John R. Goepel

Identification of novel regions of amplification and deletion within mantle cell lymphoma DNA by comparative genomic hybridization

Summary. We have carried out comparative genomic hybridization (CGH) analysis on archival biopsy material from a series of 30 UK mantle cell lymphomas. The most frequent aberrations were gains of 3q (21 cases), 6p (19 cases), 7q (8 cases), 12p (8 cases), 12q (9 cases) and 17q11q21 (8 cases), and losses of 1p13p32 (10 cases), 5p13p15.3 (9 cases), 6q14q27 (11 cases), 8p (7 cases), 11q13q23 (8 cases) and 13q (18 cases). Nineteen cases (63%) had a common region of amplification at 3q28q29, which was highly amplified in three cases, suggesting the presence of a mantle cell lymphoma (MCL)‐related oncogene in this region. There was a minimal common region of deletion at 6q25q26 in nine cases (30%). No MCL‐specific locus has previously been identified on chromosome 6 and this region may contain a tumour suppressor gene specifically implicated in the development of this subtype of lymphoma. An increased number of chromosome aberrations, gain of Xq and loss of 17p were all significantly associated with a worse prognosis. A greater understanding of the genetics of mantle cell lymphoma may allow the identification of prognostic factors which will aid the identification of appropriate treatment regimens.

Copy number gain at 12q12-14 may be important in the transformation from follicular lymphoma to diffuse large B cell lymphoma

The purpose of this study was to identify novel areas of genomic copy number change associated with transformation from follicular lymphoma (FL) to diffuse large B cell lymphoma (DLBL). DNA was extracted from tumour cells micro-dissected from paraffin- embedded tissue sections in 24 patients with FL and subsequent transformation to DLBL and 18 patients with de novo DLBL. Tumour DNA was compared to reference DNA using comparative genomic hybridization. Abnormalities common to all 3 groups were gains on chromosomes 4q, 5q, 7q, 11q and X and losses on 3p, 8p and 10q. Copy number changes seen in both transformed and de novo DLBL and not seen in FL were gains on 2p and losses on 1q, 15q and Xq. Gains on 2q, 6p, 7p and 17q and losses on 5p and 8q were specific to transformed DLBL cases. Gain on 12q12-14 was found in 52% of the transformed DLBL cases and was never seen in its follicular counterpart. Patterns of genomic copy number change associated with specific clinical events in NHL have been demonstrated and suggest that gains on 2q, 6p, 7p, 12q and 17q and losses on 5p and 8q may be important in the transformation from low to high-grade disease.

Comparative Outcomes of Primary, Recurrent, and Progressive High-risk Non–muscle-invasive Bladder Cancer

BACKGROUND The treatment of high-risk non-muscle-invasive bladder cancer (BCa) is problematic given the variable natural history of the disease. Few reports have compared outcomes for primary high-risk tumours with those that develop following previous BCas (relapses). The latter represent a self-selected cohort, having failed previous treatments. OBJECTIVE To compare outcomes in patients with primary, progressive, and recurrent high-risk non-muscle-invasive BCa. DESIGN, SETTING, AND PARTICIPANTS We identified all patients with primary and relapsing high-risk BCa tumours at our institution since 1994. Relapses were divided into progressive (previous low- or intermediate-risk disease) and recurrent (previous high-risk disease) cancers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Relationships with outcome analysed using multivariable Cox regression and log-rank analysis. RESULTS AND LIMITATIONS We identified 699 primary, 110 progressive, and 494 recurrent high-risk BCa tumours in 809 patients (average follow-up: 59 mo [interquartile range: 6-190]). Muscle invasion occurred most commonly in recurrent (23%) tumours, when compared to progressive (20%) and primary (14.6%) cohorts (log rank p<0.001). Disease-specific mortality (DSM) occurred more frequently in patients with recurrent (25.5%) and progressive (24.6%) tumours compared to primary disease (19.2%; log rank p=0.006). Other-cause mortality was similar in all groups (log rank p=0.57), and overall mortality was highest in the progressive cohort (62%) compared with the recurrent (58%) and primary groups (54%; log rank p<0.001). In multivariable analysis, progression and DSM were predicted by tumour grouping (hazard ratio [HR]: >1.15; p<0.026), stage (HR: >1.30; p<0.001), and patient age and sex (HR: >1.03; p<0.037). Carcinoma in situ was only predictive of outcome in primary tumors. Limitations include retrospective design and limited details regarding bacillus Camille-Guérin use. CONCLUSIONS Patients with relapsing, high-risk, BCa tumors have higher progression, DSM, and overall mortality rates than those with primary cancers. The use of bladder-sparing strategies in these patients should approached cautiously. Carcinoma in situ has little predicative role in relapsing, high-risk, BCa tumors.

Placental site trophoblastic tumour: a rare but potentially curable cancer

Placental site trophoblastic tumour (PSTT) is a rare form of gestational trophoblastic disease (GTD). We have conducted an analysis of all cases of PSTT managed at the Trophoblastic Disease Screening and Treatment Centre, Sheffield, from 1984 to 1996. During this time we received 4988 registrations for GTD and managed seven cases of PSTT. A large range of interval between antecedent pregnancy and presentation was observed – the most common presenting symptoms being irregular vaginal bleeding with or without preceding amenorrhoea. Three out of seven patients had disease confined to the uterus at diagnosis and were successfully treated by hysterectomy alone. Two out of seven patients had pulmonary metastases in addition to uterine tumour and were treated with combination chemotherapy – both are alive and well. Of the remaining two patients one had distant and the other loco-regional metastases and both died despite numerous therapeutic interventions.

Global epigenetic profiling in bladder cancer

Urothelial carcinoma of the bladder is a common disease that arises from two distinct molecular pathways, and is one of the most expensive malignancies to manage. Accurate biomarkers that could detect tumor recurrence or predict future progression would improve the care of patients and reduce the cost of managing the disease. DNA methylation, histone modification and ncRNA expression are important epigenetic mechanisms that regulate the expression of genes. These regulatory mechanisms are altered with bladder cancer, and therefore, represent potential biomarkers and therapeutic targets owing to the reversible nature of their modification. In this article, we will discuss these epigenetic changes in bladder cancer and assess their clinical potential.

Disease Specific Mortality in Patients with Low Risk Bladder Cancer and the Impact of Cystoscopic Surveillance

PURPOSE We determined the risk of disease specific mortality in patients with primary, low risk, noninvasive (G1pTa) bladder cancer and compared it to disease specific mortality in age and gender matched general populations. MATERIALS AND METHODS We identified all patients with primary low risk cancer at our institution. We excluded those with adverse pathological features and then matched histopathology, pharmacy, hospital episode and Cancer Registry records. We reviewed case notes on patients with subsequent muscle invasion (progression) or disease specific mortality. Patients underwent post-resection surveillance and treatment using standard regimens. National and regional disease specific mortality rates were calculated from appropriate data. RESULTS A total of 699 patients met study inclusion criteria. Median followup was 61 months (IQR 24-105). Of the patients 17 (2.4%) died of bladder cancer, including 13 of 14 with progression to muscle invasion and 4 of 19 with grade progression to high grade, nonmuscle invasive disease. On Cox regression analyses low grade dysplasia in the initial resection specimen and tumor weight were associated with disease specific mortality (p <0.003). Disease specific mortality in these patients was 5 times the background rate in matched populations. Limitations of this study include its retrospective nature and the low frequency of adverse events. CONCLUSIONS Patients with low risk bladder cancer rarely progress to muscle invasion but they are at higher risk for disease specific mortality than the general population. Current surveillance regimens appear ineffective for detecting progression in time to alter prognosis.

Cytogenetic analysis of a United Kingdom series of non-Hodgkins lymphomas

We describe cytogenetic analyses of cells derived from 40 non-Hodgkins lymphoma (NHL) node biopsies, 23 of which were from patients who had not been treated before biopsy. We noted that the chromosomes most frequently gained were X (32%), 12 (27%), and 3 (24%). Monosomies were much less common; loss of chromosome 13 (13.5%) was most frequent. Structural abnormalities primarily involved chromosomes 14 (70%), 1 (40.5%), 18 (38%), 6 (35%), and 17 (22%). Low-and high-grade disease showed similar patterns of structural changes; however, a markedly greater number of chromosome gains were associated with low-grade disease. Biopsy samples from patients who had previously been treated showed an increased frequency of structural abnormalities, as well as a significantly larger number of chromosome gains. The importance of these observations, particularly with regard to possible oncogene involvement in lymphoma evolution, is discussed.

The long‐term outcome of treated high‐risk nonmuscle‐invasive bladder cancer

The treatment of high‐risk nonmuscle‐invasive bladder cancer (NMIBC) is difficult given its unpredictable natural history and patient comorbidities. Because current case series are mostly limited in size, the authors report the outcomes from a large, single‐center series.

Elevated levels of MDM-2 and p53 expression are associated with high grade non-Hodgkin's lymphomas

The role of p53 in the evolution of non-Hodgkins lymphomas (NHL) is unclear. Mutations of the p53 gene appear to be relatively uncommon but stabilized p53 protein, as detected by immunohistochemistry, has indicated a more frequent involvement of p53. As dysfunction of p53 protein has also been suggested to occur after overexpression of the mdm-2 protein, we have therefore investigated a series of non-malignant hyperplastic reactive lymphoid tissues and NHL to examine whether the levels of expression of MDM-2 correlated to positivity of p53 protein staining. Northern blot analysis of MDM-2 expression was compared to glucose-6-phosphate dehydrogenase (G6PD) expression by densitometry to quantify the relative levels of MDM-2 expression. Consistent low levels of MDM-2 expression were observed in non-malignant lymphoid tissue and in low grade NHL, however, 13/15 high grade NHL exhibited a 2-15-fold increase in MDM-2 expression. Interestingly similar elevations in p53 mRNA expression were also observed in 6/15 high grade NHL. Positive staining of the p53 protein did not, however, correlate with elevated mRNA levels of either MDM-2 or p53. The significance of these observations is discussed.

Gestational choriocarcinoma of the ovary diagnosed by analysis of tumour DNA.

Gestational choriocarcinoma of the ovary is a rare form of malignancy which can be difficult to distinguish from primary ovarian choriocarcinoma. The ability to make such a diagnosis could, however, have important implications for therapy. We report here a case of choriocarcinoma whose origins were difficult to determine and which behaved clinically more like a primary rather than a gestational choriocarcinoma. We have analysed DNA from this tumour by using polymerase chain reaction (PCR) amplification of a range of polymorphic alleles and have demonstrated that the tumour was in fact gestational. Furthermore, the lack of chromosome Y sequences and the presence of heterozygosity of the spouses alleles, indicated that this tumour arose as a result of dispermic fertilisation of an empty ovum by sperm carrying the X chromosome.