Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features.
OBJECTIVE
This study evaluated the mutational profile of epidermal growth factor receptor (EGFR) and KRAS in non-small cell lung cancers in Hong Kong and determined their relation with smoking history and other clinicopathologic features.


METHODS
Mutational profile of exons 18 to 21 of EGFR and codons 12, 13, and 61 of KRAS were determined in 215 adenocarcinomas, 15 squamous cell (SCC), and 11 EBV-associated lymphoepithelioma-like carcinomas (LELC).


RESULTS
EGFR mutations were prevalent in adenocarcinomas (115 of 215), uncommon in LELC (1 of 11), and not found in SCC (P < 0.001). Among adenocarcinomas, mutations were associated with nonsmokers (83 of 111; P < 0.001), female gender (87 of 131; P < 0.001), and well-differentiated (55 of 86) compared with poorly differentiated (11 of 41) tumors (P < 0.001). Decreasing mutation rates with increasing direct tobacco exposure was observed, with 74.8% (83 of 111) in nonsmokers, 61.1% (11 of 18) in passive, 35.7% (10 of 28) in previous, and 19.0% (11 of 58) in current smokers. There were 53% amino acid substitutions, 43% in-frame deletions, and 4% insertions. Complex patterns with 13% double mutations, including five novel substitutions, were observed. For KRAS, mutations occurred in adenocarcinoma only (21 of 215) and were associated with smokers (11 of 58; P = 0.003), men (14 of 84; P = 0.009) and poorly differentiated (7 of 41) compared with well-differentiated (4 of 86) tumors (P = 0.037). EGFR and KRAS mutations occurred in mutually exclusive tumors. Regression analysis showed smoking history was the significant determinant for both mutations, whereas gender was a confounding factor.


CONCLUSIONS
This study shows EGFR mutations are prevalent in lung adenocarcinoma and suggests that it plays an increasing oncogenic role with decreasing direct tobacco damage.
Department of Pathology, Dental Public Health, Medicine, University of Hong Kong.
Issan Yee San
IY
Tam
Lap Ping
LP
Chung
Wai Sing
WS
Suen
Elaine
E
Wang
May C M
MC
Wong
Kok Keung
KK
Ho
Wah Kit
WK
Lam
Shui Wah
SW
Chiu
Luc
L
Girard
John D
JD
Minna
Adi F
AF
Gazdar
Maria P
MP
Wong
D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000235:genetics; D002454:Cell Differentiation; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics*; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D006566:Herpesviridae Infections / Q000150:complications / Q000235:genetics / Q000473:pathology; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D006723:Hong Kong; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D003074:Solitary Pulmonary Nodule / Q000175:diagnosis / Q000235:genetics / Q000821:virology; D014028:Tobacco Smoke Pollution
D014028:Tobacco Smoke Pollution; D066246:ErbB Receptors