title: Multiple genetic alterations cause frequent and heterogeneous human histocompatibility leukocyte antigen class I loss in cervical cancer.
abstract: 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 beta2-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.
authors.affiliation: Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. louise_koopman@yahoo.com
authors.forename: L A
authors.initials: LA
authors.lastname: Koopman
authors.forename: W E
authors.initials: WE
authors.lastname: Corver
authors.forename: A R
authors.initials: AR
authors.lastname: van der Slik
authors.forename: M J
authors.initials: MJ
authors.lastname: Giphart
authors.forename: G J
authors.initials: GJ
authors.lastname: Fleuren
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005434:Flow Cytometry; D017353:Gene Deletion; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007150:Immunohistochemistry; D018895:Microsatellite Repeats / Q000235:genetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D002583:Uterine Cervical Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens