Comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer

Jinwei Yang; Sihui Zhao; Junyan Su; Siyao Liu; Zaozao Wu; Wei Ma; Ming Tang; Jingcui Wu; Erdong Mao; Li Han; Mengyuan Liu; Jiali Zhang; Lei Cao; Jingyi Shao; Yun Shang

doi:10.3389/fonc.2023.1285508

Comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer

Front Oncol. 2023 Nov 13:13:1285508. doi: 10.3389/fonc.2023.1285508. eCollection 2023.

Authors

Jinwei Yang^#^{1

2}, Sihui Zhao^#¹, Junyan Su^#³, Siyao Liu³, Zaozao Wu¹, Wei Ma², Ming Tang⁴, Jingcui Wu¹, Erdong Mao¹, Li Han³, Mengyuan Liu³, Jiali Zhang³, Lei Cao³, Jingyi Shao⁵, Yun Shang¹

Affiliations

¹ Second Department of General Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.
² Institute of Neuroscience, Kunming Medical University, Kunming, China.
³ Department of Scientific Research Projects, Beijing ChosenMed Clinical Laboratory Co. Ltd., Beijing, China.
⁴ Department of Pathology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.
⁵ Department of Reproductive Medicine, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.

^# Contributed equally.

Abstract

Background: Colorectal cancer (CRC) is a prevalent malignancy with diverse molecular characteristics. The NGS-based approach enhances our comprehension of genomic landscape of CRC and may guide future advancements in precision oncology for CRC patients.

Method: In this research, we conducted an analysis using Next-Generation Sequencing (NGS) on samples collected from 111 individuals who had been diagnosed with CRC. We identified somatic and germline mutations and structural variants across the tumor genomes through comprehensive genomic profiling. Furthermore, we investigated the landscape of driver mutations and their potential clinical implications.

Results: Our findings underscore the intricate heterogeneity of genetic alterations within CRC. Notably, BRAF, ARID2, KMT2C, and GNAQ were associated with CRC prognosis. Patients harboring BRAF, ARID2, or KMT2C mutations exhibited shorter progression-free survival (PFS), whereas those with BRAF, ARID2, or GNAQ mutations experienced worse overall survival (OS). We unveiled 80 co-occurring and three mutually exclusive significant gene pairs, enriched primarily in pathways such as TP53, HIPPO, RTK/RAS, NOTCH, WNT, TGF-Beta, MYC, and PI3K. Notably, co-mutations of BRAF/ALK, BRAF/NOTCH2, BRAF/CREBBP, and BRAF/FAT1 correlated with worse PFS. Furthermore, germline AR mutations were identified in 37 (33.33%) CRC patients, and carriers of these variants displayed diminished PFS and OS. Decreased AR protein expression was observed in cases with AR germline mutations. A four-gene mutation signature was established, incorporating the aforementioned prognostic genes, which emerged as an independent prognostic determinant in CRC via univariate and multivariate Cox regression analyses. Noteworthy BRAF and ARID2 protein expression decreases detected in patients with their respective mutations.

Conclusion: The integration of our analyses furnishes crucial insights into CRC's molecular characteristics, drug responsiveness, and the construction of a four-gene mutation signature for predicting CRC prognosis.

Keywords: colorectal cancer; next generation sequencing; prognosis; protein validation; signature.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work is supported by the National Natural Science Foundation of China (No.82160263), The Research Innovation Team of Yunnan Province (No.2019HC022), Ten Thousand Person Plan for Famous Doctors of Yunnan Province (YNWR-MY-2018-015), and The Yunnan Digestive Endoscopy Clinical Medical Center Foundation for Health Commission of Yunnan Province (2022LCZXKF-XH05 of ZX2019-01-02).