Clonality and prognostic implications of p53 and epidermal growth factor receptor somatic aberrations in multiple primary lung cancers.
OBJECTIVE
For treatment decision and prognostic applications, we evaluated p53/epidermal growth factor receptor (EGFR) somatic aberrations in multiple primary lung cancers to differentiate multifocal tumors from intrapulmonary metastasis.


METHODS
Fifty-eight multiple primary lung cancers of 1,037 patients in a 10-year period were identified to investigate somatic mutations and altered expression of p53 and EGFR for clonality assessment. Genomic DNA was extracted from microdissected cells of paraffin-embedded multiple primary lung cancer tissues. Overexpression and somatic mutations in exons of p53 (exons 5-8) and tyrosine kinase domain of EGFR (exons 18-22) were examined by immunohistochemical staining and DNA sequencing, respectively.


RESULTS
High frequency of somatic mutations in p53 (33 of 58, 56.9%) and/or EGFR (44 of 58, 75.9%) resulted in high discrimination rate of tumor clonality (50 of 58, 86.2%) of multiple primary lung cancers. Twenty-two cases (37.9%) were assessed as having the same clonality and 28 cases (48.3%) were determined as having different clonality, which further supported the carcinogenic theory of field cancerization. Notably, the occurrence of lymph node metastasis was more commonly observed in tumors with the same clonality (P = 0.045) and was associated with poor patient 5-year survival rate (P = 0.001). However, no correlation was found between tumor clonality and patient survival (P = 0.630). The EGFR somatic aberrations in 58 multiple primary lung cancers, including vascular invasion associated with EGFR overexpression (P = 0.012) and mutation (P = 0.025), further suggested the potential benefits of target therapy of inoperable multiple primary lung cancers.


CONCLUSIONS
Our results suggest that analysis of somatic alterations in p53 and EGFR can significantly improve the clonality assessment and impact management of multiple primary lung cancer patients.
Chang
Yih-Leong
YL
Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine.
Wu
Chen-Tu
CT
Lin
Shu-Chen
SC
Hsiao
Chin-Fu
CF
Jou
Yuh-Shan
YS
Lee
Yung-Chie
YC
D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics*; D005091:Exons; D005260:Female; D016158:Genes, p53; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis; D009378:Neoplasms, Multiple Primary / Q000235:genetics* / Q000378:metabolism*; D016017:Odds Ratio; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D066246:ErbB Receptors