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Biomedical subjects

D Sidransky

Publications and source records attributed to D Sidransky.

At least 181 records · Page 10Linked to original sources
PubMed1994

Homozygous deletion on chromosome 9p and loss of heterozygosity on 9q, 6p, and 6q in primary human small cell lung cancer.

We analyzed the pattern of allelic loss in 33 primary human small cell lung cancers (SCLCs) using highly informative microsatellite markers on chromosomes 2p, 3p, 5q, 6, 9, 13q, and 17p. Nineteen of these tumors (58%) displayed loss of heterozygosity on chromosome 9. Fourteen SCLCs demonstrated loss of heterozygosity for all informative markers on both chromosomal arms; two tumors demonstrated partial loss on chromosome 9p. In one tumor, a multiplex polymerase chain reaction assay disclosed a homozygous deletion at 9p21-22 including the markers IFN-alpha, D9S126, and D9S171. Two SCLCs retained all informative markers on 9p but showed allelic loss of the entire 9q arm, while one case had a partial loss of proximal 9q extending into all of 9p. Analysis of other chromosomal arms showed loss of heterozygosity on 3p (93%), 5q (75%), 6p (46%), 6q (47%), 13q (75%), and 17p (93%). It was necessary to test multiple markers at several loci because of the frequent expression of microsatellite instability that confounded our mapping efforts in SCLCs with replication errors. This study demonstrates the frequent loss of a suppressor gene locus on chromosome 9p21-22 and identifies novel suppressor loci on 6p, 6q, and 9q in primary SCLC.

Adult↗
PubMed1994

Frequent microsatellite instability in primary small cell lung cancer.

Alterations in microsatellite sequences characterize hereditary nonpolyposis colorectal cancer. This microsatellite instability is due in some kindreds to a germline mutation of the mismatch repair gene hMSH2 on chromosome 2p. Although microsatellite alterations have been reported in other hereditary nonpolyposis colorectal cancer-associated tumors including endometrial and gastric cancers, such changes were not detected in most other major neoplasms. We found that 15 of 33 (45%) primary small cell lung cancers, tumors not found in the hereditary nonpolyposis colorectal cancer syndrome, displayed alterations of microsatellite loci which consisted of deletions or expansions of (CA)n dinucleotide repeats. In 8 of these 15 neoplasms, microsatellite instability was detected in more than 10% of all tested alleles. However, small cell lung cancers that revealed instability contained widespread allelic loss and had a uniformly poor prognosis. These results expand considerably the known spectrum of tumors with microsatellite instability.

Adult↗
PubMed1994

Detection of oncogene mutations in sputum precedes diagnosis of lung cancer.

The Johns Hopkins Lung Project developed an archive of sputum specimens during a randomized trial of lung cancer screening (1974-1982). We identified 15 patients from that trial who later developed adenocarcinoma of the lung. The primary lung carcinomas from 10 of these 15 patients contained either a ras or a p53 gene mutation. Using a polymerase chain reaction-based assay, stored sputum samples obtained prior to clinical diagnosis were examined for the presence of these same oncogene mutations. In 8 of 10 patients, the identical mutation identified in the primary tumor was also detected in at least one sputum sample. The earliest detection of a clonal population of cancer cells in sputum was in a sample obtained more than 1 year prior to clinical diagnosis. These results provide the basis of a novel approach for detection of lung cancer based on the evolving molecular genetics of this disease.

Aged↗
PubMed1994

Homozygous deletions of 9p21 in primary human bladder tumors detected by comparative multiplex polymerase chain reaction.

Deletion mapping studies of primary bladder tumors have identified nonoverlapping areas of loss on each arm of chromosome 9, indicating that two distinct tumor suppressor loci are located on this chromosome. The deleted region on the p arm overlaps an area of 9p previously reported to be lost in a variety of neoplasms. Detailed loss of heterozygosity analysis of 9p in 112 primary bladder tumors using 12 microsatellite markers identified a minimal area of loss around the alpha-interferon locus at 9p21-22. Frequent homozygous deletions of the alpha-interferon locus were then identified in these tumors by a novel, comparative, multiplex polymerase chain reaction assay and were subsequently confirmed by Southern analysis. Based on these deletions, a putative tumor suppressor gene locus involved in bladder tumorigenesis was localized to a 10 cM region (flanked by D9S162 and D9S171), previously implicated in the progression of many neoplasms. Application of the multiplex polymerase chain reaction-based assay will allow rapid identification of homozygous deletions in many neoplasms and thus aid in mapping studies of critical suppressor genes.

Chromosome Deletion↗
PubMed1994

Allelotype of head and neck squamous cell carcinoma.

To gain a better understanding of the molecular changes in head and neck squamous cell carcinoma, we tested every autosomal arm of 29 primary head and neck tumors for allelic loss. Fifty-eight microsatellite markers were used with at least two-thirds of patients informative for each chromosomal arm tested. A high frequency of allelic loss was found on chromosome 9p where 21 of 29 (72%) tumors had loss of heterozygosity for at least one polymorphic marker on this arm. Chromosomes 3, 11q, 13q, and 17p exhibited loss in over 50% of all informative cases, while chromosomes 4, 6p, 8, 14q, and 19q displayed loss in greater than 35% of all cases tested. Additionally, several other chromosomal arms exhibited loss of heterozygosity in 20 to 30% of tumors tested. This high frequency of allelic loss in these advanced stage neoplasms suggests multiple genetic steps in the progression of head and neck cancer and identifies several putative tumor suppressor loci on affected chromosomes.

Alleles↗
PubMed1994

Frequent loss of chromosome 9p21-22 early in head and neck cancer progression.

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.

Adult↗
PubMed1994

Frequent loss of chromosome 9 in human primary non-small cell lung cancer.

We analyzed the pattern of allelic loss on chromosome 9 in 40 primary human non-small cell lung cancers including 16 squamous cell, 18 adeno-, and 6 large cell carcinomas. Using 24 polymorphic microsatellite markers spanning chromosome 9, we found that 27 of 40 (67.5%) of these neoplasms displayed loss of heterozygosity (LOH) on chromosome 9. Most tumors showed LOH for all informative markers on both chromosomal arms, whereas five tumors demonstrated partial LOH on chromosome 9. In four of these tumors, allelic loss was limited to the 9p arm, whereas in the remaining specimen, LOH extended from 9p21-22 to terminal 9q. These five tumors delineate a minimal area of loss at 9p21-22, which includes a previously defined tumor suppressor gene locus. We have identified a distinct region of loss on chromosome 9p commonly involved in non-small cell lung cancer tumorigenesis.

Aged↗
PubMed1994

Progression of basal cell carcinoma through loss of chromosome 9q and inactivation of a single p53 allele.

Basal cell carcinoma (BCC) of the skin represents a unique group of tumors strongly associated with exposure to UV light. Unlike squamous carcinoma of the skin, BCC is generally indolent, noninvasive, and rarely metastatic. To study the involvement of tumor suppressor genes in these neoplasms, we analyzed 36 BCCs for p53 mutations and a subset of these tumors for loss of chromosomes 17p and 9q. Sixty-nine % of sporadic BCCs had lost a 9q allele, with the common area of loss surrounding the putative gene for nevoid BCC or Gorlin's syndrome. Forty-four % (16 of 36) of BCCs had a mutated p53 allele, usually opposite pyrimidine tracts, which is consistent with UV-induced mutations. Surprisingly, only one tumor had lost a 17p allele, and in all BCCs only one p53 allele was inactivated. This is in direct contrast to other epithelial tumors, which usually progress by the inactivation of both p53 alleles.

Adult↗
PubMed1994

p53 gene mutations as markers of tumor spread in synchronous oral cancers.

OBJECTIVE: To demonstrate how genetic mutations may be used as specific markers for the study and management of head and neck squamous cell carcinomas. DESIGN: Mutations in the p53 gene were identified by DNA sequencing in synchronous primary head and neck squamous cell carcinomas from one patient. The polymerase chain reaction and mutant-specific oligomer probes were used to detect rare tumor cells in surgical margins, lymph nodes, and swabs of the oral cavity. PATIENTS: Selected from a consecutive series of individuals with head and neck squamous cell carcinomas at a tertiary referral center. RESULTS: Two synchronous primary invasive cancers displayed different missense mutations in the p53 gene. The mutated sequence from one primary tumor was detected in metastases from both sides of the neck. Infiltrating cells from this biologically aggressive tumor were also detected by a polymerase chain reaction-based assay in a histologically normal surgical margin, accurately predicting tumor recurrence. CONCLUSIONS: p53 gene mutations were useful as molecular markers to distinguish between tumors in this case. The potential utility of detection of tumor cells in surgical margins and saliva by molecular techniques merits further investigation.

Biomarkers, Tumor↗
PubMed1994

Gene mutations in saliva as molecular markers for head and neck squamous cell carcinomas.

BACKGROUND: Cancer is caused by the accumulation of mutations that activate proto-oncogenes and inactivate tumor suppressor genes. The result is a clonal expansion of genetically identical daughter cells that eventually become clinical malignancies. The specific mutations acquired by the progenitor cell are like a fingerprint carried by each cell of the tumor. These mutations can serve as very specific markers for the presence of tumor cells in a background of normal cells. METHODS: Mutations in the p53 gene recovered from head and neck squamous cell carcinomas were sequenced, and these altered DNA sequences were used retrospectively as tumor-specific genetic markers for cancer cells in the patient's saliva. Cloned p53 sequences amplified by the polymerase chain reaction from DNA extracted from banked preoperative saliva specimens were screened for the presence of tumor-specific mutations using radiolabeled oligonucleotide probes. RESULTS: We identified tumor-specific mutations in preoperative saliva samples of 5 of the 7 patients evaluated (71%). CONCLUSIONS: These results suggest a potential for clinical applications of this novel approach to cancer detection using gene mutations as molecular markers for carcinomas.

Biomarkers, Tumor↗
PubMed1993

Evidence for two bladder cancer suppressor loci on human chromosome 9.

Most carcinomas of the bladder show loss of heterozygosity for markers on human chromosome 9, which suggests that one or more tumor suppressor genes are located on this chromosome. Several observations suggest that such alterations are an important early step in tumorigenesis. We analyzed the pattern of allelic loss in 46 primary carcinomas of the bladder using 19 polymorphic markers from chromosome 9. While most tumors with allelic loss showed loss of heterozygosity for all informative markers that were tested, six tumors demonstrated only partial loss of chromosome 9. Two tumors with partial loss contained deletions that predominantly involved the q arm, as shown by previous studies. The other four tumors contained deletions that predominantly or exclusively involved the p arm, with a common region of loss between D9S161 (9p21) and the telomere. The results show that there is no single common region of loss on chromosome 9 and identify two distinct regions of loss that may contain bladder tumor suppressor loci.

Chromosome Aberrations↗
PubMed1993

The incidence of p53 mutations increases with progression of head and neck cancer.

To establish a genetic model of the progression of head and neck squamous carcinoma we have defined the incidence and timing of p53 mutations in this type of cancer. We sequenced the conserved regions of the p53 gene in 102 head and neck squamous carcinoma lesions. These included 65 primary invasive carcinomas and 37 noninvasive archival specimens consisting of 13 severe dysplasias and 24 carcinoma in situ lesions. The incidence of p53 mutations in noninvasive lesions was 19% (7/37) and increased to 43% (28/65) in invasive carcinomas. These data suggest that p53 mutations can precede invasion in primary head and neck cancer. Furthermore, the spectrum of codon hotspots is similar to that seen in squamous carcinoma of the lung and 64% of mutations are at G nucleotides, implicating carcinogens from tobacco smoke in the etiology of head and neck squamous carcinoma.

Adult↗
PubMed1993

p53 Mutation and MDM2 amplification in human soft tissue sarcomas.

The p53 and MDM2 genes were analyzed in 24 human soft tissue sarcomas (11 malignant fibrous histiocytomas and 13 liposarcomas). Alterations of p53, consisting of point mutations, deletions, or overexpression, were detected in one-third (8 of 24) of the sarcomas. MDM2 gene amplification was detected in another 8 tumors, but no tumor contained an alteration of both genes. Monoclonal antibodies reactive with the human MDM2 gene product were developed, and immunohistochemical analysis revealed nuclear localization and overexpression of MDM2 in those tumors with amplified MDM2 genes. These data support the hypothesis that p53 and MDM2 genetic alterations are alternative mechanisms for inactivating the same regulatory pathway for suppressing cell growth.

Animals↗