Molecular and genetic targets in early detection.
ABSTRACT Recent research has revealed the existence of specific mutations in cancer. These mutations are being investigated as targets to find subjects at high risk for cancer, to detect early cancer, to detect the early recurrence of established cancer, and to find micrometastasis. These mutations are reviewed for the major anatomic sites. Some of the clinical issues related to the application of these mutations and the limitations of using molecular targets are also considered. Current methods for determining the risk of cancer are reviewed. Risk assessment is essential for defining cohorts for chemoprevention and other interventions. The concept of using surrogate anatomic and functional sites for estimating risk is introduced. Finally, the increasing complexity of molecular genetic analysis and the biologic heterogeneity of cancer are discussed in relation to early detection.
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ABSTRACT: In order to define more clearly the role of chromosome 9 loss in head and neck squamous cell carcinoma (HNSCC), 29 invasive carcinomas and 17 preinvasive lesions were analyzed for loss of heterozygosity (LOH) on chromosome 9. We found LOH in 21 of 29 (72%) HNSCC tumors using highly polymorphic microsatellite markers. In 17 of 21, LOH was found at all informative sites on the p arm with no LOH of the q arm. Further mapping in tumors, with partial LOH of the 9p arm, localized a common region of loss between markers D9S165 and D9S156. Deletion of this region on chromosome 9 has been found in several other tumor types implying the presence of a tumor suppressor gene at this locus. The inactivation of a tumor suppressor gene on chromosome 9p may represent the most commonly described genetic alteration in HNSCC. A similar incidence of allelic loss on chromosome 9p was identified in 12 of 17 (71%) preinvasive lesions. The identical frequency of loss in preinvasive and invasive lesions suggests that loss of 9p is an early event in HNSCC progression.Cancer Research 04/1994; 54(5):1156-8. · 8.65 Impact Factor
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ABSTRACT: Microsatellite instability has been reported to be an important feature of tumors from hereditary nonpolyposis colorectal carcinoma (HNPCC) patients. The recent discovery of genetic instability in small cell lung carcinoma, a neoplasm not associated with HNPCC, led us to investigate the possible presence of microsatellite alterations in other tumor types. We examined 52 microsatellite repeat sequences in the DNA of normal and tumor pairs from 100 head and neck, bladder, and lung cancer patients by the polymerase chain reaction. Although alterations were rare in dinucleotide repeats, larger (tri- or tetranucleotide) repeats were found to be more prone to expansion or deletion. We screened 100 tumors with a panel of nine tri- and tetranucleotide repeat markers and identified 26 (26%) that displayed alterations in at least one locus. This observation prompted us to examine the possibility of using microsatellite alterations as markers to detect clonal tumor-derived cell populations in pathologic samples. The identical microsatellite alterations detected in the primary tumors were successfully identified in corresponding urine, sputum, and surgical margins from affected patients. This study demonstrates that appropriately selected microsatellite loci are commonly altered in many cancers and can serve as clonal markers for their detection.Proceedings of the National Academy of Sciences 11/1994; 91(21):9871-5. · 9.74 Impact Factor
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ABSTRACT: A reliable, noninvasive method for monitoring patients with transitional cell carcinoma (TCC) of the bladder would be of great clinical benefit. Cystoscopy is currently the "gold standard," but it is invasive, expensive and uncomfortable for the patient. Recently, we demonstrated a novel approach for the detection of primary bladder cancer based on microsatellite analysis of urine DNA. To determine the feasibility of this technique for following-up patients with TCC, we tested serial urine samples from 21 patients who had been treated for bladder cancer with 20 polymorphic microsatellite markers in a blinded fashion. We detected recurrent lesions in 10 out of 11 patients and correctly predicted the existence of a neoplastic cell population in the urine of two patients, 4 and 6 months before cystoscopic evidence of the tumor. The assay was negative in 10 of 10 patients who had no evident cancer. Microsatellite analysis of urine sediment represents a novel and potentially powerful clinical tool for the detection of recurrent bladder cancer.Nature Medicine 07/1997; 3(6):621-4. · 22.86 Impact Factor