Frequent chromosome 9p losses in histologically normal nasopharyngeal epithelia from southern Chinese

Abstract

Nasopharyngeal carcinoma (NPC) is a common cancer among the Chinese population in the southern part of China. The incidence of this cancer drops markedly in northern China. A 6-to 24-fold difference exists between southern and northern Chinese. To investigate the early genetic events involved in the development of this cancer, we have examined loss of heterozygosity (LOH) on chromosome 9p, being one of the most frequent genetic alterations in NPC, in nasopharyngeal tissues including normal epithelia (NP), dysplastic lesions (DNP) and invasive carcinoma (NPC) from high-risk and low-risk regions. We found similar frequencies of 9p LOH in NPC from high-risk (77.8%) and low-risk (63.6%) regions (p ‫؍‬ 0.43). In contrast, 45% of normal nasopharyngeal epithelia from the high-risk region showed 9p LOH, while none of the NP from the low-risk region showed such abnormalities (p ‫؍‬ 0.002). Deletions of chromosome 9p were found in 66.7% dysplastic nasopharyngeal lesions. These findings suggest that LOH of chromosome 9p is an early event in the tumorigenesis of NPC. The increased risk of NPC in southern Chinese may be related to early loss of genetic materials as indicated by 9p LOH in the NP from high-and low-risk regions. We also reported previously that EpsteinBarr virus (EBV) latent infection was present in all high-grade DNP and NPC but not in any NP from fetuses or normal adults. Thus, early genetic alterations such as 9p LOH may take place prior to EBV latent infection and expand clonally thereafter.

Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma

“…We hypothesize that other important genes contributing to NPC genetic susceptibility may be uncovered in the EAO cases and the family history-positive (FH + ) cases because the onset of NPC in these two cohorts occurs earlier than in the sporadic cases. Importantly, losses of chromosomes 3p and 9p were frequently observed in the histologically normal nasopharyngeal epithelium with multiple genetically aberrant lesions and are thus generally considered as involved in crucial early events in NPC tumorigenesis (4,5). Previous studies by others and us discovered the deletion and/or methylation of a number of tumor suppressors, including Ras association domain family member 1 (RASSF1) (6), ADAM metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9) (7), protein tyrosine phosphatase, receptor type G (PTPRG) (8), zinc finger MYND-type containing 10 (ZMYND10) (BLU) (9,10), and fibulin 2 (FBLN2) (11) on chromosome 3p, and p16 on chromosome 9p (12,13).…”

An Update on Epstein-Barr Virus and Nasopharyngeal Carcinogenesis

“…2), a finding that supports the concept that EBV infection in an early event in NPC carcinogenesis [10,17,18]. The absence of EBV-infected epithelial cells in normal nasopharyngeal mucosa from individuals at high risk of developing NPC argues against a pre-existing normal reservoir infected cells from which virus-positive carcinoma arise; however, deletions in chromosome regions 3p and 9p have been identified in low-grade dysplastic lesions and normal nasopharyngeal mucosa of individuals at high risk of developing NPC indicating that these genetic events occur early in the pathogenesis of NPC and that they might cause predisposition to subsequent EBV infection [19,20]. (Table 2) (Fig.…”

“…Inactivation of the RASSF1A and p16 tumor suppressor genes on 3p21 and 9p21 by homozygous deletions and promoter methylation are the most common alterations described in NPC [30][31][32]. 3p and 9p abnormalities have been identified in low-grade dysplastic lesions and normal nasopharyngeal mucosa of individuals at high risk indicating that these genetic changes are early events in the pathogenesis of NPC [10,17,20,33]. Other genes frequently inactivated by promoter methylation in NPC include TSCL1 at 11q23 and EDNRB at 13q22, E-cadherin, and death-associated protein kinase (DAPK) [34][35][36].…”

Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line

“…H&E-stained sections from each tumour sample were examined by an experienced pathologist to confirm their histological diagnosis and assess the tumour content. If tumour content was less than 80%, tumour content was enriched by microdissection using a fine needle under a dissection microscope as described previously (Chan et al, 2000).…”