Steven B. Scholnick

Evidence for multiple tumor suppressor genes on chromosome arm 8p in supraglottic laryngeal cancer

Loss of heterozygosity studies of a variety of human tumors suggest that there are several tumor suppressor genes on chromosome arm 8p. To localize these genes more precisely, we utilized polymerase chain reaction amplification of microsatellite repeat polymorphisms and examined the allelic loss patterns of 17 marker loci on 8p in a population of 59 supraglottic laryngeal squamous cell carcinomas. Twenty‐three of these tumors (39%) had an allelic loss at one or more of the markers examined. The allelic loss patterns of these tumors support the presence of at least three different tumor suppressor genes on 8p: one in 8p23, one in 8p22–23, and another in 8p21. Genes Chromosom Cancer 16:164–169 (1996).

Prognostic significance of clinical factors and p53 expression in patients with glottic carcinoma treated with radiation therapy

Numerous clinical parameters have been suggested as predictors of outcome for patients with head and neck carcinoma treated with radiation therapy, but their applicability remains controversial. Inactivation of the p53 tumor suppressor results in radioresistance in experimental systems and might predict treatment failure in human patients. We have tested this hypothesis by comparing the predictive power of nuclear accumulation of p53 protein with that of clinical and histopathologic markers in patients with glottic carcinoma treated with primary radiotherapy.

Localization of a putative tumor suppressor gene in the sub-telomeric region of chromosome 8p

Several regions of chromsome arm 8p are frequently deleted in a variety of human malignancies including those of the prostate, head and neck, lung, and colon, suggesting that there is more than one tumor suppressor gene on this chromosome arm. Both laryngeal and oral squamous cell carcinomas exhibit three distinct and nonoverlapping regions of deletion on 8p. We have further refined the localization of the putative suppressor in 8p23 by using eight microsatellite loci to create a high resolution deletion map of 150 squamous cell carcinomas of the larynx and oral cavity. These new data demonstrate that there are two distinct classes of deletion within this relatively small region of the chromosome and suggest two possible locations for the gene within the D8S264 to D8S1788 interval. We also determined that there is little difference between the allelic loss frequencies of microsatellites mapping near the telomeric ends of other chromosome arms and loci mapping to more centromere proximal regions of the same arm. These data suggest that the high allelic loss frequencies seen at 8p23 loci are not the result of a generalized instability of chromosome ends and are instead consistent with the activation of a specific suppressor gene.

Multiple regions of deletion on chromosome arm 13q in head-and-neck squamous-cell carcinoma

Several lines of evidence suggest that the progression of head‐and‐neck squamous‐cell carcinoma (HNSCC) involves inactivation of at least one and possibly several tumor‐suppressor genes on the long arm of chromosome 13. The fact that neither Rb1 nor BRCA2 appears to be inactivated in the majority of head‐and‐neck cancers suggests that novel tumor‐suppressor genes are involved. We have used microsatellite repeat polymorphisms and PCR to detect several distinct minimal regions of deletion on 13q in supraglottic and oral squamous‐cell carcinomas. One region maps to 13q34, the second to 13q14.3 and a potential third region, not reported in previous studies, maps to 13q12.1. Overall, 69% of the 145 tumors examined demonstrated allelic loss at one or more loci on 13q. We investigated whether a novel suppressor candidate mapping to 13q14.3‐q21, leukemia‐associated gene 1, might also be involved in the progression of squamous‐cell carcinomas. Multiplexed PCR revealed homozygous deletion of leu1 in one oral cavity tumor. This suggests that this gene or one nearby may be the actual target of deletions in this region of the chromosome arm. Int. J. Cancer (Pred. Oncol.) 84:453–457, 1999.

Frequent loss of heterozygosity for Rb, TP53, and chromosome arm 3p, but not NME1 in squamous cell carcinomas of the supraglottic larynx.

Background. The inactivation of some tumor suppressor genes classically manifests itself through the loss of heterozygosity at nearby genetic mapping markers. Inactivation of these genes appears to have diagnostic/prognostic significance in some types of tumors. Molecular genetic tools based on suppressor inactivation might, therefore, have great utility in treatment planning.

Identification of two new members of the CSMD gene family

CSMD1 is a putative suppressor of squamous cell carcinomas mapping to human chromosomal region 8p23. We have cloned two new members of this gene family, CSMD2 and CSMD3. The three CSMD proteins have very similar structures, each consisting of 14 CUB domains separated from one another by a sushi domain, an additional uninterrupted array of sushi domains, a single transmembrane domain, and a short cytoplasmic tail. CUB and sushi domains are thought to be sites of protein-protein or protein-ligand interactions, suggesting that CSMD proteins are either transmembrane receptors or adhesion proteins. The cytoplasmic tail sequences are highly conserved within the vertebrate lineage. CSMD2 maps to a chromosomal region that may contain a suppressor of oligodendrogliomas, yet its expression is elevated in some head and neck cancer cell lines. Functional overlap between the CSMD1 and the CSMD2 proteins may modify the phenotype resulting from the loss of either protein in tumors.

Clinical Correlations with Allelotype in Supraglottic Squamous Cancer

Frequent allelic loss at a genetically polymorphic locus in tumors is an established marker for the presence of a tumor suppressor gene in the neighboring chromosomal region. This technique can be used to identify novel tumor suppressor genes and to monitor their status before the cloning of the gene itself. We have used the polymerase chain reaction and microsatellite loci on all 39 nonacrocentric autosomal chromosomal arms to identify sites of frequent allelic loss in squamous cell carcinomas of the supraglottic larynx. Our allelotype identified seven chromosomal arms (3p, 5q, 8p, 9p, 9q, 13q, and 17p) likely to contain tumor suppressor genes frequently inactivated during squamous tumorigenesis in the larynx. We tested for associations between allelic losses on these chromosomal arms and the clinical and histopathologic features of these tumors. There were no correlations with either T or N classifications. Allelic loss on chromosomal arm 13q is significantly associated with a number of histopathologic features characteristic of poorly differentiated or histologically aggressive tumors. Allelic loss on this arm also exhibits statistical trends toward association with early tumor recurrence and poor survival. The association with survival was substantiated by a multivariate Cox proportional hazards model.