Association of frequent hypermethylation with high grade histological subtype in lung adenocarcinoma

被引：6

作者：

Ito, Yuki ^{[1
,2
]}

Usui, Genki ^{[2
]}

Seki, Motoaki ^{[2
]}

Fukuyo, Masaki ^{[2
]}

Matsusaka, Keisuke ^{[2
,3
]}

Hoshii, Takayuki ^{[2
]}

Sata, Yuki ^{[2
]}

Morimoto, Junichi ^{[1
,2
]}

Hata, Atsushi ^{[1
,2
]}

Nakajima, Takahiro ^{[1
]}

Rahmutulla, Bahityar ^{[2
]}

Kaiho, Taisuke ^{[1
]}

Inage, Terunaga ^{[1
]}

Tanaka, Kazuhisa ^{[1
]}

Sakairi, Yuichi ^{[1
]}

Suzuki, Hidemi ^{[1
]}

Yoshino, Ichiro ^{[1
]}

Kaneda, Atsushi ^{[2
,4
]}

机构：

[1] Chiba Univ, Grad Sch Med, Dept Gen Thorac Surg, Chiba, Japan

[2] Chiba Univ, Grad Sch Med, Dept Mol Oncol, Chiba, Japan

[3] Chiba Univ Hosp, Dept Pathol, Chiba, Japan

[4] Chiba Univ, Grad Sch Med, Dept Mol Oncol, 1 8 1 Inohana, Chuo ku, Chiba 2608670, Japan

来源：

CANCER SCIENCE | 2023年 / 114卷 / 07期

关键词：

DNA methylation; high-grade subtype; histological subtype; lung adenocarcinoma; micropapillary component; DNA METHYLATION; INTERNATIONAL ASSOCIATION; LIMITED RESECTION; CANCER; CLASSIFICATION; IMPACT; PROGNOSIS; LOBECTOMY; GENE;

D O I：

10.1111/cas.15817

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Lung adenocarcinoma is classified morphologically into five histological subtypes according to the WHO classification. While each histological subtype correlates with a distinct prognosis, the molecular basis has not been fully elucidated. Here we conducted DNA methylation analysis of 30 lung adenocarcinoma cases annotated with the predominant histological subtypes and three normal lung cases using the Infinium BeadChip. Unsupervised hierarchical clustering analysis revealed three subgroups with different methylation levels: high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME). Micropapillary pattern (MPP)-predominant cases and those with MPP components were significantly enriched in HME (p = 0.02 and p = 0.03, respectively). HME cases showed a significantly poor prognosis for recurrence-free survival (p < 0.001) and overall survival (p = 0.006). We identified 365 HME marker genes specifically hypermethylated in HME cases with enrichment of "cell morphogenesis" related genes; 305 IME marker genes hypermethylated in HME and IME, but not in LME, with enrichment "embryonic organ morphogenesis"-related genes; 257 Common marker genes hypermethylated commonly in all cancer cases, with enrichment of "regionalization"-related genes. We extracted surrogate markers for each epigenotype and designed pyrosequencing primers for five HME markers (TCERG1L, CXCL12, FAM181B, HOXA11, GAD2), three IME markers (TBX18, ZNF154, NWD2) and three Common markers (SCT, GJD2, BARHL2). DNA methylation profiling using Infinium data was validated by pyrosequencing, and HME cases defined by pyrosequencing results also showed the worse recurrence-free survival. In conclusion, lung adenocarcinomas are stratified into subtypes with distinct DNA methylation levels, and the high-methylation subtype correlated with MPP-predominant cases and those with MPP components and showed a poor prognosis.

引用

页码：3003 / 3013

页数：11

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