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

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

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1285508

DOI=10.3389/fonc.2023.1285508

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Method</title><p>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.</p></sec><sec><title>Results</title><p>Our findings underscore the intricate heterogeneity of genetic alterations within CRC. Notably, <italic>BRAF</italic>, <italic>ARID2</italic>, <italic>KMT2C</italic>, and <italic>GNAQ</italic> were associated with CRC prognosis. Patients harboring <italic>BRAF</italic>, <italic>ARID2</italic>, or <italic>KMT2C</italic> mutations exhibited shorter progression-free survival (PFS), whereas those with <italic>BRAF</italic>, <italic>ARID2</italic>, or <italic>GNAQ</italic> 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 <italic>BRAF</italic>/<italic>ALK</italic>, <italic>BRAF</italic>/<italic>NOTCH2</italic>, <italic>BRAF</italic>/<italic>CREBBP</italic>, and <italic>BRAF</italic>/<italic>FAT1</italic> correlated with worse PFS. Furthermore, germline <italic>AR</italic> 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 <italic>AR</italic> 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.</p></sec><sec><title>Conclusion</title><p>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.</p></sec>