carcinomas (LIHC) (Additional files 1 and 2: Tables S1 and S2) and subjected to DNA analysis using the Genome-wide scanning using Alu-based primers (AluScan) platform based on inter-Alu polymerase chain reaction (PCR) followed by massively parallel sequencing as described in the “Methods” section
Since the numbers of GOH-M, GOH-m, and LOH mutations were higher in ΔNB than in ΔTB, and comparable in ΔPB and ΔTB, both the N-sample and P-sample cells had to be regarded as premalignant or early malignant cells despite their normal morphology and expression of immunohistochemistry (IHC) markers, in contrast with T-sample cells showing enlarged nuclei (Fig. 1c) and reduced expression of IHC markers (Additional file 1: Table S1)
Summary
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. We have reported the finding of the commonly encountered single-nucleotide variations (SNVs) in the form of gain of heterozygosities (GOHs), and massive SNVs in the form of interstitial loss of heterozygosities (LOHs) in various types of cancers [17]. This raises the question of the interrelations between the LOH and GOH mutations along with the copy number variations (CNVs) as the most abundant mutational elements of cancer cells. The same applies to the forward and reverse changes in CNVs
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