Published online before print May 18, 2007

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Copyright © 2007 American Society for Investigative Pathology
Journal of Molecular Diagnostics, doi:10.2353/jmoldx.2007.060182

Accepted for publication February 16, 2007.

Article

Mucinous Differentiation Correlates with Absence of EGFR Mutation and Presence of KRAS Mutation in Lung Adenocarcinomas with Bronchioloalveolar Features

Karin E. Finberg^*, Lecia V. Sequist, Victoria A. Joshi, Alona Muzikansky, Julie M. Miller^*, Moonjoo Han^*, Javad Beheshti^*, Lucian R. Chirieac^¶, Eugene J. Mark^*, and A. John Iafrate^*@

From the Department of Pathology,* Massachusetts General Hospital, Boston; the Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center, Boston; the Department of Biostatistics, Massachusetts General Hospital and Harvard Medical School, Boston; Laboratory for Molecular Medicine, Harvard Medical School-Partners Healthcare Center for Genetics and Genomics, Cambridge; and the Department of Pathology,^¶ Brigham and Women's Hospital, Boston, Massachusetts

^@ To whom correspondence should be addressed. E-mail: aiafrate{at}partners.org.

	Abstract

Somatic mutations in the epidermal growth factor receptor gene (EGFR) are detected in a subset of lung adenocarcinomas, particularly bronchioloalveolar carcinoma (BAC) and adenocarcinoma with bronchioloalveolar features (AWBF), and correlate with clinical response to tyrosine kinase inhibitors (TKIs). In contrast, lung adenocarcinomas refractory to TKIs often have activating mutations in KRAS but lack EGFR mutations. Some adenocarcinomas have mucinous histology, but the clinical and molecular significance of the mucinous pattern is less well studied. We analyzed 43 BAC and AWBF tumors submitted for EGFR mutation testing to identify histopathological features that predicted EGFR or KRAS mutations. EGFR mutations were detected in 14 of 30 (47%) nonmucinous tumors, whereas 0 of 13 mucinous tumors harbored an EGFR mutation (P = 0.003). Missense mutations in KRAS codon 12 were detected in six of seven (86%) mucinous adenocarcinomas but only 3 of 18 (17%) nonmucinous adenocarcinomas (P = 0.003). Thus, in BAC/AWBF mucinous differentiation was significantly correlated with the absence of EGFR mutation and presence of KRAS mutation, suggesting that mucinous BACs/AWBFs are unlikely to respond to TKIs. Therefore, our data suggest that EGFR sequence analysis could be avoided in BAC/AWBF when true mucinous morphology is identified, avoiding the associated testing costs.