Pleomorphic (giant and/or spindle cell) carcinoma of lung shows a high percentage of variant CYP1A12.
BACKGROUND
Pleomorphic carcinoma (PC) of the lung is an aggressive epithelial neoplasm composed of giant and/or spindle tumor cells and associated with short survival. Most patients are cigarette smokers. The tumor susceptibility gene P-450 1A1 (CYP1A1) is involved in the activation of polycyclic aromatic hydrocarbons, including benzo[a]pyrene, producing DNA-damaging epoxides that lead to G:C-->T:A point mutations. Isoleucine (Ile)-valine (Val) and Val-Val genotypes of the CYP1A1 exon 7 polymorphism are associated with an increased risk for lung cancer in certain populations.


RESULTS
We sought to determine whether 25 archival, formalin-fixed, paraffin-embedded PC samples had a modified CYP1A1 gene profile at exon 7 using allele-specific PCR amplification. KRAS mutation status was available for all samples. Previous investigations have shown 0.88 Ile-Ile, 0.12 Ile-Val, and rarely, Val-Val as normal baseline population frequencies. Conversely, the markedly different PC CYP1A1 population frequencies were more likely to have the heterozygote variant alleles: 0.24 (six cases, Ile-Ile) and 0.76 (19 cases, Ile-Val; P <.001). CYP1A1 genotypes were found to be similar in both tumor and nontumor samples in a given case. All KRAS-mutated cases were Ile-Val heterozygotes.


CONCLUSIONS
The increased propensity for the variant CYP1A1 allele may be the contributing factor to PC pathogenesis and may also result from KRAS mutations in these tumors.
Przygodzki
R M
RM
Department of Cellular Pathology and Genetics, The Armed Forces Institute of Pathology, 1413 Research Blvd., Bldg. 101, Rockville, MD 20850, USA. przygodz@afip.osd.mil
Koss
M N
MN
O'Leary
T J
TJ
D000483:Alleles; D001564:Benzo(a)pyrene; D002273:Carcinogens; D002277:Carcinoma / Q000235:genetics*; D018286:Carcinoma, Giant Cell / Q000235:genetics*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D005091:Exons; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008956:Models, Chemical; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012907:Smoking; D018631:ras Proteins
D002273:Carcinogens; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins