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Biomedical subjects

O I Olopade

Publications and source records attributed to O I Olopade.

At least 19 recordsLinked to original sources
PubMed2005

Phenotypic heterogeneity in multiple myeloma families.

PURPOSE: To describe a series of families with familial multiple myeloma (MM). Observations were used to generate hypotheses about the role of genetic factors, the mode of inheritance of these factors, and the association of other cancers with familial MM. PATIENTS AND METHODS: This observational study consisted of 39 families with multiple cases of MM or related disorders from four collaborating research centers. Each center followed its usual family study method. Probands were interviewed, and, when possible, cancers were verified by medical records and pathology review. A working pedigree was compiled on each family. RESULTS: Seventeen families had affected members in two or more generations, and eight families had two or more affected members in a single generation. Four families had two or more members with plasma cell dyscrasias, with or without a single case of MM. In the remaining 10 families, a single MM case occurred with a family history of other cancers. Other cancers observed in family members included hematologic malignancies and solid tumors. In families with MM in multiple generations, there was a decrease in the age at MM diagnosis in successive generations. CONCLUSION: The study of familial MM may provide insights into the pathogenesis and, ultimately, the control and prevention of MM and related disorders. Population-based epidemiologic studies are crucial, but because of the rarity of familial MM, a concerted case-finding approach may also be fruitful. Therefore, we propose an international consortium to study familial MM, and we invite all interested colleagues to participate.

Female↗
PubMed2001

A case of pulmonary toxicity associated with G-CSF and doxorubicin administration.

The cytokine growth factor, G-CSF (granulocyte colony-stimulating factor), is commonly used in oncologic practice and is generally believed to be a safe agent to administer. We describe here a case of pulmonary toxicity associated with the concurrent administration of G-CSF and doxorubicin. We contend that G-CSF contributed to the life-threatening lung injury in our patient, and discuss additional reports in the literature of pulmonary toxicity associated with the use of this agent.

Biopsy↗
PubMed2001

Identification of a 1.2 Kb cDNA fragment from a region on 9p21 commonly deleted in multiple tumor types.

Chromosome band 9p21 is a frequent target of homozygous deletion in many tumor types. Putative tumor suppressor genes, CDKN2A (p16), p14(ARF) and CDKN2B (p15), were localized to 9p21. However, there have been reports that suggest that there may be other genes targeted for inactivation in the region. We have developed a method to search for transcribed sequences within large genomic regions. We tested our approach in a 100-kilobase region on 9p21, which is 40 kilobases telomeric to CDKN2A. The method, termed expressed sequence selection (ESS), resulted in the isolation of genomic fragments known to be from 9q21 that are homologous to transcribed sequences. One fragment was used to obtain a 1.2 kilobase cDNA. The sequence of the 5' half of the cDNA was almost identical to exons 3-5 of the MTAP gene, which maps to chromosome band 9p21. The 3' portion of the cDNA had sequence homology to the ALA gene, which maps to chromosome arm 9q. Using Northern blot analysis, the 1.2 Kb cDNA identified several widely expressed transcripts ranging from 1 Kb to 8.5 Kb and displayed a complex pattern of alternative splicing in which certain exons of the 1.2 Kb cDNA are excluded from some of the splice products. Using cancer tissue Northern blots, we could show that all of the transcripts are absent from a leukemia cell line and a lung cancer cell line (K562, A549) with homozygous, genomic deletions within chromosome band 9p21. In addition, the 7 Kb transcript is also absent from two additional tumor cell lines (Molt4, a leukemia derived cell line, and in G361, a melanoma derived cell line) with homozygous deletions. Further investigation will determine whether the difference in the expression pattern between the 7 Kb transcript compared with the other sized transcripts could be due to specific targeting for alteration in certain tumor types.

3' Untranslated Regions↗
PubMed2001

Cancer genetics in oncology practice.

Cancer is a genetic disease caused by the progressive accumulation of mutations in critical genes that control cell growth and differentiation. Completion of the Human Genome Project promises to revolutionize the practice of Medicine, especially Oncology care. The tremendous gains in the knowledge of the structure and function of human genes will surely impact the diagnosis, prognosis and treatment of cancer. Moreover, it will lead to more effective cancer control through the use of genetics to quantify individual cancer risks. This article reviews the current status of genetic testing and counseling for cancer risk assessment and will suggest a framework for integrating such counseling into oncology practice.

Adenomatous Polyposis Coli↗
PubMed2001

Progesterone receptor variant increases ovarian cancer risk in BRCA1 and BRCA2 mutation carriers who were never exposed to oral contraceptives.

Oral contraceptives have been shown to be protective against hereditary ovarian cancer. The variant progesterone receptor allele named PROGINS is characterized by an Alu insertion into intron G and two additional mutations in exons 4 and 5. The PROGINS allele codes for a progesterone receptor with increased stability and increased hormone-induced transcriptional activity. We studied the role of the PROGINS allele as a modifying gene in hereditary breast and ovarian cancer. The study included 195 BRCA1 and BRCA2 carriers with a prior diagnosis of ovarian cancer, 392 carriers with a diagnosis of breast cancer and 249 carriers with neither cancer. Fifty-eight women had both forms of cancer. Five hundred and ninety-five women had a BRCA1 mutation and 183 women had a BRCA2 mutation. Overall, there was no association between disease status and the presence of the PROGINS allele. Information on oral contraception use was available for 663 of the 778 carriers of BRCA1 or BRCA2 mutations. Among the 449 subjects with a history of oral contraceptive use (74 cases and 365 controls), no modifying effect of PROGINS was observed [odds ratio (OR) 0.8; 95% confidence interval (CI) 0.5-1.3]. Among the 214 carriers with no past exposure to oral contraceptives, the presence of one or more PROGINS alleles was associated with an OR of 2.4 for ovarian cancer, compared to women without ovarian cancer and with no PROGINS allele (P = 0.004; 95% CI 1.4-4.3). The association was present after adjustment for ethnic group and for year of birth.

Adult↗
PubMed2001

Male breast cancer in Cowden syndrome patients with germline PTEN mutations.

Cowden syndrome (CS) (OMIM 158350) is a multiple hamartoma syndrome associated with germline mutations in the PTEN tumour suppressor gene. While CS is characterised most commonly by non-cancerous lesions (mucocutaneous trichilemmomas, acral and palmoplantar keratoses, and papillomatous papules), it is also associated with an increased susceptibility to breast cancer (in females) and thyroid cancer, as well as non-cancerous conditions of the breast and thyroid. Here we report two cases of male breast cancer occurring in patients with classical CS phenotypes and germline PTEN mutations. The first subject was diagnosed with CS indicated primarily by mucocutaneous papillomatosis, facial trichilemmomas, and macrocephaly with frontal bossing at the age of 31 years. He developed breast cancer at 41 years and subsequently died of the disease. A PTEN mutation, c.802delG, was identified in this subject, yet none of his family members showed evidence of a CS phenotype, suggesting that this PTEN mutation may be a de novo occurrence. The second subject had a CS phenotype including multiple trichilemmomas and thyroid adenoma, developed male breast cancer at 43 years, and died of the disease at 57 years. He was a carrier of a PTEN mutation c.347-351delACAAT that cosegregated with the CS phenotype in affected family members. These two cases of male breast cancer associated with germline PTEN mutations and the CS phenotype suggest that CS may be associated with an increased risk of early onset male as well as female breast cancer.

Adult↗
PubMed2001

Alterations of the 9p21 and 9q33 chromosomal bands in clinical bladder cancer specimens by fluorescence in situ hybridization.

PURPOSE: To better define cytogenetic mechanisms of CDKN2 loss at 9p21 and of DBCCR1 loss at 9q33 in bladder cancer, and to determine correlation with p53 and pRb. EXPERIMENTAL DESIGN: Two-color fluorescence in situ hybridization (FISH) using a chromosome 9 centromeric probe and locus-specific probes was performed. p53 and pRb were assessed by immunohistochemistry. RESULTS: Thirty-seven of fifty-five (67%) samples exhibited 9p21 loss, and 32 of 44 (73%) exhibited 9q33 loss. Twelve of 43 informative samples exhibited only 9p21 loss (5 cases) or only 9q33 loss (7 cases). Homozygous deletions were noted at 9p21 and 9q33 in 31 and 14% of cases, respectively, but 9q33 homozygous deletions were generally observed in only a minor clone. There was no correlation of any chromosome 9 loss with stage, but stage did correlate with chromosome 9 ploidy status; aneusomy 9 was observed in 33% of T(a) lesions and 71% of more advanced cases (P = 0.01). Aneusomy 9 was loosely correlated with p53 abnormalities (P = 0.07), but no correlation between any chromosome 9 and pRb abnormalities was discerned. CONCLUSIONS: This study strengthens the proposition that chromosome 9 losses occur early in bladder oncogenesis and before p53 alterations or development of aneusomy. The correlation of aneusomy 9 with p53 abnormalities is consistent with the presumed role of p53 in maintaining cytogenetic stability. Although the observed homozygous deletions strengthen the hypotheses that CDKN2 and DBCCR1 are important tumor suppressor genes, there is no evidence that either is a more critical or an earlier target for oncogenesis.

Aneuploidy↗
PubMed2000

Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations.

PURPOSE: Recent laboratory data suggest a role for BRCA1/2 in the cellular response to DNA damage. There is a paucity of clinical data, however, examining the effect of radiotherapy (RT), which causes double-strand breaks, on breast tissue from BRCA1/2 mutation carriers. Thus the goals of this study were to compare rates of radiation-associated complications, in-breast tumor recurrence, and distant relapse in women with BRCA1/2 mutations treated with breast-conserving therapy (BCT) using RT with rates observed in sporadic disease. PATIENTS AND METHODS: Seventy-one women with a BRCA1/2 mutation and stage I or II breast cancer treated with BCT were matched 1:3 with 213 women with sporadic breast cancer. Conditional logistic regression models were used to compare matched cohorts for rates of complications and recurrence. RESULTS: Tumors from women in the genetic cohort were associated with high histologic (P =.0004) and nuclear (P =.009) grade and negative estrogen (P=.0001) and progesterone (P=.002) receptors compared with tumors from the sporadic cohort. Using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity scoring, there were no significant differences in acute or chronic morbidity in skin, subcutaneous tissue, lung, or bone. The 5-year actuarial overall survival, relapse-free survival, and rates of tumor control in the treated breast for the patients in the genetic cohort were 86%, 78%, and 98%, respectively, compared with 91%, 80%, and 96%, respectively, for the sporadic cohort (P = not significant). CONCLUSION: There was no evidence of increased radiation sensitivity or sequelae in breast tissue heterozygous for a BRCA1/2 germline mutation compared with controls, and rates of tumor control in the breast and survival were comparable between BRCA1/2 carriers and controls at 5 years. Although additional follow-up is needed, these data may help in discussing treatment options in the management of early-stage hereditary breast cancer and should provide reassurance regarding the safety of administering RT to carriers of a germline BRCA1/2 mutation.

Adult↗
PubMed2000

Prevalence of BRCA1 and BRCA2 mutations among clinic-based African American families with breast cancer.

To define the prevalence and relative contributions of BRCA1 and BRCA2 mutations among African American families with breast cancer, we analyzed 28 DNA samples from patients identified through two oncology clinics. The entire coding regions of BRCA1 and BRCA2 were screened by protein truncation test, heteroduplex analysis, or single-stranded conformation polymorphism followed by DNA sequencing of variant bands. Deleterious protein-truncating BRCA1 and BRCA2 mutations were identified in five patients or 18% of the entire cohort. Only 8% (1 of 13) of women with a family history of breast cancer, but no ovarian cancer, had mutations. The mutation rates were higher for women from families with a history of breast cancer and at least one ovarian cancer (three of six, 50%). One woman with a family history of undocumented cancers was also found to carry a deleterious mutation in BRCA2. The spectrum of mutations was unique in that one novel BRCA1 mutation (1625del5) and three novel BRCA2 mutations (1536del4, 6696delTC, and 7795delCT) were identified. No recurrent mutations were identified in this cohort, although one BRCA2 (2816insA) mutation had been previously reported. In addition, two BRCA1 and four BRCA2 missense mutations of unknown significance were identified, one of which was novel. Taken together with our previous report on recurrent mutations seen in unrelated families, we conclude that African Americans have a unique mutation spectrum in BRCA1 and BRCA2 genes, but recurrent mutations are likely to be more widely dispersed and therefore not readily identifiable in this population.

Adult↗
PubMed2000

Evidence of a founder BRCA1 mutation in Scotland.

BRCA1 mutations have been identified in breast and ovarian cancer families from diverse ethnic backgrounds. We studied 17 different families with the BRCA1 2800delAA mutation; seven were ascertained in Scotland (Dundee, Edinburgh, Glasgow, St Andrews), five in Canada (Toronto, Victoria) and five in the United States (Chicago, Philadelphia, Seattle). Overall there was a clear preponderance of Scottish ancestry. Genotype analysis performed on key members from 17 families was consistent with a common haplotype, strongly suggesting a single ancestral origin. A possible link was established between two families by tracing their genealogies through the records of the Registrar General for Scotland. This is the first example of a BRCA1 mutation likely to be derived from a common founder in Scotland. Further studies will be necessary to estimate more accurately the population frequency of the BRCA1 2800delAA mutation among unselected cases of breast and ovarian cancer in Scotland and the UK.

Breast Neoplasms↗
PubMed2000

Computerized analysis of mammographic parenchymal patterns for breast cancer risk assessment: feature selection.

Our purpose in this study was to identify computer-extracted, mammographic parenchymal patterns that are associated with breast cancer risk. We extracted 14 features from the central breast region on digitized mammograms to characterize the mammographic parenchymal patterns of women at different risk levels. Two different approaches were employed to relate these mammographic features to breast cancer risk. In one approach, the features were used to distinguish mammographic patterns seen in low-risk women from those who inherited a mutated form of the BRCA1/BRCA2 gene, which confers a very high risk of developing breast cancer. In another approach, the features were related to risk as determined from existing clinical models (Gail and Claus models), which use well-known epidemiological factors such as a woman's age, her family history of breast cancer, reproductive history, etc. Stepwise linear discriminant analysis was employed to identify features that were useful in differentiating between "low-risk" women and BRCA1/BRCA2-mutation carriers. Stepwise linear regression analysis was employed to identify useful features in predicting the risk, as estimated from the Gail and Claus models. Similar computer-extracted mammographic features were identified in the two approaches. Results show that women at high risk tend to have dense breasts and their mammographic patterns tend to be coarse and low in contrast.

BRCA2 Protein↗
PubMed2000

Susceptibility gene for familial acute myeloid leukemia associated with loss of 5q and/or 7q is not localized on the commonly deleted portion of 5q.

The molecular mechanism for the occurrence of leukemia in multiple members of a family has not been fully elucidated but data support the contribution of highly penetrant mutations in leukemia susceptibility genes. We have investigated the genetic etiology of an unusual three-generation family with apparent autosomal dominant transmission of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) accompanied by somatic loss of the long arm of chromosome 5 and/or loss of heterozygosity (LOH) analysis and fluorescence in situ hybridization (FISH) of leukemia cells have been performed, confirming acquired hemi- and homozygous deletion of the long arm of chromosome 5. However, the chromosome lost in the observed LOH event is from the affected parent, in contradiction to the expectation for a two-hit hypothesis involving a tumor suppressor gene. Furthermore, genetic linkage has been performed at 5q31-33 as well as other loci (21q22 and 16q21-23.2) previously implicated in familial leukemia. In this family, linkage analysis excludes loci at 5q31-33 and 21q22, but localization to 16q21-23.2 cannot be excluded. We observed a maximum multipoint LOD score of 1.19 between marker D16S265 and D16S503 at 16q22 (P = 0.03), suggesting possible linkage to this locus. Considering this family and the previous 16q-linked family together, the linkage of a leukemia susceptibility gene to 16q22 achieved an LOD score of 3.63 at D16S265 with theta = 0. Thus, somatic deletion of the long arm of chromosome 5 appears as a necessary but surprisingly noncausative event for onset of AML and MDS in this family, thereby confirming a multistep etiology in which chromosome 5 plays an important secondary role.

Acute Disease↗
PubMed2000

Chronic daily low dose of 4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (Oltipraz) in patients with previously resected colon polyps and first degree female relatives of breast cancer patients.

The chemoprevention agent oltipraz, one of the most active chemopreventive compounds in preclinical studies, has been shown to induce glutathione-S-transferase (GST) activity in animals. Oltipraz was evaluated in a Phase I trial at daily oral doses of 20 mg (L1), 50 mg (L2), and 100 mg (L3) and twice weekly doses of 125 mg (L4) taken for 6 months with 6 patients entered at L1 and L2 and 7 patients entered at L3 and L4 (26 subjects: 19 females and 7 males). The subject population included patients with previously resected colon polyps and first-degree female relatives of breast cancer patients. Patients with resected colon polyps underwent rectal biopsy for GST and glutathione (GSH) analyses. Of the 26 subjects, the following completed 6 months of therapy: 4 of 6 patients (L1), 4 of 6 patients (L2), 5 of 7 patients (L3), and 4 of 7 patients (L4). Toxicities were mild to severe and included: gastrointestinal symptoms, photosensitivity/heat intolerance, and neurological symptoms. Monthly plasma samples were obtained 2-3 h after oltipraz ingestion with minimally detectable plasma concentrations at L1. There was a significant difference in mean oltipraz concentration across the four doses, with no significant differences in mean oltipraz concentration over time. Rectal tissue and lymphocyte GSH and GST were variable, with no significant difference in mean levels across doses. At the 100-mg/day dose (L3), 1 patient experienced significant increase in rectal tissue GSH and GST activity, whereas 3 additional patients (L1 and L4) had >50% increase in tissue GSH. Lymphocyte GSH level was significantly related to plasma oltipraz concentration. There were no significant correlations between plasma oltipraz concentration and lymphocyte GST level nor any significant correlation between plasma concentration and percentage of change in tissue GSH or GST. Further investigation of dose/schedule and biological end points is ongoing.

Anticarcinogenic Agents↗
PubMed2000

Human breast cancer susceptibility to paclitaxel therapy is independent of Bcl-2 expression.

In laboratory studies, ectopic overexpression of the antiapoptotic protein Bcl-2 has been shown to result in resistance to the cytotoxic effects of many chemotherapeutic drugs. Furthermore, posttranslational modification of moderately expressed endogenous Bcl-2 has been correlated with susceptibility to paclitaxel treatment in vitro. To determine whether tumor expression of Bcl-2 protein correlates with response and ultimate outcome in vivo, we quantified Bcl-2 expression by immunohistochemical analysis of archived biopsy specimens from metastatic breast cancer patients treated with single-agent paclitaxel. The statistical association between the degree of Bcl-2 expression, objective tumor response, and clinical outcome was then determined. In patients (n = 39) whose tumors had low (< or = 10% cells positive) Bcl-2 levels by immunohistochemical analysis, the overall response (complete response + partial response) rate was 21% versus an overall response rate of 22% in patients (n = 36) with high (>10% cells positive) Bcl-2 expression (P = 0.92). In patients with low Bcl-2 expression, the median time to progression was 126 days [95% confidence interval (CI), 63-160 days]. This was not significantly different than the 105 days for patients with high tumor Bcl-2 expression (95% CI, 84-214 days). The median survival time from initiation of paclitaxel therapy for patients with low Bcl-2 expression was 663 days (95% CI, 456-1119 days) and was not significantly different than the 450 days (95% CI, 239-1058 days) observed for patients with high Bcl-2 expression. In conclusion, we found that in metastatic breast cancer, there is no significant association between tumor Bcl-2 expression and response to paclitaxel, median time to progression, or survival, suggesting that the main mechanism of paclitaxelinduced cytotoxicity in breast tumors is independent of Bcl-2 expression.

Adult↗