The structural basis of molecular genetic deletions. An integration of classical cytogenetic and molecular analyses in pancreatic adenocarcinoma.
Molecular genetic alterations are known to be important in human carcinoma, but the structural basis of these changes is largely unknown. To examine the basis of these changes, we compared the karyotypic chromosomal abnormalities of primary pancreatic adenocarcinomas with the molecular changes identified in these same cancers. In 14 cancers with abnormal karyotypes, 65% (123 of 188) of the chromosomal arms with molecular loss of heterozygosity (LOH) were associated with karyotypic structural anomalies. Karyotypic changes accounting for these molecular allelic losses included 83 chromosome losses, 18 partial deletions, nine isochromosomes, eight additions, and five translocations. Eight bomozygous deletions were also identified by molecular analyses. Of the three homozygous deletions identified at 9p21, the only karyotypic change was a single case in which one entire copy of chromosome 9 was deleted. Of the four homozygous deletions identified at 18q21.1, one showed a loss of both copies of chromosome 18, two showed a loss of one copy of chromosome 18, and the fourth had two structurally normal copies of chromosome 18. One homozygous deletion was identified at 13q12.3, and the karyotype revealed the loss of one entire copy of chromosome 13. The second copy of chromosome 13 in this carcinoma was structurally normal. These results indicate that chromosomal structural anomalies can account for two-thirds of the LOH in pancreatic adenocarcinomas and that most homozygous deletions are likely to be interstitial chromosomal deletions that are below the detection limit of conventional karyotypic analyses. Some of the molecular deletions detected as LOH on chromosomes with karyotypically normal structure can be explained by chromosomal loss with reduplication of the remaining chromosome.
Brat
D J
DJ
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Hahn
S A
SA
Griffin
C A
CA
Yeo
C J
CJ
Kern
S E
SE
Hruban
R H
RH
D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D003582:Cytogenetics / Q000379:methods*; D017353:Gene Deletion; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007621:Karyotyping; D008875:Middle Aged; D008967:Molecular Biology / Q000379:methods*; D010190:Pancreatic Neoplasms / Q000235:genetics*