TY - JOUR
T1 - DNA hypermethylation of the ZNF132 gene participates in the clinicopathological aggressiveness of 'pan-negative'-type lung adenocarcinomas
AU - Hamada, Kenichi
AU - Tian, Ying
AU - Fujimoto, Mao
AU - Takahashi, Yoriko
AU - Kohno, Takashi
AU - Tsuta, Koji
AU - Watanabe, Shun Ichi
AU - Yoshida, Teruhiko
AU - Asamura, Hisao
AU - Kanai, Yae
AU - Arai, Eri
N1 - Publisher Copyright:
© 2020 The Author(s) 2020. Published by Oxford University Press.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - Although some previous studies have examined epigenomic alterations in lung adenocarcinomas, correlations between epigenomic events and genomic driver mutations have not been fully elucidated. Single-CpG resolution genome-wide DNA methylation analysis with the Infinium HumanMethylation27 BeadChip was performed using 162 paired samples of adjacent normal lung tissue (N) and the corresponding tumorous tissue (T) from patients with lung adenocarcinomas. Correlations between DNA methylation data on the one hand and clinicopathological parameters and genomic driver mutations, i.e. mutations of EGFR, KRAS, BRAF and HER2 and fusions involving ALK, RET and ROS1, were examined. DNA methylation levels in 12 629 probes from N samples were significantly correlated with recurrence-free survival. Principal component analysis revealed that distinct DNA methylation profiles at the precancerous N stage tended not to induce specific genomic driver aberrations. Most of the genes showing significant DNA methylation alterations during transition from N to T were shared by two or more driver aberration groups. After small interfering RNA knockdown of ZNF132, which showed DNA hypermethylation only in the pan-negative group and was correlated with vascular invasion, the proliferation, apoptosis and migration of cancer cell lines were examined. ZNF132 knockdown led to increased cell migration ability, rather than increased cell growth or reduced apoptosis. We concluded that DNA hypermethylation of the ZNF132 gene participates in the clinicopathological aggressiveness of 'pan-negative' lung adenocarcinomas. In addition, DNA methylation alterations at the precancerous stage may determine tumor aggressiveness, and such alterations that accumulate after driver mutation may additionally modify clinicopathological features through alterations of gene expression.
AB - Although some previous studies have examined epigenomic alterations in lung adenocarcinomas, correlations between epigenomic events and genomic driver mutations have not been fully elucidated. Single-CpG resolution genome-wide DNA methylation analysis with the Infinium HumanMethylation27 BeadChip was performed using 162 paired samples of adjacent normal lung tissue (N) and the corresponding tumorous tissue (T) from patients with lung adenocarcinomas. Correlations between DNA methylation data on the one hand and clinicopathological parameters and genomic driver mutations, i.e. mutations of EGFR, KRAS, BRAF and HER2 and fusions involving ALK, RET and ROS1, were examined. DNA methylation levels in 12 629 probes from N samples were significantly correlated with recurrence-free survival. Principal component analysis revealed that distinct DNA methylation profiles at the precancerous N stage tended not to induce specific genomic driver aberrations. Most of the genes showing significant DNA methylation alterations during transition from N to T were shared by two or more driver aberration groups. After small interfering RNA knockdown of ZNF132, which showed DNA hypermethylation only in the pan-negative group and was correlated with vascular invasion, the proliferation, apoptosis and migration of cancer cell lines were examined. ZNF132 knockdown led to increased cell migration ability, rather than increased cell growth or reduced apoptosis. We concluded that DNA hypermethylation of the ZNF132 gene participates in the clinicopathological aggressiveness of 'pan-negative' lung adenocarcinomas. In addition, DNA methylation alterations at the precancerous stage may determine tumor aggressiveness, and such alterations that accumulate after driver mutation may additionally modify clinicopathological features through alterations of gene expression.
UR - http://www.scopus.com/inward/record.url?scp=85102322452&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102322452&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgaa115
DO - 10.1093/carcin/bgaa115
M3 - Article
C2 - 33152763
AN - SCOPUS:85102322452
SN - 0143-3334
VL - 42
SP - 169
EP - 179
JO - Carcinogenesis
JF - Carcinogenesis
IS - 2
ER -