Genomic alterations in cervical carcinoma: losses of chromosome heterozygosity and human papilloma virus tumor status.
Specific human papilloma virus (HPV) types appear to be necessary etiological factors for most cervical cancers, yet additional genetic alterations seem to be required for their development and progression. The aim of this study is to determine the likely chromosomes location of tumorigenicity suppressor-like genes, the loss of function of which might be important in the origin or progression of cervical carcinomas. PCR with primers for 75 highly polymorphic microsatellite loci located on the major autosome arms were used to estimate the incidence of loss of heterozygosity (LOH) in 38 tumors. The HPV status of the tumors was also determined. LOH was found to involve 19 chromosome arms in 20-43% of the tumors. Chromosome arms 6p, 3p, and 18q are most frequently involved in LOH in 43, 39, and 35% of the informative carcinomas, respectively. The respective regions involved are 6p21.1-23, 3p13-25.3, and 18q12.2-21.2. LOH is generally limited to specific band segments within these regions. Similar high incidences of LOH of the same 3p segments have been reported in cervical carcinomas from different parts of the world. The same 3p and 6p segments are involved in many types of common cancers, whereas 18q changes are less frequent in other cancers. Chromosome arms 1q, 2q, 3q, 4p, 4q, 5p, 5q, 6q, 7q, 8p, 8q, 11q, 13q, 16p, 18p, and 19p are involved in LOH in 20-33% of the cervical tumors. Chromosome 11 alterations are among the most frequently found in many different types of neoplasias. In this study, 11p was involved in 16% of the tumors, and 11q was involved in 22%. Chromosome 17 alterations are found in more cancers than those of any other chromosome, frequently involving the p53 gene on 17p. LOH of 17p was found in 5 (15%) cervical tumors; 2 of these were HPV negative and expressed mutant p53. In such HPV-negative tumors, direct mutation of the wild-type p53 appears to replace the inactivation of the p53 product by oncogenic HPV types. Tumors with LOH at many loci were, on the average, at more advanced stages, as were tumors with mutant p53. The higher overall incidence of LOH in cervical carcinomas as compared to other cancers, and the diversity of LOH patterns found, suggest that different cervical carcinomas probably arise and/or progress, in part, because of the loss of function of different yet finite sets of tumorigenicity suppressor genes and genes that are involved in tumor progression and metastasis. The findings also indicate that certain chromosome segments that are often altered in cervical carcinomas are also frequently altered in several other types of cancers. It remains to be determined whether the same or different genes located within these segments are involved in the different cancer types.
Mullokandov
M R
MR
Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Kholodilov
N G
NG
Atkin
N B
NB
Burk
R D
RD
Johnson
A B
AB
Klinger
H P
HP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics* / Q000821:virology; D002869:Chromosome Aberrations; D005260:Female; D016678:Genome; D006801:Humans; D008875:Middle Aged; D027383:Papillomaviridae / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000821:virology*; D014412:Tumor Virus Infections; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology