Allele-specific chromosome 3p deletions occur at an early stage in the pathogenesis of lung carcinoma.
BACKGROUND
Deletions in the short arm of chromosome 3 (3p) are present in most lung carcinomas.


OBJECTIVE
To investigate the role of these chromosome 3p deletions in the pathogenesis of non-small cell lung carcinomas.


METHODS
Seven archival, paraffin-embedded, surgically resected lung cancer specimens were studied. Fifty precisely identified malignant and preneoplastic lesions present in bronchi, bronchioles, and alveoli were microdissected from stained slides and analyzed for allele loss using polymerase chain reaction-based assays for dinucleotide repeat polymorphisms at three chromosome 3p loci (3p14, 3p21.3, and 3p25).


METHODS
University-based medical center and affiliated hospitals.


METHODS
Samples were analyzed from seven patients who underwent surgical resection with curative intent for non-small cell lung cancer and whose specimens included extensive multifocal areas of preneoplastic lesions (hyperplasia, metaplasia, dysplasia, or noninvasive cancer).


RESULTS
Lymphocytes from all seven cases were heterozygous (ie, informative) for all three microsatellites analyzed. Six (86%) of seven invasive cancers had loss of heterozygosity at one or more chromosome 3p sites. In the accompanying preneoplastic lesions, loss of heterozygosity was detected in none of two normal bronchioles, 13 (76%) of 17 hyperplasias, six (86%) of seven dysplasias, and four (100%) of four noninvasive cancers. Loss of heterozygosity was detected throughout the respiratory tract, in bronchi, bronchioles, and alveoli. In 18 (78%) of 23 preneoplastic lesions, the specific alleles lost were identical to those lost in the corresponding carcinomas. The probability of this happening by chance is 5.3 x 10(-3).


CONCLUSIONS
Deletions in the short arm of chromosome 3 occur at the earliest stage (hyperplasia) in the pathogenesis of lung cancer and involve all regions of the respiratory tract. Allele loss is highly specific, but its mechanism remains unknown. Our findings may be of considerable biologic, prognostic, and clinical significance.
Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas 75235-8593.
J
J
Hung
Y
Y
Kishimoto
K
K
Sugio
A
A
Virmani
D D
DD
McIntire
J D
JD
Minna
A F
AF
Gazdar
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002872:Chromosome Deletion; D002893:Chromosomes, Human, Pair 3; D004247:DNA / Q000032:analysis; D005260:Female; D006579:Heterozygote; D006801:Humans; D006965:Hyperplasia; D008168:Lung / Q000473:pathology*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology
D004247:DNA