Novel and recurrent germline and somatic mutations in a cohort of 67 patients from 48 families with brooke-spiegler syndrome including the phenotypic variant of multiple familial trichoepitheliomas and correlation with the histopathologic findings in 379 biopsy specimens
Grossmann P.,Bioptical Laboratory |
Grossmann P.,Charles University |
Vanecek T.,Bioptical Laboratory |
Vanecek T.,Charles University |
And 17 more authors.
American Journal of Dermatopathology | Year: 2013
Brooke-Spiegler syndrome (BSS) is a rare, inherited, autosomal dominant disorder characterized by development of multiple adnexal cutaneous neoplasms including spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma. The syndrome of multiple familial trichoepitheliomas (MFT) is considered a phenotypic variant of BSS in which patients present with trichoepitheliomas only. We studied germline and somatic mutations of the CYLD gene by direct sequencing in patients with BSS (n = 49) and MFT (n = 18) using peripheral blood and 90 samples of frozen or formalin-fixed paraffin-embedded tumor tissue selected from 379 available histology specimens. Germline CYLD mutations were found in 51 patients (76%) from 36 families (75%). Germline CYLD mutations were found in 43 of the 49 patients with BSS (88%) but in only 8 of 18 MFT cohort (44%). Twenty-one frameshift, 15 nonsense, 3 missense, and 4 splice site mutations were found in patients with BSS, whereas 1 frameshift, 5 nonsense, and 2 splice site mutations were identified in the MFT cohort. Five novel mutations were identified including 4 frameshift mutations (c.1027dupA/p.T343NfsX7, c.2155dupA/p.M719NfsX5, c.2288-2289delTT/p.F763X, and c.2641delG/p.D881TfsX32) and 1 nonsense mutation (c.2713C>T/p. Q905X). Of the 76 tumors from 32 patients with a germline CYLD mutation, 12 were spiradenomas, 15 spiradenocylindromas, 26 cylindromas, 15 trichoepitheliomas, and 7 were other tumor types. Somatic mutations were detected in 67 specimens of these 76 tumors (88%). Of the 67 somatic mutations, 21 (31%) represented a sequence alteration and 46 (69%) showed loss of heterozygosity. In the remaining 9 cases (12%), the somatic changes remained unknown. A germline CYLD mutation was not detected in 14 tumor samples from 8 patients. In these 14 tumors, somatic mutations were identified in 6 samples (43%), all consisting of sequence alterations (1 sample showed 2 different sequence alterations). In the remaining 8 samples (53%), neither germline nor somatic mutations were found in the lesional tissue. Our study increases the catalog of known CYLD mutations in patients with BSS/MFT to 86 and documents the variability of somatic mutations that may occur in them. We confirm the absence of firm genotype-phenotype correlations and the existence of a subset of patients with BSS/MFT who lack a demonstrable germline CYLD mutation. Further studies are needed to explain the reasons for this phenomenon. Copyright © 2013 by Lippincott Williams & Wilkins.
Galvao D.A.,Edith Cowan University |
Taaffe D.R.,Edith Cowan University |
Taaffe D.R.,University of Wollongong |
Spry N.,Edith Cowan University |
And 12 more authors.
Nature Reviews Urology | Year: 2016
Active surveillance (AS) is a strategy for the management of patients with low-risk, localized prostate cancer, in which men undergo regular monitoring of serum PSA levels and tumour characteristics, using multiparametric MRI and repeat biopsy sampling, to identify signs of disease progression. This strategy reduces overtreatment of clinically insignificant disease while also preserving opportunities for curative therapy in patients whose disease progresses. Preliminary studies of lifestyle interventions involving basic exercise advice have indicated that exercise reduces the numbers of patients undergoing active treatment, as well as modulating the biological processes involved in tumour progression. Therefore, preliminary evidence suggests that lifestyle and/or exercise interventions might have therapeutic potential in this growing population of men with prostate cancer. However, several important issues remain unclear: the exact value of different types of lifestyle and exercise medicine interventions during AS; the biological mechanisms of exercise in delaying disease progression; and the influence of the anxieties and distress created by having a diagnosis of cancer without then receiving active treatment. Future studies are required to confirm and expand these findings and determine the relative contributions of each lifestyle component to specific end points and patient outcomes during AS. © 2016 Macmillan Publishers Limited. All rights reserved.
Tiwari S.M.,Sir Charles Gairdner Hospital |
Wood B.A.,Dermatopathology Group |
Wood B.A.,University of Western Australia |
Skender-Kalnenas T.,Hollywood Specialist Center |
Cook N.,Royal Perth Hospital
Australasian Journal of Dermatology | Year: 2014
Abatacept is a novel biological agent that dampens the immune response by blocking the co-stimulation of T-cells, thus downregulating T-cell activation. It is currently approved for the treatment of rheumatoid arthritis (RA). The group of novel immunomodulatory agents, referred to as biologics, have now been used extensively, with established safety and side-effect profiles. There are, however, increasing reports of adverse paradoxical reactions, most notably resulting from anti-tumour necrosis factor (TNF) therapy. While cutaneous adverse reactions to abatacept are rare, there are a few reports of such paradoxical reactions. We report a case of an idiosyncratic paradoxical neutrophilic dermatosis associated with the use of abatacept. © 2014 The Australasian College of Dermatologists.
O'Brien B.A.,Tissugen Pty Ltd |
O'Brien B.A.,University of Western Australia |
Brown A.L.,Tissugen Pty Ltd |
Shannon T.,Hollywood Specialist Center |
And 2 more authors.
Prostate Cancer and Prostatic Diseases | Year: 2010
We reviewed the status of prostate cancer diagnosis in Western Australia (WA) with the aim of improving decision-making about PSA testing and prostate biopsy. Our patient cohort was 5145 men undergoing an initial biopsy for prostate cancer diagnosis in WA between 1998 and 2004. Transrectal ultrasound-guided biopsies were performed by one of 18 clinicians whereas all pathology was assessed by one urological pathologist. Cancer detection rates were 59% for initial biopsies and 32% for repeat biopsies. High-grade cancer (Gleason sum ≥7) accounted for 69 and 38% of tumours diagnosed on initial and repeat biopsy, respectively. The rates of cancer diagnosis and detection of high-grade tumours were both 1.6-fold higher in WA patients compared with those obtained at baseline screening of the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial of US men (P<0.001). These higher than expected rates of cancer detection and high histological grade indicate that urological practice in WA between 1998 and 2004 was significantly more conservative than US practice over this time period, probably leading to underdiagnosis of prostate cancer. Our findings may be relevant to other countries where urological practice differs from that in the United States. © 2010 Macmillan Publishers Limited All rights reserved.
Sima R.,Charles University |
Vanecek T.,Charles University |
Kacerovska D.,Charles University |
Trubac P.,Hospital Ceske Budejovice |
And 12 more authors.
Diagnostic Molecular Pathology | Year: 2010
Brooke-Spiegler syndrome (BSS) is an inherited autosomal dominant disease characterized by the development of multiple adnexal cutaneous neoplasms including spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma (cribriform trichoblastoma). BSS patients have various mutations in the CYLD gene, a tumor suppressor gene located on chromosome 16q. Our search of the literature revealed 51 germline CYLD mutations reported to date. Somatic CYLD mutations have rarely been investigated. We studied 10 patients from 8 families with BSS. Analysis of germline mutations of the CYLD gene was performed using either peripheral blood or nontumorous tissue. In addition, 19 formalin-fixed paraffin-embedded tumor samples were analyzed for somatic mutations, including loss of heterozygosity studies. A total of 38 tumors were available for histopathologic review. We have identified 8 novel germline mutations, all of which consisted of substitutions, deletions, and insertions/duplications and all except one led to premature stop codons. The substitution mutation in a single case was also predicted to disrupt protein function and seems causally implicated in tumor formation. We demonstrate for the first time that somatic events, loss of heterozygosity, or sequence mutations may differ among multiple neoplasms even of the same histologic type, occurring in the same patient. Copyright © 2010 by Lippincott Williams & Wilkins.