TY - JOUR
T1 - Alterations of LKB1 and KRAS and risk of brain metastasis
T2 - Comprehensive characterization by mutation analysis, copy number, and gene expression in non-small-cell lung carcinoma
AU - Zhao, Ni
AU - Wilkerson, Matthew D.
AU - Shah, Usman
AU - Yin, Xiaoying
AU - Wang, Anyou
AU - Hayward, Michele C.
AU - Roberts, Patrick
AU - Lee, Carrie B.
AU - Parsons, Alden M.
AU - Thorne, Leigh B.
AU - Haithcock, Benjamin E.
AU - Grilley-Olson, Juneko E.
AU - Stinchcombe, Thomas E.
AU - Funkhouser, William K.
AU - Wong, Kwok Kin
AU - Sharpless, Norman E.
AU - Hayes, D. Neil
N1 - Publisher Copyright:
© 2014 The Authors.
PY - 2014/11/1
Y1 - 2014/11/1
N2 - Background: Brain metastases are one of the most malignant complications of lung cancer and constitute a significant cause of cancer related morbidity and mortality worldwide. Recent years of investigation suggested a role of LKB1 in NSCLC development and progression, in synergy with KRAS alteration. In this study, we systematically analyzed how LKB1 and KRAS alteration, measured by mutation, gene expression (GE) and copy number (CN), are associated with brain metastasis in NSCLC. Materials and methods: Patients treated at University of North Carolina Hospital from 1990 to 2009 with NSCLC provided frozen, surgically extracted tumors for analysis. GE was measured using Agilent 44,000 custom-designed arrays, CN was assessed by Affymetrix GeneChip Human Mapping 250K Sty Array or the Genome-Wide Human SNP Array 6.0 and gene mutation was detected using ABI sequencing. Integrated analysis was conducted to assess the relationship between these genetic markers and brain metastasis. A model was proposed for brain metastasis prediction using these genetic measurements. Results: 17 of the 174 patients developed brain metastasis. LKB1 wild type tumors had significantly higher LKB1 CN (. p<. 0.001) and GE (. p=. 0.002) than the LKB1 mutant group. KRAS wild type tumors had significantly lower KRAS GE (. p<. 0.001) and lower CN, although the latter failed to be significant (. p=. 0.295). Lower LKB1 CN (. p=. 0.039) and KRAS mutation (. p=. 0.007) were significantly associated with more brain metastasis. The predictive model based on nodal (. N) stage, patient age, LKB1 CN and KRAS mutation had a good prediction accuracy, with area under the ROC curve of 0.832 (. p<. 0.001). Conclusion: LKB1 CN in combination with KRAS mutation predicted brain metastasis in NSCLC.
AB - Background: Brain metastases are one of the most malignant complications of lung cancer and constitute a significant cause of cancer related morbidity and mortality worldwide. Recent years of investigation suggested a role of LKB1 in NSCLC development and progression, in synergy with KRAS alteration. In this study, we systematically analyzed how LKB1 and KRAS alteration, measured by mutation, gene expression (GE) and copy number (CN), are associated with brain metastasis in NSCLC. Materials and methods: Patients treated at University of North Carolina Hospital from 1990 to 2009 with NSCLC provided frozen, surgically extracted tumors for analysis. GE was measured using Agilent 44,000 custom-designed arrays, CN was assessed by Affymetrix GeneChip Human Mapping 250K Sty Array or the Genome-Wide Human SNP Array 6.0 and gene mutation was detected using ABI sequencing. Integrated analysis was conducted to assess the relationship between these genetic markers and brain metastasis. A model was proposed for brain metastasis prediction using these genetic measurements. Results: 17 of the 174 patients developed brain metastasis. LKB1 wild type tumors had significantly higher LKB1 CN (. p<. 0.001) and GE (. p=. 0.002) than the LKB1 mutant group. KRAS wild type tumors had significantly lower KRAS GE (. p<. 0.001) and lower CN, although the latter failed to be significant (. p=. 0.295). Lower LKB1 CN (. p=. 0.039) and KRAS mutation (. p=. 0.007) were significantly associated with more brain metastasis. The predictive model based on nodal (. N) stage, patient age, LKB1 CN and KRAS mutation had a good prediction accuracy, with area under the ROC curve of 0.832 (. p<. 0.001). Conclusion: LKB1 CN in combination with KRAS mutation predicted brain metastasis in NSCLC.
KW - Brain metastasis
KW - KRAS
KW - LKB1
KW - NSCLC
KW - Prognostic model
UR - http://www.scopus.com/inward/record.url?scp=84908398337&partnerID=8YFLogxK
U2 - 10.1016/j.lungcan.2014.08.013
DO - 10.1016/j.lungcan.2014.08.013
M3 - Article
C2 - 25224251
AN - SCOPUS:84908398337
SN - 0169-5002
VL - 86
SP - 255
EP - 261
JO - Lung Cancer
JF - Lung Cancer
IS - 2
ER -