Analysis of Actionable Gene Fusions in a Large Cohort of Chinese Patients with Colorectal Cancer

Overview

Journal Gastroenterol Rep (Oxf)

Specialty Gastroenterology

Date 2024 Oct 11

PMID 39391592

Authors

Fu-Rong Kou

Jian Li

Zheng-Hang Wang

Ting Xu

Juan-Juan Qian

En-Li Zhang

Li-Jun Zhang

Lin Shen

Xi-Cheng Wang

Affiliations

Soon will be listed here.

Abstract

Background: The prevalence of gene fusion is extremely low in unselected patients with colorectal cancer (CRC). Published data on gene fusions are limited by relatively small sample sizes, with a primary focus on Western populations. This study aimed to analyse actionable gene fusions in a large consecutive Chinese CRC population.

Methods: This study included 5,534 consecutive CRC patients from the Genecast database. Genomic profiling was performed using a panel of 769 cancer-related genes. Data for 34 CRC patients with actionable gene fusions were also collected from cBioPortal and ChimerSeq.

Results: Among 5,534 CRC patients, 54 (0.98%) had actionable gene fusions, with being the most common fusion (0.38%), accounting for 38.9% (21/54) of those with fusions. Actionable gene fusion enrichment was higher in patients with microsatellite instability-high (MSI-H) (6.7% vs. 0.5%, <0.001), wildtype (2.0% vs. 0.2%, <0.001) and mutation (7.7% vs. 0.4%, <0.001) than in patients with microsatellite stability/MSI-low, mutation and wildtype, respectively. When these markers were combined, the fusion detection rate increased. Among patients with wildtype and MSI-H, fusions were detected in 20.3% of patients. The fusion detection rate further increased to 37.5% when mutation was added. The fusion detection rate was also higher in colon cancer than in rectal cancer. No significant differences in clinical or molecular features were found in patients with actionable gene fusions between the Genecast, cBioPortal, and ChimerSeq databases.

Conclusions: Approximately 1% of the unselected Chinese CRC population carries actionable gene fusions, mostly involving . Actionable gene fusions are more prevalent in MSI-H, wildtype, or -mutated CRC, as well as in colon cancer. Mapping of these molecular markers can markedly increase the fusion detection rate, which can help clinicians select candidates for fusion testing and targeted therapy.

Citing Articles

Identification and Characterization of a Novel Gene Rearrangement in an Advanced Colorectal Cancer Patient: A Case Report.

Carlos Montero J, Tur R, Jimenez-Perez A, Filipovich E, Alcaraz S, Rodriguez M Int J Mol Sci. 2024; 25(23).

PMID: 39684377 PMC: 11641570. DOI: 10.3390/ijms252312665.

References

Doebele R, Drilon A, Paz-Ares L, Siena S, Shaw A, Farago A . Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2019; 21(2):271-282. PMC: 7461630. DOI: 10.1016/S1470-2045(19)30691-6. View

Siegel R, Miller K, Jemal A . Cancer statistics, 2020. CA Cancer J Clin. 2020; 70(1):7-30. DOI: 10.3322/caac.21590. View

Akhoundova D, Hussung S, Sivakumar S, Topfer A, Rechsteiner M, Kahraman A . ROS1 genomic rearrangements are rare actionable drivers in microsatellite stable colorectal cancer. Int J Cancer. 2022; 151(12):2161-2171. PMC: 9804412. DOI: 10.1002/ijc.34257. View

Li M, Datto M, Duncavage E, Kulkarni S, Lindeman N, Roy S . Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2016; 19(1):4-23. PMC: 5707196. DOI: 10.1016/j.jmoldx.2016.10.002. View

Yakirevich E, Resnick M, Mangray S, Wheeler M, Jackson C, Lombardo K . Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target. Clin Cancer Res. 2016; 22(15):3831-40. DOI: 10.1158/1078-0432.CCR-15-3000. View

Cocco E, Benhamida J, Middha S, Zehir A, Mullaney K, Shia J . Colorectal Carcinomas Containing Hypermethylated MLH1 Promoter and Wild-Type BRAF/KRAS Are Enriched for Targetable Kinase Fusions. Cancer Res. 2019; 79(6):1047-1053. PMC: 6420871. DOI: 10.1158/0008-5472.CAN-18-3126. View

Van Cutsem E, Cervantes A, Adam R, Sobrero A, van Krieken J, Aderka D . ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016; 27(8):1386-422. DOI: 10.1093/annonc/mdw235. View

Tsilimigras D, Ntanasis-Stathopoulos I, Bagante F, Moris D, Cloyd J, Spartalis E . Clinical significance and prognostic relevance of KRAS, BRAF, PI3K and TP53 genetic mutation analysis for resectable and unresectable colorectal liver metastases: A systematic review of the current evidence. Surg Oncol. 2018; 27(2):280-288. DOI: 10.1016/j.suronc.2018.05.012. View

Lai Z, Markovets A, Ahdesmaki M, Chapman B, Hofmann O, McEwen R . VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research. Nucleic Acids Res. 2016; 44(11):e108. PMC: 4914105. DOI: 10.1093/nar/gkw227. View

10.

Le D, Durham J, Smith K, Wang H, Bartlett B, Aulakh L . Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017; 357(6349):409-413. PMC: 5576142. DOI: 10.1126/science.aan6733. View

11.

Messersmith W . NCCN Guidelines Updates: Management of Metastatic Colorectal Cancer. J Natl Compr Canc Netw. 2019; 17(5.5):599-601. DOI: 10.6004/jnccn.2019.5014. View

12.

Bellio H, Fumet J, Ghiringhelli F . Targeting BRAF and RAS in Colorectal Cancer. Cancers (Basel). 2021; 13(9). PMC: 8124706. DOI: 10.3390/cancers13092201. View

13.

Wang J, Li R, Li J, Yi Y, Liu X, Chen J . Comprehensive analysis of oncogenic fusions in mismatch repair deficient colorectal carcinomas by sequential DNA and RNA next generation sequencing. J Transl Med. 2021; 19(1):433. PMC: 8522100. DOI: 10.1186/s12967-021-03108-6. View

14.

Pagani F, Randon G, Guarini V, Raimondi A, Prisciandaro M, Lobefaro R . The Landscape of Actionable Gene Fusions in Colorectal Cancer. Int J Mol Sci. 2019; 20(21). PMC: 6861915. DOI: 10.3390/ijms20215319. View

15.

Delaye M, Ibadioune S, Julie C, Marin C, Peschaud F, Lupinacci R . Rational testing for gene fusion in colorectal cancer: MSI and RAS-BRAF wild-type metastatic colorectal cancer as target population for systematic screening. Eur J Cancer. 2022; 170:85-90. DOI: 10.1016/j.ejca.2022.04.024. View

16.

Vankova B, Vanecek T, Ptakova N, Hajkova V, Dusek M, Michal M . Targeted next generation sequencing of MLH1-deficient, MLH1 promoter hypermethylated, and BRAF/RAS-wild-type colorectal adenocarcinomas is effective in detecting tumors with actionable oncogenic gene fusions. Genes Chromosomes Cancer. 2020; 59(10):562-568. DOI: 10.1002/gcc.22861. View

17.

Aisner D, Nguyen T, Paskulin D, Le A, Haney J, Schulte N . ROS1 and ALK fusions in colorectal cancer, with evidence of intratumoral heterogeneity for molecular drivers. Mol Cancer Res. 2013; 12(1):111-8. PMC: 4140177. DOI: 10.1158/1541-7786.MCR-13-0479-T. View

18.

Bocciarelli C, Caumont C, Samaison L, Cariou M, Aline-Fardin A, Doucet L . MSI-High RAS-BRAF wild-type colorectal adenocarcinomas with MLH1 loss have a high frequency of targetable oncogenic gene fusions whose diagnoses are feasible using methods easy-to-implement in pathology laboratories. Hum Pathol. 2021; 114:99-109. DOI: 10.1016/j.humpath.2021.05.006. View

19.

Jang Y, Jang I, Kim S, Cho S, Kim D, Kim K . ChimerDB 4.0: an updated and expanded database of fusion genes. Nucleic Acids Res. 2019; 48(D1):D817-D824. PMC: 7145594. DOI: 10.1093/nar/gkz1013. View

20.

Mosele F, Remon J, Mateo J, Westphalen C, Barlesi F, Lolkema M . Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2020; 31(11):1491-1505. DOI: 10.1016/j.annonc.2020.07.014. View