Is the EGFR Mutation Distributed Heterogeneously within Tumors?
Yasushi Yatabe. Aichi Cancer Center, Nagoya, Japan
Background: Some studies have shown heterogeneous distribution of the EGFR mutation in individual tumors. On the other hand, recent results of clinical trials, such as IPASS, WJTOG3405, and NEJ002, have demonstrated that clinical response to EGFR-TKIs was associated with the EGFR mutation, although most of the EGFR examinations were conducted using small biopsy specimens. The results suggest that the EGFR mutation status in a portion of a tumor represents that of the entire nodule, i.e., homogeneous distribution of the mutation.
Design: Distribution of EGFR mutation within tumors was examined on the three points as follows. 1. I speculated that if the EGFR mutation was heterogeneously distributed, a combination of two different hot spot mutations would be detected in some tumors, as the EGFR mutation occurs very frequently in Asian individuals. Therefore, I examined the frequency of simultaneous dual hot spot mutations using our mutation database. 2. Three small areas in each of 50 individual adenocarcinomas known to have the EGFR mutation were micro-dissected. In addition, three tumors with the EGFR mutation were divided into 100 segments. The mutational status was accessed in each sample. 3. A total of 100 pairs of primary adenocarcinomas with the EGFR mutation and corresponding lymph node metastasis, and 54 primary adenocarcinomas with the EGFR mutation and recurrent tumor pairs were examined for EGFR mutation status.
Results: In our database of 2781 primary lung cancers, the EGFR mutation at L858R or a deletion in exon 19 was detected in 862 tumors. None had simultaneous dual hot spot mutations, as all trans-sectional samples for each tumor examined showed an identical EGFR mutation. In addition, no discordant mutation patterns were found in the 154 paired samples.
Conclusions: The results in this study clearly demonstrated that heterogeneous distribution of the EGFR mutation within a tumor is extremely rare. However, it is possible that pseudo-heterogeneity occurs due to a combination of mutant allele specific imbalance (PLoS One. 2009;4:e4576) and heterogeneous distribution of EGFR amplification (Cancer Res 2008;68:2106), especially when a less sensitive method is used for detection. Namely, in some tumors, a mutant allele is specifically amplified, and amplification occurs specifically in a part related to invasive growth. Accordingly, the invasive part significantly over-represents the mutation signal relative to that in a non-invasive part. Such unbalanced mutation signals might cause pseudo-heterogeneity.
Monday, February 28, 2011 1:45 PM
Platform Session: Section E, Monday Afternoon