Analysis of EGFR and KRAS Mutations in High-Grade Neuroendocrine Carcinomas of the Lung
N Rekhtman, M He, C Lau, K Nafa, GJ Riely, MF Zakowski, M Ladanyi. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: EGFR and KRAS mutations are found in 20% and 25% of lung adenocarcinomas (AdCA), respectively. The prevalence of EGFR and KRAS mutations in small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) is not well established. Based on limited published data, these mutations are thought to be confined to AdCA. However, recent case reports have described three unusual EGFR-mutant SCLCs, arising in association with AdCA. These studies highlight the need for a more systematic analysis of EGFR and KRAS mutations in high-grade neuroendocrine carcinomas.
Design: Archival tissue blocks from SCLC (n=20) and LCNEC (n=10) were macrodissected and DNA was extracted. We screened for known point mutations in EGFR and KRAS by Sequenom (MALDI-TOF mass spectrometry genotyping platform). EGFR exon 19 mutations were tested by length analysis of fluorescently labeled PCR products. In addition, point mutations in other key signaling genes (NRAS, HRAS, BRAF, HER2, PIK3CA, MEK1, AKT1) were analyzed by Sequenom. The findings were correlated with clinicopathological parameters using a two-tailed t test or a Fisher's exact test.
Results: No EGFR mutations were identified. However, KRAS mutations were found in 1 of 20 SCLC (5%) and 4 of 10 LCNEC (40%). The only SCLC with KRAS mutation had a separate synchronous AdCA. KRAS mutations involved codons 12 (n=4) and 13 (n=1). Interestingly, the type of KRAS mutations paralleled the distribution of these mutations in smoking-related AdCA with G>T transversions (n=4) found more frequently than G>A transitions (n=1). In addition, within the group as a whole (n=30), KRAS mutations were associated with heavier smoking history: average pack-years 70 vs 43 for KRAS-mutated vs KRAS-non-mutated tumors (P=0.027). KRAS mutations were not associated with age, gender, tumor size, or metastasis. No mutations were found in any other tested genes.
Conclusions: This study uncovered a high rate of KRAS mutations in LCNEC (40%), whereas none of pure SCLC harbored either KRAS or EGFR mutations. One KRAS-mutated SCLC was associated with a synchronous AdCA, similar to previously reported SCLCs with EGFR mutations. Our findings suggest that SCLC and LCNEC are molecularly distinct, and that the EGFR or KRAS mutations in SCLC may be limited to tumors arising in association with AdCA. The significance of frequent KRAS mutations in LCNEC and their association with smoking warrants further investigation.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 245, Tuesday Afternoon