Frequent loss of heterozygosity in the β2-microglobulin region of chromosome 15 in primary human tumors

Abstract

Downregulation or total loss of HLA class I expression on tumor cells is known as a mechanism of cancer immune escape. Alterations of the HLA phenotype are frequently due to mutations affecting genes encoding the HLA class I heavy chains located on chromosome 6p21 or the β2-microglobulin (β2m) gene encoding the light chain of the HLA complex located on chromosome 15q21. Frequently irreversible total loss of HLA class I molecules is due to the coincidence of two molecular events, the mutation of one β2m gene and the loss of the second copy. The latter is detectable as loss of heterozygosity (LOH) of microsatellite markers in the β2m region on chromosome 15q21 (LOH-15q21). Thus, LOH-15q21 might be an important event in the processes of HLA class I downregulation and total loss. Here we studied the frequency of LOH-15q21 in tumor tissues of different entities. By determining the status of heterozygosity of two microsatellite markers we detected LOH-15q21 in 44% of bladder carcinomas (n = 69), in 35% of colon carcinomas (n = 95), in 16% of melanomas (n = 70) but only in 7% of renal cancers (n = 45). Moreover, we observed a frequent coincidence of LOH-15q21 and LOH-6p21 in colorectal carcinoma, bladder carcinoma and melanoma, but not for renal carcinoma. We believe that the high incidence of LOH-15q21 in some malignancies and especially the coincidence of LOH-15q21 and LOH-6p21 might have a strong impact on tumor immunogenicity and on the efficiency of cancer immunotherapy.

Investigation of genomic instability in cholesteatoma of patients

“…Allelic losses of these regions, particularly in many human cancers including head and neck cancers were found in high frequency. It was reported that highest LOH frequency was observed in colorectal and bladder cancers; relatively low LOH frequency was observed in kidney cancer [19]. However, in our study while LOH was not observed in any patients at D6S273 and D6S473 markers, MSI was observed in two patients.…”

Genetic Evolution of T-cell Resistance in the Course of Melanoma Progression

“…Notably, loss of chromosome 15q material in melanoma is not a very rare event (37,38). Of 70 metastatic melanoma samples analyzed, 16% were positive for loss of heterozygosity in chromosome region 15q21-22 (39). In the near future, exome studies will provide more detailed information about the frequency of B2M gene mutations in melanoma metastases, which we expect to be lower than B2M allelic losses.…”

The urgent need to recover MHC class I in cancers for effective immunotherapy

“…In this case, tumor cells cannot recover the antigen presentation capacity and the tumor microenvironment retains tumor escape phenotype favoring cancer progression. ‘Hard’ HLA-I aberrations in tumors (LOH in chromosomes 6 or 15 and beta 2-microglobulin mutations) are in the range of 30–40% of human cancers [55, 56]. In order to restore HLA-I expression in human tumors with ‘hard’ lesions we have made a recombinant adenovirus carrying beta 2-microglobulin gene and demonstrated a recovery of HLA-I expression on tumor cells deficient in beta 2-microglobulin.…”