Molecular characteristics and clinical outcomes of patients with Neurofibromin 1-altered metastatic colorectal cancer

Hiroyuki Arai, Andrew Elliott, Joshua Millstein, Joanne Xiu, Fang Shu Ou, Federico Innocenti, Jingyuan Wang, Francesca Battaglin, Priya Jayachandran, Natsuko Kawanishi, Shivani Soni, Wu Zhang, Davendra Sohal, Richard M. Goldberg, Michael J. Hall, Aaron J. Scott, Mohd Khushman, Jimmy J. Hwang, Emil Lou, Benjamin A. WeinbergAlbert Craig Lockhart, Anthony Frank Shields, Jim P. Abraham, Daniel Magee, Phillip Stafford, Jian Zhang, Alan P. Venook, W. Michael Korn, Heinz Josef Lenz

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Loss-of-function alterations of Neurofibromin 1 (NF1) activate RAS, a driver of colorectal cancer. However, the clinical implications of NF1 alterations are largely unknown. We performed a comprehensive molecular profiling of NF1-mutant colorectal cancer using data from 8150 patients included in a dataset of commercial CLIA-certified laboratory (Caris Life Sciences). In addition, NF1 expression levels were tested for associations with clinical outcomes using data from 431 patients in the CALGB/SWOG 80405 trial. In the Caris dataset, 2.2% of patients had pathogenic or presumed pathogenic NF1 mutations. NF1-mutant tumors more frequently harbored PIK3CA (25.0% vs. 16.7%) and PTEN mutations (24.0% vs. 4.2%) than wild type tumors. Gene set enrichment analysis revealed that MAPK and PI3K pathway signatures were enriched in NF1-mutant tumors. In the CALGB/SWOG 80405 cohort, low NF1 expression was associated with poor prognosis, and high NF1 expression was associated with better efficacy of cetuximab than bevacizumab. Together, we revealed concurrent genetic alterations in the PI3K pathways in NF1-mutant tumors, suggesting the need to simultaneously block MAPK and PI3K pathways in treatment. The potential of NF1 alteration as a novel biomarker for targeted therapy was highlighted, warranting further investigations in clinical settings.

Original languageEnglish
Pages (from-to)260-267
Number of pages8
Issue number2
StatePublished - Jan 5 2022


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