Frequency and genetic basis of MHC, beta‐2‐microglobulin and MEMO‐1 loss of heterozygosity in sporadic breast cancer

Abstract

The Human Leukocyte Antigen (HLA) class I molecules are critical factors in T cell recognition of abnormal, including neoplastic, cells. Loss of HLA class I expression phenotypes, as defined by immunohistochemistry-based tests, have been previously described in many types of cancer. Here we describe a microsatellite marker DNA-based loss of heterozygosity (LOH) analysis of three distinct chromosomal regions which have been implicated in HLA class I expression on a cohort of 99 unselected sporadic breast cancer samples. These regions comprise the 4Mb major histocompatibility complex (MHC) region on chromosome 6p, which contains the HLA class I heavy chain loci and other genes responsible for antigen processing, the HLA class I light chain (beta-2-microglobulin, beta2m) gene on chromosome 15q, and the putative HLA class I modifier of methylation gene (MEMO-1) on chromosome 1p. Additional chromosome 6 markers were also employed to determine the likely genetic mechanism for MHC loss. We show that 25/99 (25%) of samples show allelic loss within the MHC, 28/95 informative samples (29%) show allelic loss of beta2m and 21/76 informative samples (28%) show allelic loss of MEMO-1. Approximately half of the samples are predicted to have compromised HLA class I gene expression due to LOH at one and/or other of these three loci. Sequencing of the remaining beta2m allele in samples displaying beta2m LOH failed to detect any additional intragenic mutations. Analysis of the frequency of samples showing LOH at either 0, 1, 2 or 3 of the genomic regions analyzed suggested clustering of tumors into either 'no loci loss' or '3 loci loss' categories. These results reveal major underlying genetic causes for the high level of HLA class I expression loss seen in breast cancer.

Evidence for whole chromosome 6 loss and duplication of the remaining chromosome in acute lymphoblastic leukemia

“…D1S407 is within the “minimum region of deletion” as defined by Cheng et al (1996). Further information on the markers used, including PCR primer sequences, can be found in McEvoy et al (2002).…”

Associations between HLA-C alleles and papillary thyroid carcinoma

“…Several lines of evidence describe the contribution of HLA class I proteins in various types of cancers, including epithelial cancers, which could be due to a selective immunogenic T cell response in these conditions [4,5]. T cell based immunotherapy procedures are potentially effective in cancer treatment [4].…”

“…T cell based immunotherapy procedures are potentially effective in cancer treatment [4]. A better understanding of the immune system mechanism in thyroid carcinoma may enhance future treatment options [6].…”

Targeting HLA class I expression to increase tumor immunogenicity

“…Among the ‘hard’ lesions, the loss of heterozygosity (LOH) of chromosome 6p21 is an important mechanism that generates HLA haplotype loss in various human tumors with high incidence. Mutations in β2m gene and loss of another gene copy due to LOH in chromosome 15 are responsible for the irreversible total loss of HLA class I expression, and it has been described in various types of malignancy, both in cell lines and in tumor tissues (36–48) (Table 1). LOH in chromosome 15 may be unnoticed as tumor cells might have a ‘normal’ HLA class I pattern and could represent one of the early events in malignant cells leading to precommitted tumors becoming MHC escape variants (34).…”