The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators.

Predisposition to prostate cancer has a genetic component, and there are reports of familial clustering of breast and prostate cancer. Two highly penetrant genes that predispose individuals to breast cancer (BRCA1 and BRCA2) are known to confer an increased risk of prostate cancer of about 3-fold and 7-fold, respectively, in breast cancer families. Blood DNA from affected individuals in 38 prostate cancer clusters was analyzed for germ-line mutations in BRCA1 and BRCA2 to assess the contribution of each of these genes to familial prostate cancer. Seventeen DNA samples were each from an affected individual in families with three or more cases of prostate cancer at any age; 20 samples were from one of affected sibling pairs where one was < or = 67 years at diagnosis. No germ-line mutations were found in BRCA1. Two germ-line mutations in BRCA2 were found, and both were seen in individuals whose age at diagnosis was very young (< or = 56 years) and who were members of an affected sibling pair. One is a 4-bp deletion at base 6710 (exon 11) in a man who had prostate cancer at 54 years, and the other is a 2-bp deletion at base 5531 (exon 11) in a man who had prostate cancer at 56 years. In both cases, the wild-type allele was lost in the patient's prostate tumor at the BRCA2 locus. However, intriguingly, in neither case did the affected brother also carry the mutation. Germ-line mutations in BRCA2 may therefore account for about 5% of prostate cancer in familial clusters.

Germline mutations in fumarate hydratase (FH) do not predispose to prostate cancer.

Inherited susceptibility to prostate cancer has been linked to a number of chromosomal regions, however no genes have been unequivocally shown to underlie reported linkages. The putative gene localised to chromosome 1q42-q43, has been designated PCaP. We have recently shown that germline mutations in the fumarate hydratase (FH) gene located on 1q43 cause smooth muscle tumours and renal cell carcinoma. It is conceivable that germline FH mutations might confer an increased risk of prostate cancer and underlie linkage of prostate cancer to PCaP. To examine this proposition we have analysed the entire coding region of FH in 160 prostate cancer cases in 77 multiple case families. No pathogenic mutations in FH were identified in any of the cases. This data makes it highly unlikely that mutations in FH confer susceptibility to prostate cancer.

Neoadjuvant phase II multicentre study of new agents in patients with malignant glioma after minimal surgery. Report of a cohort of 187 patients treated with temozolomide.

BACKGROUND: The aim of this study was to assess the efficacy of new agents in patients with malignant glioma in a neoadjuvant setting not confounded by surgery. The first study of neoadjuvant temozolomide aimed to provide a benchmark for future evaluation of new treatments. PATIENTS AND METHODS: This was a multicentre phase II study of chemotherapy in patients with histologically verified glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) who had undergone biopsy alone. Patients were planned to receive two cycles of temozolomide at 200 mg/m(2) orally daily for 5 days at a 28-day interval prior to radiotherapy. Response was assessed by two central observers on pre- and post-chemotherapy enhanced scans using bi-dimensional criteria and as progression-free survival (PFS) at the time of second assessment prior to radiotherapy. Withdrawal from the study due to worsening clinical condition was, in the absence of second imaging, assessed as progressive disease. Survival and quality of life (QOL) were secondary endpoints. RESULTS: Between August 1999 and June 2002, 188 patients from 15 UK and two Italian centres were entered into the study and 187 were analysed. Overall, 162 patients were assessable for response; seven had partial and 25 had minimal response. The objective response rate was 20% [95% confidence interval (CI) 14-26%] and PFS prior to commencing radiotherapy was 64% (95% CI 57-72%). The median survival was 10 months, and 1-year survival 41%. The median survival of responders was 16 months compared to 3 months in patients with progressive disease (P <0.001 on multivariate analysis). CONCLUSION: The phase II study design of primary chemotherapy in patients with malignant glioma following biopsy alone is feasible and provides as objective a method of assessment of efficacy as is currently available. The baseline data on temozolomide provide a benchmark for assessment of efficacy of other agents and combinations.

Verrucous carcinoma of the temporal bone.

A case report of a patient suffering from severe otalgia for 12 months and intermittent otorrhoea over a 53 year period is presented. Diagnosed as verrucous carcinoma of the temporal bone, this is only the ninth case found in the literature. The difficulty of histological diagnosis and subsequent management are important features.

Thalidomide as an anti-angiogenic agent in relapsed gliomas.

BACKGROUND: Thalidomide (alpha-phthalimidoglutarimide), a synthetic sedative drug, has anti-angiogenic properties due to inhibition of growth-factor mediated neovascularisation and has been shown to inhibit tumour growth in experimental solid tumour models. AIM: To assess response of recurrent malignant gliomas to thalidomide. METHODS: Eighteen patients with recurrent gliomas were enrolled to an open, non-randomised phase II trial between October 1997 and December 1999. All patients had failed following treatment with radiotherapy and chemotherapy with PCV and/or temozolomide regimens. Eleven patients had high-grade gliomas de novo and 7 high-grade gliomas following transformation of low-grade gliomas. Thalidomide was prescribed at 100 mg/day p.o. continuously. Response was assessed at 4-weekly intervals. Disease progression was defined as neurological deterioration and/or radiological evidence of increased tumour size. Treatment was discontinued at the time of disease progression, or if toxicity occurred, or at patients' request. RESULTS: Thalidomide was prescribed for a median of 42 days (range 7-244). Treatment was discontinued due to toxicity (peripheral sensory neuropathy) in 1 patient. Six patients died before response could be fully assessed and are classified as non-responders. Of 12 who continued treatment for more than 4 weeks, 1 patient had clinical and radiological response (PR), 2 patients had stable disease for 2 and 4 months respectively and 9 patients had disease progression. The median survival from the start of thalidomide was 2.5 months. CONCLUSION: The efficacy of thalidomide in terms of response in recurrent gliomas is low, with a partial response rate of only 6%. Future studies should investigate thalidomide in combination with other agents and at an earlier stage of disease. Methods to assess anti-angiogenic properties such as changes in tumour vasculature could be employed as initial surrogate end-points in the investigation of efficacy.

Temozolomide as second-line chemotherapy for relapsed gliomas.

BACKGROUND: Temozolomide, an imidazotetrazine prodrug has shown activity in phase II studies in patients with high-grade glioma at first recurrence. We assessed the efficacy of temozolomide as second-line therapy following failure of PCV chemotherapy in patients with recurrent/progressive gliomas. PATIENTS AND METHODS: Between September 1994 and November 2000, 32 patients with high-grade gliomas at second recurrence/progression received temozolomide as salvage therapy and results were reviewed retrospectively. RESULTS: Of 32 assessable patients 7 had clinical improvement; there were no imaging responses. Median survival of the cohort was 4 months, with 28% alive at 6 months. Age, performance status, histology and previous response to PCV chemotherapy did not predict for clinical response to temozolomide. CONCLUSION: In the small cohort of patients with recurrent malignant glioma who failed PCV chemotherapy temozolomide demonstrated limited activity as second-line treatment although this remains within the confidence intervals of response seen in patients with glioblastoma.

No germline mutations in the dimerization domain of MXI1 in prostate cancer clusters. The CRC/BPG UK Familial Prostate Cancer Study Collaborators. Cancer Research Campaign/British Prostate Group.

There is evidence that predisposition to cancer has a genetic component. Genetic models have suggested that there is at least one highly penetrant gene predisposing to this disease. The oncogene MXI1 on chromosome band 10q24-25 is mutated in a proportion of prostate tumours and loss of heterozygosity occurs at this site, suggesting the location of a tumour suppressor in this region. To investigate the possibility that MXI1 may be involved in inherited susceptibility to prostate cancer, we have sequenced the HLH and ZIP regions of the gene in 38 families with either three cases of prostate cancer or two affected siblings both diagnosed below the age of 67 years. These are the areas within which mutations have been described in some sporadic prostate cancers. No mutations were found in these two important coding regions and we therefore conclude that MXI1 does not make a major contribution to prostate cancer susceptibility.

Allelic imbalance in familial and sporadic prostate cancer at the putative human prostate cancer susceptibility locus, HPC1. CRC/BPG UK Familial Prostate Cancer Study Collaborators. Cancer Research Campaign/British Prostate Group.

A recent report has provided strong evidence for a major prostate cancer susceptibility locus (HPC1) on chromosome 1q24-25 (Smith et al, 1996). Most inherited cancer susceptibility genes function as tumour-suppressor genes (TSGs). Allelic loss or imbalance in tumour tissue is often the hallmark of a TSG. Studies of allelic loss have not previously implicated the chromosomal region 1q24-25 in prostate cancer. However, analysis of tumour DNA from cases in prostate cancer families has not been reported. In this study, we have evaluated DNA from tissue obtained from small families [3-5 affected members (n = 17)], sibling pairs (n = 15) and sporadic (n = 40) prostate tumours using the three markers from Smith et al (1996) that defined the maximum multipoint linkage lod score. Although widely spaced (12-50 cM), each marker showed evidence of allelic imbalance in only approximately 7.5% of informative tumours. There was no difference between the familial and sporadic cases. We conclude that the incidence of allelic imbalance at HPC1 is low in both sporadic tumours and small prostate cancer families. In this group of patients, HPC1 is unlikely to be acting as a TSG in the development of prostate cancer.

Androgen receptor polymorphisms: association with prostate cancer risk, relapse and overall survival.

Several reports have suggested that one or both of the trinucleotide repeat polymorphisms in the human androgen receptor (hAR) gene, (CAG)n coding for polyglutamine and (GGC)n coding for polyglycine, may be associated with prostate cancer risk; but no study has investigated their association with disease progression. We present here a study of both hAR trinucleotide repeat polymorphisms not only as they relate to the initial diagnosis but also as they are associated with disease progression after therapy. Lymphocyte DNA samples from 178 British Caucasian prostate cancer patients and 195 control individuals were genotyped by PCR for the (CAG)n and (GGC)n polymorphisms in hAR. Univariate Cox proportional hazard analysis indicated that stage, grade and GGC repeat length were individually significant factors associated with disease-free survival (DFS) and overall survival (OS). The relative risk (RR) of relapse for men with more than 16 GGC repeats was 1.74 (95% CI 1. 08-2.79) and of dying from any cause, 1.98 (1.13-3.45). Adjusting for stage and grade, GGC effects remained but were not significant (RR(DFS)= 1.60, p = 0.052; RR(OS)= 1.65, p = 0.088). The greatest effects were in stage T1-T2 (RR(DFS)= 3.56, 95% CI 1.13-11.21) and grade 1 (RR(DFS)= 6.47, 95% CI 0.57-72.8) tumours. No differences between patient and control allele distributions were found by odds-ratio analysis, nor were trends with stage or grade evident in the proportion of short CAG alleles. Non-significant trends with stage and grade were found in the proportion of short GGC alleles. The (GGC)n polymorphism in this population is a significant predictor of disease outcome. Since the (GGC)(n) effect is strongest in early-stage tumours, this marker may help forecast aggressive behaviour and could be used to identify those patients meriting more radical treatment.

High risk genes predisposing to prostate cancer development-do they exist?

There is evidence for genetic predisposition to prostate cancer. However, prostate cancer genes have been more difficult to find than genes for some of the other common cancers, such as breast and colon cancer. The reasons for this are discussed in this article and it is now becoming clear that prostate cancer is probably due to multiple genes, many of which are moderate or low penetrance. The advances in the Human Genome Project and technology, especially that of robotics, will help to overcome these problems. Prostate Cancer and Prostatic Diseases (2000) 3, 241-247

ATM polymorphisms as risk factors for prostate cancer development.

The risk of prostate cancer is known to be elevated in carriers of germline mutations in BRCA2, and possibly also in carriers of BRCA1 and CHEK2 mutations. These genes are components of the ATM-dependent DNA damage signalling pathways. To evaluate the hypothesis that variants in ATM itself might be associated with prostate cancer risk, we genotyped five ATM variants in DNA from 637 prostate cancer patients and 445 controls with no family history of cancer. No significant differences in the frequency of the variant alleles at 5557G>A (D1853N), 5558A>T (D1853V), ivs38-8t>c and ivs38-15g>c were found between the cases and controls. The 3161G (P1054R) variant allele was, however, significantly associated with an increased risk of developing prostate cancer (any G vs CC OR 2.13, 95% CI 1.17-3.87, P=0.016). A lymphoblastoid cell line carrying both the 3161G and the 2572C (858L) variant in the homozygote state shows a cell cycle progression profile after exposure to ionising radiation that is significantly different to that seen in cell lines carrying a wild-type ATM gene. These results provide evidence that the presence of common variants in the ATM gene, may confer an altered cellular phenotype, and that the ATM 3161C>G variant might be associated with prostate cancer risk.

Immunohistochemical expression of BRCA2 protein and allelic loss at the BRCA2 locus in prostate cancer. CRC/BPG UK Familial Prostate Cancer Study Collaborators.

Many epidemiological studies have reported an association between breast and prostate cancer. BRCA2 functions as a tumour-suppressor gene in about 35% of large familial breast-cancer clusters; its role in the pathogenesis of sporadic breast cancer is less clear. We have evaluated immunohistochemical expression of BRCA2 protein and allelic loss of markers at the BRCA2 locus in tissue derived both from sporadic and from familial cases of prostate cancer. Immunohistochemical analysis was performed in 167 paraffin-embedded archival specimens. Normal prostate and 75% (120/160) of prostate-cancer tissue did not express BRCA2 protein. However, 25% (40/160) of cancer cases did express patchy staining; of these, 17% (2711 60) expressed positive nuclear staining in normal glandular tissue adjacent to tumour (either in addition to, or, independent of tumour). Allelic loss is the hallmark of a tumour-suppressor gene. Markers flanking (D13S267, D13S260) and within (D13S171) the BRCA2 gene indicated allelic loss in at least one locus in 23% (17/73) of tumours analyzed. There was no difference in the rates of allelic loss between sporadic and familial tumours, nor was there any association between immunohistochemical staining and allelic loss. Although immunohistochemical staining provided no useful prognostic information, allelic loss at BRCA2 was shown in univariate analysis to be associated with poorer survival (log-rank test, p = 0.046).

Linkage analysis of chromosome 1q markers in 136 prostate cancer families. The Cancer Research Campaign/British Prostate Group U.K. Familial Prostate Cancer Study Collaborators.

Prostate cancer shows evidence of familial aggregation, particularly at young ages at diagnosis, but the inherited basis of familial prostate cancer is poorly understood. Smith et al. recently found evidence of linkage to markers on 1q, at a locus designated "HPC1," in 91 families with multiple cases of early-onset prostate cancer. Using both parametric and nonparametric methods, we attempted to confirm this finding, in 60 affected related pairs and in 76 families with three or more cases of prostate cancer, but we found no significant evidence of linkage. The estimated proportion of linked families, under a standard autosomal dominant model, was 4%, with an upper 95% confidence limit of 31%. We conclude that the HPC1 locus is responsible for only a minority of familial prostate cancer cases and that it is likely to be most important in families with at least four cases of the disease.