Frequency of driver mutations in lung adenocarcinoma from female never-smokers varies with histologic subtypes and age at diagnosis.
OBJECTIVE
Our previous study revealed that 90% [47 of 52; 95% confidence interval (CI), 0.79-0.96] of Chinese never-smokers with lung adenocarcinoma harbor known oncogenic driver mutations in just four genes EGFR, ALK, HER2, and KRAS. Here, we examined the status of known driver mutations specifically in female never-smokers with lung adenocarcinoma.


METHODS
Tumors were genotyped for mutations in EGFR, KRAS, ALK, HER2, and BRAF. Data on age, stage, tumor differentiation, histologic subtypes, and molecular alterations were recorded from 349 resected lung adenocarcinomas from female never-smokers. We further compared the clinicopathologic parameters according to mutational status of these genes.


RESULTS
Two hundred and sixty-six (76.2%) tumors harbored EGFR mutations, 16 (4.6%) HER2 mutations, 15 (4.3%) EML4-ALK fusions, seven (2.0%) KRAS mutations, and two (0.6%) BRAF mutations. In univariate analysis, patients harboring EGFR mutations were significantly older (P < 0.001), whereas patients harboring HER2 mutations were significantly younger (P = 0.036). Higher prevalence of KRAS (P = 0.028) and HER2 (P = 0.021) mutations was found in invasive mucinous adenocarcinoma (IMA). The frequency of EGFR mutations was positively correlated with acinar predominant tumors (P = 0.002). Multivariate analysis revealed that older age at diagnosis (P = 0.013) and acinar predominant subtype (P = 0.005) were independent predictors of EGFR mutations. Independent predictors of HER2 mutations included younger age (P = 0.030) and IMA (P = 0.017). IMA (P = 0.006) and poor differentiation (P = 0.028) were independently associated with KRAS mutations.


CONCLUSIONS
The frequency of driver mutations in never-smoking female lung adenocarcinoma varies with histologic subtypes and age at diagnosis. These data have implications for both clinical trial design and therapeutic strategies.
Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai 200032, China.
Yang
Y
Zhang
Yihua
Y
Sun
Yunjian
Y
Pan
Chenguang
C
Li
Lei
L
Shen
Yuan
Y
Li
Xiaoyang
X
Luo
Ting
T
Ye
Rui
R
Wang
Haichuan
H
Hu
Hang
H
Li
Lei
L
Wang
William
W
Pao
Haiquan
H
Chen
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009367:Neoplasm Staging; D009857:Oncogenes / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D012907:Smoking; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D048493:Proto-Oncogene Proteins B-raf; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D018631:ras Proteins; C000626173:ALK protein, human; C482119:BRAF protein, human