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

Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
Journal of Molecular Diagnostics (Impact Factor: 4.85). 08/2007; 9(3):320-6. DOI: 10.2353/jmoldx.2007.060182
Source: PubMed


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.

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    • "KRAS mutations are observed in close to 30% of adenocarcinomas of the lung, but are uncommon in SQCC (about 5%) [138]. KRAS mutations are found in majority of mucinous adenocarcinomas [139, 140]. Point mutations at codons 12, 13, or 61 in the KRAS oncogene lead to constitutive activation of KRAS protein via changes at the GTP binding domain, which prevents the conversion of GTP to GDP. "
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    • "On the other hand, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-RAS) is a critical downstream effector of the EGFR pathway. K-RAS mutations are associated with intrinsic tyrosine kinase inhibitor (TKI) resistance in patients with lung cancer [7,8]. Thus, molecular diagnosis of these mutations is increasingly important in making therapeutic decisions. "
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    • "Im Gegensatz dazu konnte bei muzinösen Adenokarzinomen bislang noch keine EGFR-Mutation nachgewiesen werden. Muzinöse Karzinome zeigen jedoch deutlich häufi ger Mutationen des KRAS-Gens141516. Bei Plattenepithelkarzinomen wurden EGFR-Genmutationen nur in einem geringen Prozentsatz (1–4 %) gefun- den [17]. "
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