[1812] Genotype-Phenotype Correlation in Lung Adenocarcinoma

VE Klepeis, EG Mark, D Dias-Santagata, AJ Iafrate, M Mino-Kenudson. Massachusetts General Hospital & Harvard Medical School, Boston

Background: With the advancement of personalized treatment for non-small cell lung cancer, especially adenocarcinoma (ADA), identification of molecular targets in an efficient fashion is of the utmost importance in therapeutic decision making. However, there have been controversial reports on using histologic features to predict the presence of some mutations.
Design: Seventy-four ADAs, surgically resected or excised and submitted for molecular testing, were classified based on WHO criteria as ADA with bronchioloalveolar (mucinous or non-mucinous), papillary, acinar and/or solid patterns. Of those, 110 described mutations of 13 genes were studied using mutiplex PCR in 58 tumors (33 positive for mutation, 25 negative for known mutation). Point mutations of EGFR or KRAS were found by direct sequencing in the remaining 16 cases. The association between dominant histologic features and mutations were evaluated.
Results: While the majority of cases studied displayed a mixed histologic pattern, a dominant pattern was always evident.

Correlation between Histologic Pattern and Mutation Type

	All patterns	BAC, non-mucinous	BAC,mucinous	Papillary/Micropapillary	Acinar	Solid	Others
EGFR	26	11	0	10	4	1	0
EGFR+CTNNB1+/-TP53	4	0	0	0	1	0	3
KRAS	17	4	4	3	3	3	0
PIK3CA	2	1	0	0	0	1	0
No mutations	25	6	1	8	5	4	1
Total cases:	74	22	5	21	13	9	4

EGFR mutations were associated with the 2 most common histologic patterns, non-mucinous BAC (42%) and papillary (38%). In contrast, K-ras mutations were most commonly associated with BAC, either mucinous (4/17) or non-mucinous (4/17), and some extent of mucinous differentiation was present in a total of 10 K-ras mutants (59% vs. 12 % of non-Kras mutants, p < 0.001). While EGFR and K-ras mutations were mutually exclusive, 4 EGFR cases demonstrated an additional mutation in ß-catenin (CTNNB1), which was usually associated with a unique phenotype, such as a fetal lung pattern (2/4) or prominent cytoplasmic clearing (1/4). Finally, 43% of cases (25/58) lacked a detectable mutation using our panel and exhibited various dominant histologic patterns.
Conclusions: The results confirm and expand previously described genotype-phenotype correlations in lung ADAs. However, many tumors do not express a known mutation, despite displaying the various histologic patterns. Therefore, expansion of molecular testing and comprehensive histologic sub-typing is required to define new potential molecular targets for therapy and to discover unanticipated histologic-genetic correlations.
Category: Pulmonary

Monday, March 22, 2010 9:30 AM

Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 235, Monday Morning