Chandramohan S. Ishwad

Frequent allelic loss and homozygous deletion in chromosome band 8p23 in oral cancer

Frequent loss of heterozygosity on chromosome 8p in a variety of human malignancies, including head and neck cancers, has suggested the presence of a tumor suppressor gene (or genes) associated with the pathogenesis of these cancers. To test the role of genetic alterations at 8p23 in oral carcinogenesis, we studied 51 squamous cell carcinomas of the head and neck and 29 oral squamous cell carcinoma cell lines for allelic loss using 7 microsatellite markers spanning approximately 5 cM of chromosome band 8p23. Twenty-three of 51 tumors (45%) and 23 of 29 cell lines (79%) showed allelic loss at 1 or more loci. Three cell lines showed homozygous deletion of loci within a 3 cM region defined by the markers D8S1781 and D8S262. Our results suggest that a tumor suppressor gene (or genes) is located in 8p23 and is associated with the development and/or progression of oral carcinomas.

Two discrete regions of deletion at 7q in uterine leiomyomas

This study further defines the region of consistent deletion of chromosome 7 in uterine leiomyomas. We have examined 74 leiomyomas for allelic loss of markers spanning the 7q22 region defined by markers D7S518 and D7S471. Forty tumors with cytogenetically defined 7q deletions, twenty‐nine tumors without cytogenetically visible 7q deletions, and five tumors with no cytogenetic information were examined for allelic loss of D7S518, D7S666, D7S515, D7S658, D7S496, D7S692, and D7S471. Loss of heterozygosity for one or more of these loci was observed in twenty‐eight leiomyomas with cytogenetically defined 7q deletions and in three leiomyomas with a normal karyotype. Allelic loss of D7S666 was common and was observed in all twenty‐three informative tumors with 7q deletions and in two tumors with normal karyotypes. This study indicates the presence of a tumor suppressor gene in close proximity to the D7S666 locus. Eight tumors followed an unusual pattern of allelic loss. These tumors showed retention of heterozygosity for at least one locus flanked by deleted loci. These results suggest the possibility that two discrete regions of deletion at 7q22 are involved in the development of a subset of leiomyomas. Genes Chromosom. Cancer 19:156–160, 1997.

Loss of heterozygosity of the short arm of chromosomes 3 and 9 in oral cancer

Loss of heterozygosity (LOH) on chromosomes 3p and 9p has been documented in a variety of malignancies, which suggests the presence of tumor suppressor gene loci on these chromosomes. We have studied 77 oral carcinomas for LOH using 16 microsatellite markers distributed over 5 human chromosomes. Fifty‐five (71%) of these tumors showed LOH at one or more loci. A significant proportion of LOH at the informative tumors was observed at chromosomes 3p and 9p: 58% and 48%, respectively. A majority of the tumors showed losses at multiple loci on chromosomes 3p or 9p or on both. Our results suggest that tumor suppressor genes located on the short arms of chromosomes 3 and 9 may be involved in the pathogenesis of oral carcinoma. These regions of deletion observed in oral cancers overlap those reported in other neoplasms. However, we did not find any evidence of these changes in tumor margins with early pathological changes.

Association of 8p23 deletions with poor survival in head and neck cancer

OBJECTIVE: Allelic loss at 8p23 occurs frequently in head and neck squamous cell carcinoma. The objective of this study was to determine the prognostic importance of 8p23 loss. STUDY DESIGN AND SETTINGS: We tested 51 primary tumors and 19 lymph node metastases for loss of heterozygosity with 7 microsatellite polymorphisms at 8p23 and correlated the results with disease-free interval and disease-specific survival. RESULTS: The Kaplan-Meier analysis demonstrated statistically significant association of 8p23 allelic loss with both shorter disease-free interval and disease-specific survival. For the pN stage, the log-rank test indicated significance in correlation with the disease-free interval, whereas the pT stage showed a significant correlation with disease-specific survival. Multivariate analysis identified loss of heterozygosity at 8p23 as independent prognostic marker for disease-free interval. CONCLUSION: Our data suggest that 8p23 allelic loss is associated with poor prognosis in head and neck squamous cell carcinoma and could be useful refining diagnosis of these tumors.

The presence of multiple regions of homozygous deletion at the CSMD1 locus in oral squamous cell carcinoma question the role of CSMD1 in head and neck carcinogenesis.

We and others previously identified a region of hemizygous or homozygous deletion at chromosome band 8p23 in oral and oropharyngeal squamous cell carcinomas (OSCCs) and many other cancer types, suggesting the presence of a tumor‐suppressor gene (TSG) in this region. Recently, based on a single region of homozygous deletion in head and neck squamous cell carcinomas (HNSCC), a putative TSG, CUB and sushi multiple domains‐1 (CSMD1), has been identified. In the present study, we mapped three OSCC cell lines with previously described homozygous deletions at a high resolution onto a detailed physical map. Critically, this map covered a wider region than that used in previous studies, and in contrast to these studies, our results revealed multiple regions of homozygous deletion within a small interval on 8p23. To investigate this deletion pattern further, we generated a panel of 34 sequence tagged site (STS) markers spanning the region and tested these three cell lines and an additional 34 OSCC cell lines, identifying homozygous deletions in a further four. Combining the results from all seven deleted cell lines identified three non‐overlapping regions of homozygous deletion. This complex pattern could be consistent with the presence of multiple TSGs or one very large TSG in this region, and/or specific chromosomal instability. CSMD1 spans two of the three deleted regions and, therefore, would appear to be an excellent candidate for a TSG. However, deletion mapping with STSs corresponding to the exons of CSMD1 shows that some of the deletions do not interrupt its coding region, and in other cell lines the coding region is interrupted by two discontinuous homozygous deletions, suggesting the presence of redundant deletions. These results call into question whether the CSMD1 gene is the 8p23 TSG or whether this or any other genes at this locus are involved in the development of OSCC.

RNASEL and RNASEL‐inhibitor variation and prostate cancer risk in Afro‐Caribbeans

Afro‐Caribbeans from Tobago are at high risk of developing prostate cancer. This elevated risk of prostate cancer is shared by populations of African ancestry living in diverse environments in the Western hemisphere. Variation in the ribonuclease L (RNASEL) gene has recently been reported to be associated with an increased risk of prostate cancer. However, whether RNASEL variation contributes to the increased risk of prostate cancer observed in populations of African ancestry remains unclear.