Distinctive histological variants of
lung cancer are increasingly recognized to have specific genetic changes that affect
tumor biology and response to
therapy. In this study, we evaluated true
papillary adenocarcinoma of the lung, proposed as a distinct diagnostic category with relatively poor response to
therapy, to determine whether these
tumors also have specific molecular alterations that would affect sensitivity to
chemotherapy. Specifically, we measured
protein levels of P53, excision repair cross-complementation 1 (ERCC1) and
ribonucleotide reductase M1 (RRM1) by immunohistochemistry and evaluated the Kelch-like erythroid cell-derived
protein with cap-n-collar homology (ECH)-associated
protein 1 (KEAP1) gene for mutations, correlating mutations of this gene with total and nuclear expression of the nuclear factor erythroid-2-related factor 2 (NRF2). We found high levels of P53 in 23 of the 55 specimens (41.8%), similar to the rate of P53 gene mutations observed in general for pulmonary
adenocarcinoma, and levels of ERCC1 and RRM1 also showed distributions similar to those reported generally for non-small lung cell
cancer (NSCLC). However, KEAP1 alterations were observed at a significantly higher frequency in
papillary adenocarcinoma tumors (60%) than what has been reported previously for NSCLC (3-19%). These mutations of KEAP1 were associated with increased nuclear accumulation of NRF2 in
tumors, as expected for functional alterations. Thus, high rates of KEAP1 mutations and NRF2 overexpression in true
papillary adenocarcinoma could be related to poor prognosis and
chemotherapy resistance. Furthermore, this distinctive molecular characteristic supports the recognition of true
papillary adenocarcinoma as a diagnostic entity.