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Biomedical subjects

D Sidransky

Publications and source records attributed to D Sidransky.

At least 163 records · Page 9Linked to original sources
PubMed1995

Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck.

BACKGROUND: Although epidemiologic studies have long associated tobacco and alcohol use with the development of squamous-cell carcinoma of the head and neck, the molecular targets of these carcinogens have yet to be identified. We performed a molecular analysis to determine the pattern of mutations in the p53 gene in neoplasms from patients with squamous-cell carcinoma of the head and neck and a history of tobacco or alcohol use. METHODS: Sequence analysis of the conserved regions of the p53 gene was performed in tumor samples from 129 patients with primary squamous-cell carcinoma of the head and neck. We then used statistical analysis to identify any patient characteristics associated with mutation of the p53 gene. RESULTS: We found p53 mutations in 42 percent of the patients (54 of 129). Fifty-eight percent of the patients who smoked cigarettes and used alcohol (37 of 64; 95 percent confidence interval, 45 to 70 percent), 33 percent of the patients who smoked but abstained from alcohol (13 of 39; 95 percent confidence interval, 19 to 50 percent), and 17 percent of the patients who neither smoked nor drank alcohol (4 of 24, 95 percent confidence interval, 5 to 37 percent) had p53 mutations (P = 0.001). (Two patients used alcohol but did not smoke, and neither had a p53 mutation.) Furthermore, 100 percent of the mutations in the patients who neither drank nor smoked occurred at sites containing cytidine phosphate guanosine dinucleotides (potentially representing endogenous mutations) within the p53 gene (5 of 5 mutations; 95 percent confidence interval, 48 to 100 percent), whereas only 23 percent of those in cigarette smokers consisted of such changes (12 of 53 mutations; 95 percent confidence interval, 12 to 36 percent; P = 0.001). CONCLUSIONS: In our study, a history of tobacco and alcohol use was associated with a high frequency of p53 mutations in patients with squamous-cell carcinoma of the head and neck. Preliminary evidence linked cigarette smoking to p53 mutations at nonendogenous mutation sites. Our findings suggest a role for tobacco in the molecular progression of squamous-cell carcinoma of the head and neck and support the epidemiologic evidence that abstinence from smoking is important to prevent head and neck cancer.

Base Composition↗
PubMed1995

Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck.

BACKGROUND: Surgical oncologists rely heavily on the histopathological assessment of surgical margins to ensure total excision of the tumor in patients with head and neck cancer. However, current techniques may not detect small numbers of cancer cells at the margins of resection or in cervical lymph nodes. METHODS: We used molecular techniques to determine whether clonal populations of infiltrating tumor cells harboring mutations of the p53 gene could be detected in histopathologically negative surgical margins and cervical lymph nodes of patients with squamous-cell carcinoma of the head and neck. RESULTS: We identified 25 patients with primary squamous-cell carcinoma of the head and neck containing a p53 mutation who appeared to have had complete tumor resection on the basis of a negative histopathological assessment. In 13 of these 25 patients, molecular analysis was positive for a p53 mutation in at least one tumor margin. In 5 of 13 patients with positive margins by this method (38 percent), the carcinoma has recurred locally, as compared with none of 12 patients with negative margins (P = 0.02 by the log-rank test). Furthermore, molecular analysis identified neoplastic cells in 6 of 28 lymph nodes (21 percent) that were initially negative by histopathological assessment. CONCLUSIONS: Among specimens initially believed to be negative by light microscopy, a substantial percentage of the surgical margins and lymph nodes from patients with squamous-cell carcinoma of the head and neck contained p53 mutations specific for the primary tumor. Patients with these positive margins appear to have a substantially increased risk of local recurrence. Molecular analysis of surgical margins and lymph nodes can augment standard histopathological assessment and may improve the prediction of local tumor recurrence.

Aged↗
PubMed1995

Localization of tumor suppressor loci on chromosome 9 in primary human renal cell carcinomas.

To investigate the potential loss of tumor suppressor gene loci on chromosome 9 in human renal cell tumorigenesis we analyzed 42 paired normal and tumor DNAs with 18 polymorphic microsatellite markers spanning this chromosome. Fourteen of 42 (33%) tumors showed partial or complete deletion of chromosome 9. Deletion mapping provided evidence for the presence of a suppressor locus on both the short and long arm of chromosome 9. Homozygous deletion at 9p21-22 in one renal tumor and a selective deletion of distal 9q in another tumor localized the critical regions. The CDKN2/p16 gene was further investigated as a candidate suppressor locus on 9p21-22 by multiplex PCR, Southern analysis, and exon sequencing. We found no additional cases of homozygous deletion nor any rearrangements or point mutations of CDKN2/p16. This is the first report of 9p loss of heterozygosity, homozygous deletion of 9p21-22 and selective deletion of 9q in primary renal cell carcinomas. Understanding the molecular genetic basis of renal cell progression will require the isolation and characterization of additional tumor suppressor genes on chromosome 9.

Carcinoma, Renal Cell↗
PubMed1995

Squamous cell carcinoma of the head and neck in the elderly.

OBJECTIVE: While squamous cell carcinoma of the head and neck (HNSCC) most commonly affects individuals in the fifth to seventh decades of life, it occasionally arises in older patients. Biologic and epidemiologic factors of HNSCC in elderly patients have been investigated to shed light on the process of neoplastic transformation in that population. DESIGN: The medical records of patients with new onset of HNSCC presenting between 1988 and 1993 were reviewed retrospectively. SETTING: Tertiary-care hospital-based clinic. PATIENTS: Eighty-one individuals who developed HNSCC of the upper aerodigestive tract after their 75th birthday constituted the study group. A control group consisting of 102 patients who developed HNSCC between the ages of 40 and 70 years was also analyzed. MAIN OUTCOME MEASURE: Information about each individual's tobacco and ethanol exposure, family history of cancer, history of second primary cancer, treatment provided, and current disease status were derived from the medical record. The presence or absence of p53 gene mutation was tabulated for a subset of individuals in both the elderly and the middle-aged groups. RESULTS: The elderly patients had a significantly lower degree of alcohol and tobacco exposure, but a significantly higher rate of second primary cancers, especially in sites outside the upper aerodigestive tract. There was no difference in the incidence of cancer in first-degree relatives in the two groups. These findings were interpreted in light of results from our laboratory examining the incidence of p53 gene mutation in a large number of patients with HNSCC. A significantly higher percentage of tumors from the younger group contained a p53 gene mutation. Major surgery was an integral part of the treatment plan for most of the older patient group despite their advanced age. CONCLUSIONS: These findings suggest that HNSCC arising after the seventh decade of life less frequently involves a genetic change commonly found in younger patients. Heavy carcinogen exposure and p53 gene mutations are present less often in elderly individuals, whereas this group appears to be more susceptible to multiple cancers. The precise biologic factors involved in neoplastic transformation in this older population await discovery. Since aggressive therapy can be successfully tolerated by many elderly patients, an individualized approach to treatment is advocated.

Adult↗
PubMed1995

Frequent loss of chromosome arms 8p and 13q in collecting duct carcinoma (CDC) of the kidney.

Collecting duct carcinoma (CDC) is a malignant renal neoplasm that is believed to arise from the epithelium of the ducts of Bellini in the distal nephron. These tumors are clinically aggressive and more often occur in a younger population than is typical of the more common clear cell renal carcinoma (RCC). Using highly informative polymorphic microsatellite markers on chromosome arms 3p, 5q, 6q, 9p, 9q, 11p, 13q, 17p, and 18q, we analyzed DNA from nonmalignant and tumor tissue in 6 cases of CDC. We found no evidence of 3p loss of heterozygosity (LOH) in these renal tumors by using multiple markers, a finding that distinguishes CDC from RCC in which 3p LOH has frequently been observed. We found LOH of 8p in 50% of the tumors examined; in addition, we observed LOH of 13q in 50% of the tumors studied. Interestingly, 8p LOH may be associated with high stage and poor clinical prognosis. These data suggest that the molecular events responsible for the development of CDC differ from those associated with the origin of RCC, and that tumor suppressor genes on 8p and 13q may be involved in the pathogenesis of CDC.

Adolescent↗
PubMed1995

Frequency of homozygous deletion at p16/CDKN2 in primary human tumours.

Many tumour types have been reported to have deletion of 9p21 (refs 1-6). A candidate target suppressor gene, p16 (p16INK4a/MTS-1/CDKN2), was recently identified within the commonly deleted region in tumour cell lines. An increasing and sometimes conflicting body of data has accumulated regarding the frequency of homozygous deletion and the importance of p16 in primary tumours. We tested 545 primary tumours by microsatellite analysis with existing and newly cloned markers around the p16 locus. We have now found that small homozygous deletions represent the predominant mechanism of inactivation at 9p21 in bladder tumours and are present in other tumour types, including breast and prostate cancer. Moreover, fine mapping of these deletions implicates a 170 kb minimal region that includes p16 and excludes p15.

Blotting, Southern↗
PubMed1995

Microsatellite instability in primary neoplasms from HIV + patients.

AIDS is associated with a high risk of certain malignancies, notably Kaposi's sarcoma (KS) and B-cell non-Hodgkin's lymphoma (NHL). The pathogenesis of these malignancies is not fully understood. One mechanism of malignant transformation recently described in colon tumorigenesis results from defects in DNA mismatch repair, manifest as widespread microsatellite instability. We demonstrate a high rate of microsatellite instability in KS and aggressive lymphomas obtained from HIV-infected patients, whereas there is no evidence of instability in similar lesions from HIV-negative patients. Further elucidation of the underlying mechanisms responsible for HIV-associated instability in primary tumours may provide insight into the pathogenesis of these AIDS-related neoplasms.

DNA Repair↗
PubMed1995

5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers.

Loss of heterozygosity on chromosome 9p21 is one of the most frequent genetic alterations identified in human cancer. The rate of point mutations of p16, a candidate suppressor gene of this area, is low in most primary tumours with allelic loss of 9p21. Monosomic cell lines with structurally unaltered p16 show methylation of the 5' CpG island of p16. This distinct methylation pattern was associated with a complete transcriptional block that was reversible upon treatment with 5-deoxyazacytidine. Moreover, de novo methylation of the 5' CpG island of p16 was also found in approximately 20% of different primary neoplasms, but not in normal tissues, potentially representing a common pathway of tumour suppressor gene inactivation in human cancers.

5-Methylcytosine↗
PubMed1995

Molecular genetics of head and neck cancer.

Head and neck cancers arise and progress through specific genetic alterations. Elucidation of these genetic changes has led to the development of a preliminary molecular progression model. Critical oncogenes and areas of chromosomal loss have been identified in a high proportion of squamous cell carcinomas. Oncogene mutations have given insight into the origin of these neoplasms and the fundamental cellular pathways that must be altered for progression. Further characterization of these genetic alterations will lead to improved molecular assays with important implications for diagnosis, prognosis, and therapy.

Carcinoma, Squamous Cell↗
PubMed1995

Molecular markers in cancer diagnosis.

Clonal genetic alterations are a hallmark of human cancer pathogenesis. These genetic alterations may include specific gene mutations that drive the cancer process or phenotypic changes such as microsatellite instability that may be caused by specific genetic events. Identification of clonal cell populations that share a specific genetic alteration is virtually synonymous with the detection of cancer. These clonal cells can be detected among a large population of normal cells from limited clinical samples by DNA amplification techniques. Because of their unprecedented sensitivity and specificity, these approaches offer new hope for the early diagnosis of human cancer.

Chromosome Mapping↗
PubMed1995

AIDS-related Kaposi's sarcoma is a clonal neoplasm.

Kaposi's sarcoma is generally believed to be a non-neoplastic hyperproliferation because it may regress spontaneously and its spindle cells lack features of typical tumor cells, such as aneuploidy, nuclear atypia, and permissive growth in cell culture. A fundamental characteristic of neoplasms is clonality, in that they arise from clonal replication of a single cell whereas reactive processes are derived from polyclonal proliferation. We used an X chromosome inactivation assay to determine the clonality of Kaposi's sarcoma nodules from patients with AIDS-related disease. The assay is based on a methyl-sensitive restriction digest followed by PCR amplification of the highly polymorphic androgen receptor gene. Two of three evaluable cases had a monoclonal pattern of inactivation, and the third case had a clonal expansion of cells with an altered microsatellite repeat sequence. These data suggest that Kaposi's sarcoma (at least in the AIDS setting) is a clonal neoplasm.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Microsatellite alterations as clonal markers for the detection of human cancer.

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.

Base Sequence↗
PubMed1994

Infrequent inactivation of the retinoblastoma gene despite frequent loss of chromosome 13q in head and neck squamous cell carcinoma.

Our recent allelic analysis of head and neck squamous cell carcinomas identified a high incidence of chromosomal loss on 13q. To further define an area of minimal loss, we tested 60 primary head and neck squamous cell carcinomas in 59 patients for loss of heterozygosity (LOH) by using 10 polymorphic microsatellite markers spanning the long arm of chromosome 13. We examined the same primary tumors for inactivation of the retinoblastoma (Rb) gene by immunohistochemical analysis of paraffin-embedded specimens. Thirty-one of 60 (52%) tumors demonstrated LOH in at least one 13q marker. Twenty-nine of 31 (94%) lost a portion of 13q that included D13s133, which lies just telomeric to the Rb gene at 13q14.3. However, immunohistochemical staining revealed absence of Rb protein in only 6 of these 31 tumors (19.4%) with LOH. All but one tumor without LOH on 13q displayed normal Rb protein staining. Although Rb may be inactivated by an unusual mechanism in some head and neck squamous cell carcinomas, our data suggest that another tumor suppressor gene locus at 13q14 is likely to be involved in head and neck tumor progression.

Adult↗
PubMed1994

A region of homozygous deletion on chromosome 9p21-22 in primary nasopharyngeal carcinoma.

Using 21 microsatellite polymorphic markers spanning both p and q arms, we have performed detailed deletion mapping on chromosome 9 in 18 primary nasopharyngeal carcinomas. All 18 tumors were informative at multiple loci. Eleven of the 18 cases (61%) demonstrated allelic deletion of chromosome 9. Among these 11, 6 cases are likely to be tumors with monosomy of chromosome 9. The other 5 cases demonstrated partial deletion by showing multiple areas of allelic loss. In one of the 5 cases, a homozygous deletion region was identified which includes D9S126, D9S171, and IFNA loci at 9p21-22, situated between loci D9S161 (9p21) and D9S162 (9p21-22). The presence of a homozygous deletion strongly suggests the presence of tumor suppressor gene(s) involved in the tumorigenesis of nasopharyngeal carcinoma. The same region has been reported to include some potential tumor suppressor gene loci in other cancers. This is the first reported finding of frequent genetic loss observed on chromosome 9 in nasopharyngeal carcinomas in addition to allelic loss on chromosome 3p at specific regions. Our results suggest that tumorigenesis and progression of nasopharyngeal carcinomas, like other solid tumors, involves multiple genetic changes associated with the inactivation of tumor suppressor genes.

Alleles↗
PubMed1994

Mutations in the conserved regions of p53 are infrequent in betel-associated oral cancers from Papua New Guinea.

Seventy-five % of the world's oral cancers arise in developing countries. In high incidence areas of Southeast Asia such as Papua New Guinea (PNG) the major region-specific risk exposure is betel quid chewing. While it has been shown that p53 gene mutations in the conserved midregion (exons 5-9) are a common feature of oral cancers in the developed world, there is no information on this type of genetic lesion in betel quid-associated oral cancers. We examined 50 oral squamous cell carcinomas, 20 from Baltimore, MD and 30 from PNG, for mutations in exons 5-9 of the p53 gene. DNA extracted from frozen biopsies was amplified by polymerase chain reaction, the purified product was sequenced directly, and mutations were confirmed by repeating the entire procedure. Mutations were found in 3 of 30 tumors from PNG (10%), whereas 9 mutations were detected among the 20 tumors (45%) from Baltimore, MD. This difference in frequency is statistically significant (P < 0.01) by chi 2 analysis. Nuclear accumulation of p53 protein, determined by immunohistochemistry with the CM-1 antiserum, was observed in the PNG cases harboring a missense mutation of the p53 gene. In agreement with the low number of PNG cancers with mutations, only 17% of the cases from PNG were immunostain positive. To explore whether less conserved regions of the gene are preferential targets for alterations in this patient group, sequence analysis in tumors from PNG was extended to outlying regions of the gene (all of exons 4 and 10, and splice sites), but mutations in only two additional tumors were identified. The presence of human papillomavirus DNA in PNG cases was examined with a polymerase chain reaction-based procedure, and viral sequences (human papillomavirus strains 11/16) were detected in two tumors. Human papillomavirus-triggered degradation of the tumor suppressor protein is thus unlikely to be a typical pathway to p53 dysfunction in tumors from PNG.

Adult↗