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Published online 13 March 2000.
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*Cervical Cancer
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© The Rockefeller University Press, 0022-1007/2000/3/961/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 6, March 20, 2000 961-976

Original Article

Multiple Genetic Alterations Cause Frequent and Heterogeneous Human Histocompatibility Leukocyte Antigen Class I Loss in Cervical Cancer

Louise A. Koopmana, Willem E. Corvera, Arno R. van der Slikb, Marius J. Giphartb, and Gert Jan Fleurena
a Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
b Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Correspondence to: Louise A. Koopman, Dept. of Pathology, L1-Q/P1-40, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Tel:31-71-5266596 Fax:31-71-5248158 E-mail:louise_koopman{at}yahoo.com.

Released online: 13 March 2000

The nature and frequency of human histocompatibility leukocyte antigen (HLA) class I loss mechanisms in primary cancers are largely unknown. We used flow cytometry and molecular analyses to concurrently assess allele-specific HLA phenotypes and genotypes in subpopulations from 30 freshly isolated cervical tumor cell suspensions.

Tumor-associated HLA class I alterations were present in 90% of the lesions tested, comprising four altered pheno/genotype categories: (a) HLA-A or -B allelic loss (17%), mostly associated with gene mutations; (b) HLA haplotype loss, associated with loss of heterozygosity at 6p (50%). This category included cases with additional loss of a (third) HLA-A or -B allele due to mutation, as well as one case with an HLA class I–negative tumor cell subpopulation, caused by a ß2-microglobulin gene mutation; (c) Total HLA class I antigen loss and retention of heterozygosity (ROH) at 6p (10%); and (d) B locus or HLA-A/B downregulation associated with ROH and/or allelic imbalance at 6p (10%). Normal HLA phenotypes and ROH at 6p were observed in 10% of the cases. One case could not be classified (3%).

Altered HLA class I antigen expression occurs in most cervical cancers, is diverse, and is mainly caused by genetic changes. Combined with widespread tumor heterogeneity, these changes have profound implications for natural immunity and T cell–based immunotherapy in cervical cancer.

Key Words: cervix neoplasms/immunology, genes, MHC class I, DNA, neoplasm/genetics, loss of heterozygosity, mutation


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