Progression of microsatellite instability from premalignant lesions to tumors of the head and neck

Abstract

The role of microsatellite alterations other than loss of heterozygosity (LOH) in the progression of benign epithelium to head-and-neck squamous cell cancer (HNSCC) has not been previously described. As the severity of the dysplasia increases at the microscopic level, there is an increase in the prevalence of LOH as defined by microsatellite analysis. Other alterations have been detected in the form of microsatellite instability (MSI), represented by insertions or deletions of base pairs. It is unknown, however, whether the prevalence of these alterations likewise increases during these early stages of tumor progression. Key words: microsatellite instability; head-and-neck squamous cell carcinoma; loss of heterozygosity; hereditary nonpolyposis colon cancerThe molecular progression of head-and-neck squamous cell carcinoma (HNSCC) correlates with the phenotypic spectrum of dysplasia found in premalignant lesions of the upper respiratory tract epithelium. Loss of heterozygosity (LOH) studies using microsatellite markers on head-and-neck malignancies have demonstrated extensive areas of loss. [1][2][3][4][5] Moreover, premalignant lesions studied in the initial description of a genetic progression model revealed the timing of genetic alterations such as LOH as premalignant lesions advance toward malignancy. 6 These specific genetic events can be detected in the saliva and serum of patients with head and neck malignancy, 7,8 opening the door to new strategies for early cancer detection and tumor surveillance. These genetic alterations included LOH and other microsatellite changes, such as simple insertions or deletions of base pairs, referred to as microsatellite instability (MSI).These simple base pair insertions/deletions are dominant features of certain solid tumors with significant mismatch repair (MMR) defects, such as hereditary non-polyposis colon cancer (HNPCC). 9 However, the reduced prevalence of such alterations and the lack of mutations in gene products known to maintain MMR functions in HNSCC do not support classification of HNSCC as a tumor type with a dominant feature of MMR deficiency. Nevertheless, when detected in HNSCC at selected loci, the shifted alleles can be quite useful in detecting the presence of altered clonal populations in body fluids, including saliva and serum. 7,8 It is important to emphasize that the microsatellite markers selected in these studies were known to exhibit LOH and MSI in lung tumors; therefore, identification of MSI in these head-andneck tumors does not implicate HNSCC as an MMR-deficient tumor type.However, MSI has not been studied comprehensively in premalignant lesions of the head and neck. Further definition of the temporal occurrence of such alterations in premalignant lesions in HNSCC should provide insight into the detection of premalignant lesions using analyses of both MSI and LOH.We looked at 5 different categories of head-and-neck lesions, predominantly from the oral cavity: hyperplasia without atypia, mild dysplasia, moderate dysplasia, severe dysplasia/ca...

Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma

“…Upregulation of NOTCH4 is associated with breast and mammary cancer (Weng and Aster, 2004). Independent confirmation of our observations is provided by recent expression array studies, which found significant upregulation of JAG1 and NOTCH4 in oral SCC compared to normal tissue (Leethanakul et al, 2000;Ha et al, 2003). These studies together with the data reported here indicate a role for deregulation of notch signaling in oral cancer.…”

“…On the other hand, notch signaling promotes differentiation in skin (Lefort and Dotto, 2004) and loss of function of notch is permissive for tumor formation in mouse models (Nicolas et al, 2003). Although two expression array studies found upregulation of some members of the wnt and notch signaling pathways in head and neck SCC (Leethanakul et al, 2000;Ha et al, 2003), the hedgehog and notch pathways have not been previously characterized in oral squamous cell tumorigenesis. Therefore, we investigated whether expression levels of other members of the hedgehog and notch pathways were altered in oral SCC.…”

The clinical relevance of microsatellite alterations in head and neck squamous cell carcinoma: a critical review

“…Most studies show that invasive carcinomas manifest more MSI than precursor lesions, suggesting progressive accumulation of MSI during tumor development 12,28 (Table 1). Furthermore, precursor lesions that show MSI are more prone to progress to HNSCC.…”

Tetranucleotide Microsatellite Instability in Surgical Margins for Prediction of Local Recurrence of Head and Neck Squamous Cell Carcinoma

“…Some of the markers can be used to determine premalignant conditions before the appearance of a histopathologically evident abnormality (8).…”