Loss of heterozygosity on chromosome 2q: possibly a poor prognostic factor in head and neck cancer.

BACKGROUND: Loss of heterozygosity (LOH) correlates with inactivated tumor suppressor genes. The aim of this study was to see if LOH on chromosomes 2q, 3p, 5q, 9p, and 17p correlated with survival in early squamous cell carcinoma of the head and neck (SCCHN). METHODS: A case control study was performed. Ten patients with stage I or II tumors who ultimately died of their disease were identified and matched with suitable controls. None of the controls had a local recurrence and at time of last follow-up were alive with no evidence of disease or had died of an unrelated illness. The deoxyribonucleic acid (DNA) was extracted from paraffin blocks, and LOH studies were performed using microsatellite markers. RESULTS: The respective incidence of allelic loss for the index and control patients was as follows: chromosome 2q, 75% and 20% (p = .03); chromosome 3p, 71% and 57%, respectively (not significant); chromosome arm 5q, 30% and 25% (not significant); chromosome arm 9p, 71% and 73% (not significant); and chromosome arm 17p, 75% and 46% (not significant). Therefore, loss on chromosome 2q strongly correlated with poor survival (odds ratio = 10.4). CONCLUSION: Loss of heterozygosity on chromosome 2q may correlate with a poor prognosis in early-stage SCCHN.

Loss of heterozygosity studies in squamous cell carcinomas of the head and neck.

BACKGROUND: Loss of heterozygosity (LOH) studies have been pivotal in identifying tumor suppressor genes involved in the pathogenesis of a number of cancers. In squamous cell carcinomas of the head and neck region (SCCHN), LOH studies using the Southern blot technique are scarce. METHODS: SCCHNs were obtained immediately after surgical resection from 78 patients. Histologic confirmation was made by frozen section and tumors with less than 50% malignant cells were excluded. DNA was digested with restriction enzymes, and after Southern blotting the membranes were hybridized with radio-labeled probes. Chromosome arms analyzed included 1p, 3p, 4p, Sq, 8p, lOp, 11p, 11q, 13q, 17p, 17q, 18q, 21q, and 22q. RESULTS: The average rate LOH was 25% per chromosome arm. Significantly higher rates of LOH were observed for chromosome arms 5q (56%) and 17p (45%). Other investigators have reported high rates of LOH for the H- ras-1 locus, and chromosome arms 11p, 11q, and 13q. However, these results were not confirmed in this study. For patients with stage 1 or 2 tumors, the overall LOH rate was 13%, and for patients with stage 3 or 4 disease the rate was 23%. This difference was statistically significant (p < 0.025). CONCLUSIONS: tumors progress to higher stages, they appear to accumulate an increasing number of genetic abnormalities. Chromosome arms 5q and 17p contain tumor suppressor genes which are likely to be involved in the pathogenesis of SCCHN:

Prognostic factors in gliomas. A multivariate analysis of clinical, pathologic, flow cytometric, cytogenetic, and molecular markers.

BACKGROUND: The ability to divide subsets of patients with glial neoplasms into prognostic groups currently is limited because only a few clinical and pathologic variables are available. The goal of this investigation was to identify biologic factors of potential prognostic value in patients with cerebral gliomas. METHODS: This prospective investigation used clinical, pathologic, flow cytometric, cytogenetic, and molecular genetic variables as potential prognostic factors in 207 patients with newly diagnosed gliomas (153 astrocytic tumors of the fibrillary type, 31 oligodendrogliomas, and 23 pilocytic astrocytomas). Classification and regression tree (CART) analysis was performed as part of the multivariate statistical analysis. RESULTS: The age of the patient and the grade of the tumor were confirmed as strong prognostic factors. Cytogenetic or molecular genetic abnormalities of chromosomes 7 and 10 were associated with poor survival in univariate analysis (P < 0.0001). CART multivariate analysis identified several subsets of patients with different prognoses. In the subset of patients younger than 66.5 years with Grade 4 tumors, the survival time was longer for those with aneuploid tumors than for those with nonaneuploid tumors. In the subset of patients with Grades 1-3 tumors, the survival time was longer for those whose tumors had a %G2M of less than 6.9 than for those whose tumors had a %G2M of 6.9 or greater. CONCLUSION: This investigation provides further evidence that flow cytometry, cytogenetic, and molecular genetic factors that may have prognostic value in patients with gliomas can be identified.

Cytogenetic and loss of heterozygosity studies in ependymomas, pilocytic astrocytomas, and oligodendrogliomas.

Cytogenetic and/or loss of heterozygosity studies were performed on 13 ependymomas, 11 pilocytic astrocytomas, and 18 oligodendrogliomas. Loss of chromosome 22 was the most frequent genetic abnormality among the ependymomas. We found no consistent genetic abnormality in pilocytic astrocytomas. The most common genetic abnormality in oligodendrogliomas was loss of a portion of chromosome 19. Each informative oligodendroglioma had loss of alleles mapped to the long arm (q) of chromosome 19. One oligodendroglioma had an apparent homozygous deletion of the D19S8 locus. Our results, when combined with those in the literature, indicate that chromosomes 9, 11, and 22 may harbor genes important for the pathogenesis of ependymomas and that 19q probably harbors a gene important for the pathogenesis of oligodendrogliomas.

Correlation of cytogenetic analysis and loss of heterozygosity studies in human diffuse astrocytomas and mixed oligo-astrocytomas.

The aims of this study were to correlate cytogenetic studies and molecular genetic loss of heterozygosity (LOH) analyses in human astrocytomas and mixed oligo-astrocytomas, and to locate putative tumor suppressor genes on chromosome 10. Paired blood and tumor samples from 53 patients were analyzed. The tumors included 45 diffuse astrocytomas (39 grade 4, 4 grade 3, and 2 grade 2), 1 astroblastoma, and 7 mixed oligo-astrocytomas (2 grade 4, 4 grade 3, and 1 grade 2). By cytogenetic analyses the most common numeric chromosome abnormalities were +7, -10, -13, -14, -17, +19, -22, and -Y. The most common structural abnormalities involved chromosome arms 1p, 1q, 5p, and 9p. By LOH and dosage analysis the most common molecular genetic abnormalities were of chromosome arms 5p, 6p, 7q, 9p, 10p, 10q, 13q, 14q, 17p, and 19p. When the results of all methods were combined, the most commonly abnormal chromosomes were, in descending frequency, 10, Y, 17, 7, 13, and 9. In 80 percent of cases the cytogenetic and molecular genetic studies were concordant. LOH studies were more sensitive in detecting loss of genetic material than cytogenetic analyses and accounted for 60% of the discordant results. When there were structural abnormalities, such as translocations or inversions, cytogenetic analysis was more sensitive in detecting an abnormality than molecular genetic studies. In addition to the 24 tumors which appeared to lose an entire copy of chromosome 10, there were 10 tumors with molecular genetic or cytogenetic evidence of loss of only a portion of chromosome 10. The genetic analyses of these tumors suggest that there are 2 regions on chromosome 10 that may contain potential tumor suppressor genes. One lies distal to locus D10S22 from 10q22 to 10qter, and the other lies proximal to locus TST1 on the 10q arm near the centromere or on the 10p arm.

Molecular analysis of deletions of the short arm of chromosome 9 in human gliomas.

Previous studies have suggested that structural abnormalities involving the short arm of chromosome 9 are frequently associated with gliomas. The alpha-, beta-, and omega-interferon (IFNA, IFNB1, and IFNW, respectively) and the methylthioadenosine phosphorylase (MTAP) genes have been mapped to the short arm of chromosome 9, band p22. Homozygous deletions of these genes have been reported in many leukemia- and glioma-derived cell lines. In this report, we present a detailed analysis of partial and complete homozygous or hemizygous deletions of DNA sequences on 9p in human cell lines and primary tumor samples of glioma patients. Ten of 15 (67%) glioma-derived cell lines had hemizygous or homozygous deletion of IFN genes or rearrangement of sequences around these genes, while 13 of 35 (37%) primary glioma tumor samples had hemizygous (8 tumors) or homozygous (5 tumors) deletion of the IFN genes. The shortest region of overlap of these deletions maps in the interval between the centromeric end of the IFN gene cluster and the MTAP gene. In the cell lines and primary tumors examined, these gross genomic alterations were seen only in association with high grade or recurrent gliomas. Our observations confirm that loss of DNA sequences on 9p, particularly the IFN genes, occurs at a significant frequency in gliomas, and may represent an important step in the progression of these tumors. These results are consistent with a model of tumorigenesis in which the development or progression of cancer involves the loss or inactivation of a gene or several genes that normally act to suppress tumorigenesis. One such gene may be located on 9p; this gene may be closely linked to the IFN genes. Nevertheless, loss of the IFN genes, when it occurs, may play an additional role in the progression of these tumors.

A pilot study of three sequential chemotherapeutic regimens in metastatic breast cancer.

The aim of this pilot study was to estimate the toxicity and response rate of an alternating chemotherapeutic program in chemotherapy-naive metastatic breast cancer patients. Treatment consisted of regimen A (given days 1-28): cyclophosphamide 100 mg/m2 PO days 1-14, doxorubicin 30 mg/m2 i.v. days 1 and 8, and 5-fluorouracil 500 mg/m2 i.v. days 1 and 8 (CAF regimen); regimen B (given days 29-56): dibromodulcitol 135 mg/m2 p.o. days 30-39, mitoxantrone 9 mg/m2 i.v. day 29, and vincristine 1.2 mg/m2 i.v. (maximum 2.0 mg) day 29 (DMV regimen); and regimen C (given days 57-84): thiotepa 12 mg/m2, doxorubicin 45 mg/m2 and vinblastine 4.5 mg/m2 all i.v. on day 57. There were 27 eligible patients with a median age of 51 years (range 34-78). On 14 episodes the leukocyte count fell to less than 1 X 10(9)/L during the first six cycles of treatment (14% of 99 cycles). There were no treatment-related deaths. Common non-life-threatening toxicities included thrombocytopenia, anemia, vomiting, and alopecia. Despite having no drugs in common, the leukocyte and platelet nadirs after CAF correlated with the nadir counts after DMV (r values of 0.6829 and 0.5892, respectively; p = 0.01). Among the 23 patients with measurable and/or evaluable disease there were five complete responses (22%) and nine partial responses (39%), with a median time to treatment failure of 29 weeks. The overall median survival was 19 months.

Papillary serous carcinoma of the peritoneum. A review of 33 cases treated with platin-based chemotherapy.

Thirty-three patients were identified who had papillary serious carcinoma of the peritoneum (PSCP). The gross operative specimens, histopathologic condition, and treatment records were reviewed. The median age at presentation was 60 years (age range, 22 to 78 years). Abdominal pain and distention were the most common presenting symptoms. All patients had a total abdominal hysterectomy and bilateral salpingo-oophorectomy, and all but two had debulking surgery. All patients had disease involving the omentum, the abdominal and pelvic peritoneum, and the surface of the ovaries, but none had intrinsic disease of the ovaries. Eight patients had disease outside of the abdominal cavity. Seven of these patients had malignant pleural effusions. All patients received platin-based chemotherapy. Sixteen patients underwent second-look laparotomy, two had no evidence of disease, and one had microscopic disease only. The median survival time for all patients was 17 months. Three patients are alive 6 to 7 years after the initial diagnosis. In conclusion, long-term survival can be achieved in some PSCP patients by debulking surgery and platin-based chemotherapy.

Cranial nerve lesions due to base of the skull metastases in prostate carcinoma.

We studied 11 patients with prostate cancer metastatic to the base of skull that caused cranial nerve deficits. Patients with occipital condyle, jugular foramen, middle fossa, parasellar, and orbital syndromes are described. Other patients had combinations of these syndromes or other cranial nerve involvements. Two patients had 6th nerve palsies secondary to prepontine cistern and clivus lesions. The median survival time from the diagnosis of cranial nerve involvement was 4 months. Two patients had cranial nerve involvement and, on subsequent investigation, were found to have carcinoma of the prostate. Interestingly, these patients are still alive at 42 and 84 months after diagnosis.

Expression of anionic glutathione-S-transferase and P-glycoprotein genes in human tissues and tumors.

The development of multidrug resistance in MCF-7 human breast cancer cells and the acquisition of broad resistance to xenobiotics in rat hyperplastic nodules are both associated with increased P-glycoprotein (mdr) gene expression as well as changes in activities of intracellular detoxication enzymes; among these changes is a significant increase in the activity of the anionic isozyme of glutathione-S-transferase (GST). We have isolated a cDNA encoding the human anionic glutathione-S-transferase, GST pi-1, from a cDNA library constructed from multidrug-resistant MCF-7 cells. The deduced amino acid sequence of GST pi-1 shows that while the human anionic GST displays 85% nucleotide and amino acid sequence homology to the rat anionic isozyme, it is markedly less related to human basic GST isozymes. We have examined the expression of GST pi and P-glycoprotein in 170 specimens of human tissues and tumors. P-Glycoprotein RNA expression was positive in eight of 23 lymphomas and two of 12 colon tumors; however, many other normal and malignant tissues, including lung, bladder, and breast tumors, had low or undetectable levels of P-glycoprotein RNA expression. In contrast, GST pi was readily detected in a wide variety of normal and malignant tissues. The level of GST pi mRNA expression in normal tissues was heterogeneous, with lowest levels found in liver and the highest levels found in lung, esophagus, and placenta. GST pi was also variably expressed in human tumors, with the lowest relative levels occurring in lymphoma and breast cancer and the highest levels found in lung cancer and head and neck tumors. In addition, comparison of paired specimens from the same patient indicated that GST pi expression was increased in many tumors relative to matched normal tissue.