TY - JOUR
T1 - Molecular characteristics and clinical outcomes of patients with Neurofibromin 1-altered metastatic colorectal cancer
AU - Arai, Hiroyuki
AU - Elliott, Andrew
AU - Millstein, Joshua
AU - Xiu, Joanne
AU - Ou, Fang Shu
AU - Innocenti, Federico
AU - Wang, Jingyuan
AU - Battaglin, Francesca
AU - Jayachandran, Priya
AU - Kawanishi, Natsuko
AU - Soni, Shivani
AU - Zhang, Wu
AU - Sohal, Davendra
AU - Goldberg, Richard M.
AU - Hall, Michael J.
AU - Scott, Aaron J.
AU - Khushman, Mohd
AU - Hwang, Jimmy J.
AU - Lou, Emil
AU - Weinberg, Benjamin A.
AU - Lockhart, Albert Craig
AU - Shields, Anthony Frank
AU - Abraham, Jim P.
AU - Magee, Daniel
AU - Stafford, Phillip
AU - Zhang, Jian
AU - Venook, Alan P.
AU - Korn, W. Michael
AU - Lenz, Heinz Josef
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/1/5
Y1 - 2022/1/5
N2 - 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.
AB - 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.
KW - Colorectal Neoplasms/genetics
KW - Humans
KW - Neoplasm Metastasis
KW - Neurofibromin 1/metabolism
KW - Survival Analysis
KW - Treatment Outcome
UR - http://www.scopus.com/inward/record.url?scp=85118454846&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000713936100002&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1038/s41388-021-02074-z
DO - 10.1038/s41388-021-02074-z
M3 - Article
C2 - 34728807
SN - 0950-9232
VL - 41
SP - 260
EP - 267
JO - Oncogene
JF - Oncogene
IS - 2
ER -