THESIS
2018
xiii, 193 pages : color illustrations ; 30 cm
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 LOH...[
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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.
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