Epidermal growth factor receptor mutation and p53 overexpression during the multistage progression of small adenocarcinoma of the lung.
BACKGROUND
A progression model of atypical adenomatous hyperplasia (AAH) to bronchioloalveolar carcinoma (BAC) to invasive adenocarcinoma (ADC) has been proposed. However, the genetic alterations of the AAH-BAC-ADC sequence are not clearly established. We examined the mutation of the epidermal growth factor receptor (EGFR) gene and p53 protein overexpression in the AAH, BAC, and small ADC to understand their role in the pulmonary ADC pathogenesis.


METHODS
Twenty AAH, 43 BAC (21 Noguchi type A and 22 type B), and 47 small ADC (Noguchi type C) were enrolled in this study. EGFR mutations at exons 18-21 and p53 protein overexpression were examined by polymerase chain reaction-direct sequencing and immunohistochemistry, respectively.


RESULTS
Mutations of the EGFR gene were noted in 45 (40.9%) lesions, which included 7 (35.0%) of AAH, 15 (34.9%) of BAC, and 23 (48.9%) of ADC. Twenty-six (23.6%) of the mutations were detected as exon 19 deletion, 18 (16.4%) as exon 21 point mutation, and 1 (0.9%) as exon 18 point mutation. Overexpression of p53 protein was found in 19 (17.2%) lesions, none of AAH, 4 (9.8%) of BAC, and 15 (31.9%) of ADC. Multivariate analysis showed that p53 overexpression was associated with invasive ADC (P = 0.003).


CONCLUSIONS
High frequency and similar incidence of EGFR mutation in AAH, BAC, and ADC support that EGFR gene mutation occurs in the early stage of pulmonary ADC development and tumor initiation from the preneoplastic lung parenchyma to neoplastic conditions. On the contrary, p53 overexpression is a late event during tumor development and plays a role in the progression of the peripheral pulmonary ADC.
Yoo
Seol Bong
SB
Department of Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
Chung
Jin-Haeng
JH
Lee
Hyun Ju
HJ
Lee
Choon-Taek
CT
Jheon
Sanghoon
S
Sung
Sook Whan
SW
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018255:Adenomatosis, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors