Mechanism of ERBB2 gene overexpression by the formation of super-enhancer with genomic structural abnormalities in lung adenocarcinoma without clinically actionable genetic alterations

Author:

Kaneko SyuzoORCID,Takasawa KenORCID,Asada KenORCID,Shiraishi KouyaORCID,Ikawa Noriko,Machino HidenoriORCID,Shinkai NorioORCID,Matsuda Maiko,Masuda MariORCID,Adachi Shungo,Takahashi Satoshi,Kobayashi Kazuma,Kouno Nobuji,Bolatkan Amina,Komatsu MasaakiORCID,Yamada MasayoshiORCID,Miyake MototakaORCID,Watanabe HirokazuORCID,Tateishi Akiko,Mizuno TakaakiORCID,Okubo Yu,Mukai MasamiORCID,Yoshida Tatsuya,Yoshida Yukihiro,Horinouchi HidehitoORCID,Watanabe Shun-Ichi,Ohe Yuichiro,Yatabe Yasushi,Saloura Vassiliki,Kohno TakashiORCID,Hamamoto RyujiORCID

Abstract

Abstract Background In an extensive genomic analysis of lung adenocarcinomas (LUADs), driver mutations have been recognized as potential targets for molecular therapy. However, there remain cases where target genes are not identified. Super-enhancers and structural variants are frequently identified in several hundred loci per case. Despite this, most cancer research has approached the analysis of these data sets separately, without merging and comparing the data, and there are no examples of integrated analysis in LUAD. Methods We performed an integrated analysis of super-enhancers and structural variants in a cohort of 174 LUAD cases that lacked clinically actionable genetic alterations. To achieve this, we conducted both WGS and H3K27Ac ChIP-seq analyses using samples with driver gene mutations and those without, allowing for a comprehensive investigation of the potential roles of super-enhancer in LUAD cases. Results We demonstrate that most genes situated in these overlapped regions were associated with known and previously unknown driver genes and aberrant expression resulting from the formation of super-enhancers accompanied by genomic structural abnormalities. Hi-C and long-read sequencing data further corroborated this insight. When we employed CRISPR-Cas9 to induce structural abnormalities that mimicked cases with outlier ERBB2 gene expression, we observed an elevation in ERBB2 expression. These abnormalities are associated with a higher risk of recurrence after surgery, irrespective of the presence or absence of driver mutations. Conclusions Our findings suggest that aberrant gene expression linked to structural polymorphisms can significantly impact personalized cancer treatment by facilitating the identification of driver mutations and prognostic factors, contributing to a more comprehensive understanding of LUAD pathogenesis.

Funder

JSPS Grant-in-Aid for Scientific Research

The Takeda Science Foundation

The Princess Takamatsu Cancer Research Fund

AMED Innovative Cancer Medical Practice Research Project

JST CREST

JSPS Grant-in-Aid for Scientific Research on Innovative Areas

JST AIP-PRISM

The MEXT subsidy for the Advanced Integrated Intelligence Platform

Publisher

Springer Science and Business Media LLC

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