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PubMed2002

Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status.

BACKGROUND: Management of early-stage breast cancer in young women with mutations in BRCA1 or BRCA2 remains controversial. This study assessed the long-term risks of ipsilateral and contralateral breast cancer in a cohort of young women who underwent breast-conserving surgery followed by radiotherapy. METHODS: Between 1975 and 1998, 290 women with breast cancer diagnosed at age 42 years or younger underwent lumpectomy followed by radiotherapy at our hospital. We recruited 127 of these women for complete sequencing of BRCA1 and BRCA2. Demographic, clinical, pathological, and outcome data were recorded. The primary endpoints were rates of ipsilateral and contralateral breast cancer, in relation to germline BRCA1/2 status. FINDINGS: 105 women were classified as having sporadic disease (94 with wild-type or known polymorphisms and 11 with variants of unclear significance) and 22 as having genetic predisposition (deleterious mutations in BRCA1 [15] or BRCA2 [seven]). At 12 years of follow-up, the genetic group had significantly higher rates of ipsilateral (49% vs 21%, p=0.007) and contralateral events (42% vs 9%, p=0.001) than the sporadic group. The majority of events were classified as second primary tumours. No patient in the genetic group had undergone oophorectomy or was taking prophylactic agents such as tamoxifen. INTERPRETATION: Patients with germline mutations in BRCA1 or BRCA2 have a high risk of developing late ipsilateral and contralateral second primary tumours. With breast-conserving therapy, chemoprophylaxis or other interventions to reduce the rate of second cancers may be valuable. Alternatively, bilateral mastectomy may be considered, to minimise the risk of second tumours in the breasts.

Adult↗
PubMed1998

Pediatric brain tumors: loss of heterozygosity at 17p and TP53 gene mutations.

Cytogenetic and molecular analyses of primitive neuroectodermal tumors (PNETs) of the central nervous system (CNS) have demonstrated material losses of 17p, the region that contains the TP53 gene, as the most frequent abnormality. Mutations in the TP53 gene are, however, very rare in these tumors. These findings strongly suggest that another, as yet unidentified, gene on 17p may be involved. We performed a search for loss of heterozygosity (LOH) on 17p by microsatellite markers on 26 childhood CNS tumors as well as TP53 gene mutations (exons 5-8) by single-strand conformational polymorphism analysis on 41 pediatric brain tumor samples of distinct histologic types. LOH was detected in 10 cases: 7 PNET, 2 astrocytomas, and 1 glioblastoma multiforme. In 4 of the PNETs the losses were limited to more distal markers. On the other hand, TP53 mutations were detected in 6 of 41 samples studied. Our results not only confirm the low penetrance of the TP53 gene on pediatric CNS tumors, but also provide further evidence of a putative tumor suppressor gene distal to TP53, between markers (D17S938, D17S926) and 17pter, specifically taking part in the development of PNET.

Adolescent↗
PubMed1999

p53 gene alterations in prostate cancer after radiation failure and their association with clinical outcome: a molecular and immunohistochemical analysis.

This study evaluates the prevalence of p53 gene mutations in prostate cancer in salvage prostatectomies after radiation failure using single strand conformational polymorphism (SSCP) and direct sequencing of the polymerase chain reaction (PCR) product. Findings were correlated with immunohistochemically (IHC) detectable p53 expression in residual prostate cancer. The usefulness of p53 as a marker of clinical outcome was evaluated. Thirty-three cases were available for molecular and immunohistochemical analysis. Immunohistochemical stains for p53 were performed with clone DO7. PCR-SSCP for mutations in the coding region of p53 DNA (exons 4-9) was performed on all immunopositive cases and 12 of 23 immunonegative cases. All samples with an SSCP shift were sequenced for the respective exon. Patients were evaluated for biochemical failure for 1-82 months (median 38 months) following surgery. Immunohistochemical p53 reactivity was noted in 10 of 33 (30%) patients. Among p53 immunopositive cases SSCP shifts were seen in 7 of 10 (70%) samples with 5 of the 7 (71%) showing p53 mutations. Univariate analysis revealed abnormal expression of p53 protein by immunohistochemistry to be a significant predictor of poorer outcome (p = 0.025, log rank), however this was not independent of pathologic stage, surgical margin status and Gleason score. The presence of p53 gene mutations by PCR-SSCP and direct sequencing did not predict for outcome. In our study 30% of prostate cancers at the time of salvage prostatectomy after radiation failure expressed immunohistochemically detectable p53. PCR-SSCP and sequencing shows that not all of these cases have detectable mutations in the most frequent mutation sites (exons 4-9). Clinical failure is more common in the group of prostate cancer patients with abnormal p53 immunoreactivity.

Aged↗
PubMed2003

Inherited and acquired risk factors and their combined effects in pediatric stroke.

The aim of this study was to identify hereditary and acquired risk-factors as they are related to the occurrence of stroke in children. We identified 21 children with stroke. A search of the Factor V Leiden mutation, the Factor II G20210A variant, and the thermolabile variant of methylenetetrahydrofolate reductase was performed in patients and in a control group (n = 115). We identified risk factors of acquired and/or hereditary nature for stroke in 19 of 21 children. Eleven children had three or more risk factors, seven had two risk factors, and one child had only one risk factor. We found three carriers (14.3%) of the Factor V Leiden mutation, two carriers (9.5%) of the Factor II G20210A variant, eleven (52.4%) thermolabile variant of methylenetetrahydrofolate reductase heterozygote carriers, and one (4.8%) homozygotes for this variant. Frequencies of the Factor V Leiden mutation and the Factor II variant were higher in patients than in controls, suggesting that these variants are associated with an increased risk of stroke in childhood. Homozygosity for the thermolabile variant of methylenetetrahydrofolate reductase was equally frequent amongst patients and controls. Our study confirms that stroke in children is commonly associated with a combination of multiple risk factors, both genetic and acquired, and that the Factor V Leiden mutation and the Factor II G20210A variant are predisposing factors for this situation.

Antibodies, Antiphospholipid↗
PubMed2002

Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia.

Through sequencing analysis of blood or bone marrow samples from patients with chronic myeloid leukemia, we identified BCR-ABL kinase domain mutations in 29 of 32 patients whose disease relapsed after an initial response to the tyrosine kinase inhibitor imatinib. Fifteen different amino acid substitutions affecting 13 residues in the kinase domain were found. Mutations fell into two groups-those that alter amino acids that directly contact imatinib and those postulated to prevent BCR-ABL from achieving the inactive conformational state required for imatinib binding. Distinct mutations conferred varying degrees of imatinib resistance. Mutations detected in a subset of patients with stable chronic phase disease correlated with subsequent disease progression. Multiple independent mutant clones were detected in a subset of relapsed cases. Our data support a clonal selection model of preexisting BCR-ABL mutations that confer imatinib resistance.

Alleles↗
PubMed2002

Aberrant expression of p16 and RB protein in eccrine porocarcinoma.

BACKGROUND: Eccrine porocarcinoma is a rare malignant tumor of the sweat gland and very little is known about its etiology and molecular basis. METHODS: To investigate the expression of p16 and retinoblastoma (RB) protein and their relationship, an immunohistochemical method was performed on nine eccrine porocarcinomas and five eccrine poromas. Furthermore, one case of eccrine porocarcinoma was analyzed for p16 gene mutation. RESULTS: A striking inverse correlation between p16 and RB expression was noted in all of the eccrine porocarcinomas and poromas. Strong immunoreactivity for p16 protein was observed in both nuclei and cytoplasm of the tumor cells in eight out of nine cases of eccrine porocarcinomas, while RB expression was negative in these cases. Conversely, one case of eccrine porocarcinoma did not show immunoreactivity for p16 protein, whereas RB protein was positive in the scattered nuclei. On the other hand, immunostaining of p16 was negative in all cases of five poromas, whereas RB-positive nuclei were sparse. No p16 gene mutation was detected in the investigated eccrine porocarcinoma case. CONCLUSIONS: These results indicate that detectable p16 protein and loss of RB protein are common occurrences in eccrine porocarcinoma lesions. Moreover, overexpression of p16 protein may be an additional, simple and useful diagnostic marker for eccrine porocarcinoma on routine laboratory screening.

Acrospiroma↗
PubMed2005

Dynamics of chronic myeloid leukaemia.

The clinical success of the ABL tyrosine kinase inhibitor imatinib in chronic myeloid leukaemia (CML) serves as a model for molecularly targeted therapy of cancer, but at least two critical questions remain. Can imatinib eradicate leukaemic stem cells? What are the dynamics of relapse due to imatinib resistance, which is caused by mutations in the ABL kinase domain? The precise understanding of how imatinib exerts its therapeutic effect in CML and the ability to measure disease burden by quantitative polymerase chain reaction provide an opportunity to develop a mathematical approach. We find that a four-compartment model, based on the known biology of haematopoietic differentiation, can explain the kinetics of the molecular response to imatinib in a 169-patient data set. Successful therapy leads to a biphasic exponential decline of leukaemic cells. The first slope of 0.05 per day represents the turnover rate of differentiated leukaemic cells, while the second slope of 0.008 per day represents the turnover rate of leukaemic progenitors. The model suggests that imatinib is a potent inhibitor of the production of differentiated leukaemic cells, but does not deplete leukaemic stem cells. We calculate the probability of developing imatinib resistance mutations and estimate the time until detection of resistance. Our model provides the first quantitative insights into the in vivo kinetics of a human cancer.

Benzamides↗
PubMed2002

Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy.

Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (STI571, Glivec/Gleevec) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs, particularly in patients with advanced disease. We sought to determine the underlying mechanisms. Sixty-six patients with CML in myeloid blast crisis (n = 33), lymphoid blast crisis (n = 2), accelerated phase (n = 16), chronic phase (n = 13), and BCR-ABL-positive acute lymphoblastic leukemia (n = 2) resistant to imatinib were investigated. Median duration of imatinib therapy was 148 days (range 6-882). Patients were evaluated for genomic amplification of BCR-ABL, overexpression of BCR-ABL transcripts, clonal karyotypic evolution, and mutations of the imatinib binding site in the BCR-ABL tyrosine kinase domain. Results were as follows: (1) Median levels of BCR-ABL transcripts, were not significantly changed at the time of resistance but 7/55 patients showed a >10-fold increase in BCR-ABL levels; (2) genomic amplification of BCR-ABL was found in 2/32 patients evaluated by fluorescence in situ hybridization; (3) additional chromosomal aberrations were observed in 19/36 patients; (4) point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 23/66 patients. In conclusion, although the heterogeneous development of imatinib resistance is challenging, the fact that BCR-ABL is active in many resistant patients suggests that the chimeric oncoprotein remains a good therapeutic target. However, patients with clonal evolution are more likely to have BCR-ABL-independent mechanisms of resistance. The observations warrant trials combining imatinib with other agents.

Antineoplastic Agents↗
PubMed2006

Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples.

In acute myeloid leukemia (AML), activating mutations in the fms-like tyrosine kinase 3 (FLT3) gene predict poor prognosis. We determined FLT3 internal tandem duplications (FLT3/ITD) and D835 point mutations in paired initial and relapse samples from 80 pediatric and adult AML patients. One D835 point mutation was found in an initial pediatric AML sample. Fms-like tyrosine kinase 3/ITDs were present in 21 initial and 22 relapse samples (26.3 and 27.5%, respectively). Interestingly, FLT3/ITD positivity was related to a significantly shorter time to relapse, most pronounced when the ITD-positive status was found at relapse (P<0.001). However, FLT3/ITD status changed between diagnosis and relapse in 14 cases. In four patients, the FLT3/ITD became undetectable at relapse in five patients FLT3/ITDs were only detected at relapse, and in five patients the length or number of FLT3/ITDs changed. Gain of FLT3/ITDs may suggest oligoclonality with selective outgrowth of the FLT3/ITD-positive clone, whereas losses may reflect ITDs in the more mature leukemic cells rather than in the leukemic stem cell, or, alternatively, that other genetic aberrations provided a greater selective advantage. Studying FLT3/ITD kinetics in minimal residual disease setting may provide some answers for the changes we observed. Fms-like tyrosine kinase 3/ITD is a relevant marker for prognosis, and remains an important target for therapeutic inhibition.

Adolescent↗
PubMed2006

Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q.

We used gene expression profiling, mutation analyses of FGFR3 and TP53, and LOH analyses of chromosome 9 and the TP53 region on chromosome arm 17p, to molecularly characterize 75 Ta and T1 bladder carcinomas. We identified four major cellular processes related to cell cycle, protein synthesis, immune response, and extra cellular components that contribute to the expressional heterogeneity of early-stage urothelial cell carcinoma (UCC). Activating FGFR3 mutations were found at the highest frequency in G1 tumors (80%), and showed a strong correlation with FGFR3 expression. In contrast, G3 tumors displayed mutations in less than 10% of the cases and a low level of FGFR3 expression. Even though LOH on chromosome 9 was not associated with any specific expression pattern, our data indicate that loss of chromosome 9 is associated with tumor development rather than initiation. The combined analyses suggest the existence of two types of UCC tumors, one which is characterized by FGFR3 mutation or expression, high expression of protein synthesis genes, and low expression of cell cycle genes. Furthermore, the presented data underscore FGFR3 receptor involvement in urothelial cell transformation as the presence of FGFR3 mutations has a major impact on the global gene expression profile of bladder carcinomas.

Chromosomes, Human, Pair 17↗
PubMedDate not supplied

Lumpectomy and breast radiotherapy in breast cancer patients with a family history of breast cancer, ovarian cancer, or both.

This article presents an outcomes review of breast cancer patients identified from the cancer registries of four area hospitals. These patients had family histories of breast cancer, ovarian carcinoma, or both and were treated with conservative surgery and radiation to the involved breast. Patients were as follows: group 1, one first-degree relative ( n = 165, one synchronous bilateral breast cancer); group 2, > or =2 first-degree relatives ( n = 21); group 3, one second-degree relative ( n = 20); and group 4, > or =2 second-degree relatives ( n = 18). The total of patients and breast cancer events was 224 and 225, respectively. Group 5 was a subgroup of 53 patients with a substantial risk (>10%) of a BRCA1 or BRCA2 mutation. After a median follow-up of 3.9 years, 5 patients had local failure (2%), and 5 developed a contralateral breast cancer (2%). There were no significant differences in local failure rates between groups (p = 1.0): group 1, 5 of 166 (3%); group 2, 0 of 21 (0%); group 3, 0 of 20 (0%); and group 4, 0 of 18 (0%). Local failure for group 5 was 2% (1 of 53). Four of 143 patients (3%) with a minimum 3 years of follow-up (median, 5.6 years) had local failure, and 5 (4%) developed a contralateral breast cancer. A univariate analysis was statistically significant for differentiation only (well, 0 of 67; moderately, 1 of 57 [1.8%]; poor, 3 of 26 [11.5%], p = 0.008). Overall survival for groups 1-4 did not differ significantly. Although follow-up has been relatively short, we have not found that breast cancer patients with various degrees of family histories of breast/ovarian carcinoma have had a detrimental outcome when treated with conservative therapy.

Analysis of Variance↗
PubMedDate not supplied

BRCA status, molecular markers, and clinical variables in early, conservatively managed breast cancer.

Conservatively treated premenopausal breast cancer has a higher rate of local relapse as well as an increased genetic predisposition to cancer. The current study's purpose was to evaluate the interactions between BRCA-1/2 status and molecular biologic markers in a cohort of conservatively managed breast cancer patients. Seventy-six premenopausal women treated with breast-conserving surgery and radiation therapy were this study's focus. All patients were treated with wide local excision with or without axillary dissection, followed by radiation to the intact breast. Systemic therapy was administered as clinically indicated. All patients in this study had an available paraffin block from the primary tumor and agreed to undergo complete sequencing of the BRCA-1 and BRCA-2 genes. The primary breast tumor tissue from each patient was immunohistochemically stained for estrogen receptor (ER), progesterone receptor (PR), p53, HER-2/neu, and Proliferating Cell Nuclear Antigen (PCNA). Of the 76 patients tested for BRCA, 50 patients had wild-type BRCA-1 and BRCA-2, 15 had variants of unclear significance, 6 had deleterious mutations in BRCA-1, and 5 had deleterious mutations in BRCA-2. p53 positivity correlated with deleterious mutations in BRCA-1 (p = 0.023), but not in BRCA-2. Though not significant, there was a trend for ER and PR negativity to correlate with BRCA-1 mutation (p = 0.087 and 0.054, respectively); there were no correlations between ER, PR, and BRCA-2. Though not significant, all 11 tumors with BRCA mutations were HER-2/neu negative. Patients with BRCA mutations have a unique molecular profile. These data can be helpful in understanding differences in the biologic behavior of patients with familial breast cancers.

Adult↗
PubMed1994

[p53: an important or most overvalued tumor gene?].

Mutations in the tumour-suppressor gene p53 are the most frequent molecular alterations detected in human tumours. p53 protein, which has been called "guardian of the genome", seems to play a key role in cellular DNA repair. Loss of p53 protein function by genetic mutation thereby makes the cell vulnerable to DNA damage, and disposes it to malignant transformation. In different human tumour types the prognostic relevance of p53 alterations is quite variable: While there is evidence of poor prognosis in breast cancer carrying p53 alterations, no such prognostic correlation could be found in low grade astrocytic gliomas. In both tumour types p53 mutations are equally frequent. Malignant transformation is considered a multistep process, and p53 mutations occur at different positions in this cascade in different tumour types. While p53 mutations seem to be an early event in astrocytic gliomas, they affect e.g. colon tumours rather late, during malignant progression from adenoma to carcinoma. These observations underscore the biological importance of p53 mutations in human tumour formation, even if the simple investigation for a prognostic relevance may lead to different results in tumours of different tissues.

Astrocytoma↗
PubMed1980

Temperature-sensitive tumorigenicity of cells transformed by a mutant of Moloney sarcoma virus.

Normal rat kidney cells were nonproductively infected either with CP27, a mutant of Moloney sarcoma virus that is temperature-sensitive for maintenance of transformation, or with the parental wild-type virus. The nonproducer cells were inoculated into the tails of athymic nude mice that were subsequently incubated at 28 or 36 degrees C. CP27-infected cells induced tumors only at 28 degrees C, whereas cells infected with wild-type Moloney sarcoma virus were tumorigenic at both temperatures. Tumors induced at 28 degrees C by wild-type virus-infected cells grew faster after shift of the mice to 36 degrees C. In contrast, tumors induced by CP27-infected cells regressed upon shift to 36 degrees C, indicating that continuous expression of viral functions is required for persistence and growth of the tumors. After regression, secondary tumor growth was observed late after upshift of temperature-sensitive tumors. Cells recovered from these late-appearing tumors were tumorigenic at the nonpermissive temperature, and tumors induced by these cells did not regress after upshift. Virus rescued from these recovered cells retained the temperature-sensitivity for focus formation, indicating that the occurrence of the phenotypically wild-type cells was due to host cell modifications rather than to reversion of the CP27 genome.

Animals↗