p27 Deficiency Cooperates with Bcl-2 but Not Bax to Promote T-Cell Lymphoma

The effect of Bcl-2 on oncogenesis is complex and expression may either delay or accelerate oncogenesis. The pro-oncogenic activity is attributed to its well characterized anti-apoptotic function while the anti-oncogenic function has been attributed to its inhibition of cellular proliferation. Recent studies demonstrate that p27 may mediate the effects of Bcl-2 on cellular proliferation. We hypothesized that p27 may suppress tumor formation by Bcl-2 family members. To test this hypothesis, cell cycle inhibition and lymphoma development were examined in Lck-Bcl-2 and Lck-Bax38/1 transgenic mice deficient in p27. Strikingly, p27 deficiency synergistically cooperates with Bcl-2 to increase T cell hyperplasia and development of spontaneous T cell lymphomas. Within 1 year, >90% of these mice had developed thymic T cell lymphomas. This high penetrance contrasts with a one year incidence of <5% of thymic lymphoma in Lck-Bcl-2 or p27 −/− mice alone. In contrast, p27 deficiency had no effect on tumor formation in Lck-Bax38/1 transgenic mice, another model of T cell lymphoma. Histologically the lymphomas in p27 −/− Lck-Bcl-2 mice are lymphoblastic and frequently involve multiple organs suggesting an aggressive phenotype. Interestingly, in mature splenic T cells, Bcl-2 largely retains its anti-proliferative function even in the absence of p27. T cells from p27 −/− Lck-Bcl-2 mice show delayed kinetics of CDK2 Thr-160 phosphorylation. This delay is associated with a delay in the up regulation of both Cyclin D2 and D3. These data demonstrate a complex relationship between the Bcl-2 family, cellular proliferation, and oncogenesis and demonstrate that p27 up-regulation is not singularly important in the proliferative delay observed in T cells expressing Bcl-2 family members. Nonetheless, the results indicate that p27 is a critical tumor suppressor in the context of Bcl-2 expression

Detailed analysis of X chromosome inactivation in a 49,XXXXX pentasomy

<p>Abstract</p> <p>Background</p> <p>Pentasomy X (49,XXXXX) has been associated with a severe clinical condition, presumably resulting from failure or disruption of X chromosome inactivation. Here we report that some human X chromosomes from a patient with 49,XXXXX pentasomy were functionally active following isolation in inter-specific (human-rodent) cell hybrids. A comparison with cytogenetic and molecular findings provided evidence that more than one active X chromosome was likely to be present in the cells of this patient, accounting for her abnormal phenotype.</p> <p>Results</p> <p>5-bromodeoxyuridine (BrdU)-pulsed cultures showed different patterns among late replicating X chromosomes suggesting that their replication was asynchronic and likely to result in irregular inactivation. Genotyping of the proband and her mother identified four maternal and one paternal X chromosomes in the proband. It also identified the paternal X chromosome haplotype (P), indicating that origin of this X pentasomy resulted from two maternal, meiotic non-disjunctions. Analysis of the <it>HUMANDREC </it>region of the androgen receptor (<it>AR</it>) gene in the patient's mother showed a skewed inactivation pattern, while a similar analysis in the proband showed an active paternal X chromosome and preferentially inactivated X chromosomes carrying the 173 <it>AR </it>allele. Analyses of 33 cell hybrid cell lines selected in medium containing hypoxanthine, aminopterin and thymidine (HAT) allowed for the identification of three maternal X haplotypes (M1, M2 and MR) and showed that X chromosomes with the M1, M2 and P haplotypes were functionally active. In 27 cell hybrids in which more than one X haplotype were detected, analysis of X inactivation patterns provided evidence of preferential inactivation.</p> <p>Conclusion</p> <p>Our findings indicated that 12% of X chromosomes with the M1 haplotype, 43.5% of X chromosomes with the M2 haplotype, and 100% of the paternal X chromosome (with the P haplotype) were likely to be functionally active in the proband's cells, a finding indicating that disruption of X inactivation was associated to her severe phenotype.</p

Paternal occupation and retinoblastoma: a case-control study based on data for Great Britain 1962-1999.

OBJECTIVES: To examine the association between paternal occupational exposures and retinoblastoma using birth registration data for cases from the National Registry of Childhood Tumours (NRCT) and controls from the general population of Great Britain. METHODS: A case-control study of paternal occupational data for 1318 cases of retinoblastoma, born and diagnosed in Great Britain between 1962 and 1999, and 1318 controls matched on sex, date of birth and birth registration sub-district. Paternal occupations at birth were grouped according to inferred exposure using an occupational exposure classification scheme. A conditional (matched) case-control analysis was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for each paternal occupational exposure group. RESULTS: For non-heritable retinoblastoma, a statistically significant increased risk was found with father's definite occupational exposure to oil mists in metal working (OR = 1.85 (95% CI 1.05 to 3.36)). Together with a (non-significant) risk (OR = 1.64 (0.73 to 3.83)) amongst the heritable cases, this occupational exposure was also associated with a significant increased risk when all retinoblastoma cases were considered together (OR = 1.77 (1.12 to 2.85)). No statistically significant associations were observed for other exposure groups. CONCLUSIONS: Our finding for exposure to oil mists in metal working (a subset of metal workers) is not directly comparable to those for metal working previously reported in the literature. Overall, our findings do not support the hypothesis that paternal occupational exposure is an important aetiological factor for retinoblastoma, however, the study has low power and other methodological limitations

Retinoblastoma in Great Britain 1963-2002.

AIM: This paper describes the epidemiology and family history status of 1601 children with retinoblastoma in Great Britain diagnosed 1963-2002 and summarises the practical consequences for diagnosis and counselling of developments in molecular genetics. METHODS: Incidence rates were analysed according to year of diagnosis and tumour laterality. Cases were classified as heritable or non-heritable on the basis of laterality and family history of the disease. RESULTS: There were 998 unilateral cases, 581 bilateral and 22 of unknown laterality. Bilateral cases tended to be diagnosed at a younger age than unilateral. All bilateral cases are regarded as heritable, and 35% had a family history of the disease. 7% of the unilateral cases had a family history and are therefore heritable. Thus, at least (41%) of our cases are heritable. This is an underestimate, since these data on family history are incomplete. For unilateral cases aged below 1 year, the reported incidence rate increased significantly (p&lt;0.0001) by about 2.5% per year; for the age group 1-4 years, the average increase was about 0.5% per year (not significant)

Non-ocular tumours following retinoblastoma in Great Britain 1951 to 2004.

BACKGROUND: Retinoblastoma occurs in both a heritable and a non-heritable form. In the heritable form, there is a predisposition to the development of non-ocular tumours. OBJECTIVES: To identify the types of non-ocular tumour occurring in retinoblastoma survivors and to produce estimates of risk for these tumours. METHODS: We carried out a cohort study that included 1927 cases of retinoblastoma diagnosed in Great Britain between 1951 and 2004. Cases were ascertained through the National Registry of Childhood Tumours and followed up for the occurrence of non-ocular tumours using the routine notification system based on the National Health Service Central Registers in Britain. RESULTS: Of the 1927 cases, 809 were known to have the heritable form of the disease and 1118 assumed to have the non-heritable form. 102 of the heritable and 13 of those classified as non-heritable developed a non-ocular tumour. The cumulative risk of developing such a tumour 50 years after retinoblastoma diagnosis was 48.3% (95% confidence interval: 38.1 to 59.7%) in the heritable and 4.9% (1.9 to 12.4%) in the non-heritable cases. The main categories of non-ocular tumours observed in the heritable cases were soft-tissue sarcomas (36 of which 21 were leiomyosarcoma), osteosarcoma (32), carcinoma (13), brain and central nervous system tumours (10), melanoma (9), leukaemia (4) and others (4). There were a total of 108 non-ocular tumours in 102 cases. CONCLUSIONS: There is a high risk of non-ocular tumours occurring in survivors of heritable retinoblastoma. These results have important implications for the clinical follow-up and counselling of survivors

A national survey of restorative consultants' treatment provision for head and neck oncology patients

Aim: To investigate current UK practices in the treatment of head and neck oncology patients by consultants in restorative dentistry. Method: A postal questionnaire requesting details of surgical and restorative head and neck oncology care from diagnosis to oral rehabilitation was circulated to all 315 consultants in restorative dentistry in the UK. If a reply was not received within 12 weeks a follow up was sent. Results: One hundred and thirty-two (43%) completed questionnaires were returned. On average 46% of respondents treated head and neck oncology patients, this varied with geographical location. Sixty percent of consultants' weekly workload was less than 25% oncology related, while 13% indicated more than 75%. Of the cohort providing oncology care only 12% thought there was always time for dental screening pre-radiotherapy, furthermore 67% had difficulty liaising with primary care. Within the UK great variety existed between attendance at multidisciplinary team meetings, dental care professional support, and provision of dental implant reconstruction including timing, manufacturer, operator, and funding. Conclusion: Significant variation in dental input into head and neck oncology patients' pathways exists, most notably with pre-radiotherapy screening. This study highlights a change in trend for patient rehabilitation with dental implants, and an increase to 52% of restorative dentistry consultants' attendance during a multidisciplinary team meeting