Frequent loss of heterozygosity on chromosome arm 18q in squamous cell carcinomas. Identification of 2 regions of loss--18q11.1-q12.3 and 18q21.1-q23.

OBJECTIVES: To determine the frequency and regions of loss on chromosome arm 18q in uncultured head and neck squamous cell carcinomas. DESIGN: Polymerase chain reaction amplification of DNA extracted from 18 tumor specimens (1 patient had 2 tumors) and blood samples from 17 patients with head and neck squamous cell carcinoma was performed using primers flanking 16 microsatellite repeat polymorphisms spanning most of chromosome 18q. DNA was extracted only from specimens with greater than 70% tumor nuclei. SETTING: Research university. PATIENTS: Seventeen individuals with newly diagnosed head and neck cancer. MAIN OUTCOME MEASURE: Loss of heterozygosity (LOH). RESULTS: There was LOH at more than 1 locus in 52% (9/ 17) of the tumors; 3 tumors had LOH at all informative markers. Four had loss at only 1 locus, raising the total with loss to 12 (75%) of 16. Loss of 18q11.1-q12.3 in 4 tumors without distal loss defines a proximal region of loss. Loss of heterozygosity affecting 18q21.1 in 1 tumor, without proximal loss and LOH for 18q21.1, 18q22, or 18q23 in 9 (52%) of 17 tumors defines a distal region of loss. CONCLUSIONS: Loss of heterozygosity on chromosome arm 18q is not an artifact of in vitro culture. The finding of 18q LOH in 50% to 70% tumors makes 18q an important region for study. Regions 18q11.1-q12.3 and 18q21.1-q23 are common regions of loss, indicating that there may be more than one 18q tumor suppressor gene involved in the genesis and progression of head and neck squamous cell carcinomas.

Identifying genetic changes associated with tumor progression in squamous cell carcinoma.

Tumor behavior is the result of specific genetic changes that alter gene expression. From our cytogenetic studies chromosome 18 loss emerged as a common genetic change in squamous carcinoma cell lines. In this report we summarize data that link loss of 18 to tumor progression and reduced survival, indicating that one or more tumor suppressor gene(s) are located on this chromosome. Tumors grown in vitro were karyotyped either as short-term or permanent cultures. Loss of chromosome 18 was measured by karyotype, decreased frequency of heterozygosity at the DCC locus, and loss of heterozygosity (LOH) for microsatellite repeat polymorphisms (MSRP). Loss of any part of chromosome 18 was observed in approximately 63% of cultured tumors. Primary and secondary tumors from the same individuals sometimes differed in loss of 18 indicating that this genetic change is associated with tumor progression. Heterozygosity for DCC was present in only 3/19 cultured SCC (16%), compared with 68% (11/16) of blood samples from unrelated donors, which is consistent with LOH in roughly one half of the cases. Of 4 informative cases with normal and tumor tissue, LOH was observed in 2. Microsatellite analysis also shows loss of 18q in 55% of fresh tumors. Analysis of tumor tissue and cell lines from the same patient gave identical results. There was an excess of deaths from cancer in the group with 18 loss (20/25) when compared with the group without (5/15). Loss of chromosome 18 appears to be a marker of tumor progression in SCC. It is likely that mutation affecting DCC or another gene on 18 affects tumor growth or spread, leading to more rapid progression and reduced survival.