Maher B.H.,Griffith University |
Kerr M.,Griffith University |
Cox H.C.,Griffith University |
MacMillan J.C.,Queensland Clinical Genetics Service |
And 7 more authors.
Neurogenetics | Year: 2012
Investigations into migraine genetics have suggested that susceptibility loci exist on the X chromosome. These reports are supported by evidence that demonstrates male probands as having a higher proportion of affected first-degree relatives as well as the female preponderance of 3:1 that the disorder displays. We have previously implicated the Xq24-28 locus in migraine using two independent multigenerational Australian pedigrees that demonstrated excess allele sharing at the Xq24, Xq27 and Xq28 loci. Here, we expand this work to investigate a further six independent migraine pedigrees using 11 microsatellite markers spanning the Xq27-28 region. Furthermore, 11 candidate genes are investigated in an Australian case-control cohort consisting of 500 cases and 500 controls. Microsatellite analysis showed evidence of excess allele sharing to the Xq27 marker DXS8043 (LOD*1.38 P=0.005) in MF879 whilst a second independent pedigree showed excess allele sharing to DXS8061 at Xq28 (LOD*1.5 P=0.004). Furthermore, analysis of these key markers in a case control cohort showed significant association to migraine in females at the DXS8043 marker (T1 P=0.009) and association with MO at DXS8061 (T1 P=0.05). Further analysis of 11 key genes across these regions showed significant association of a three-marker risk haplotype in the NSDHL gene at Xq28 (P=0.0082). The results of this study add further support to the presence of migraine susceptibility loci on chromosome Xq27 and Xq28 as well as point to potential candidate genes in the regions that warrant further investigation. © Springer-Verlag 2012.
Rosty C.,Queensland Institute of Medical Research |
Rosty C.,University of Queensland |
Walsh M.D.,Queensland Institute of Medical Research |
Walters R.J.,Queensland Institute of Medical Research |
And 20 more authors.
American Journal of Surgical Pathology | Year: 2013
Serrated polyposis (SP) is a clinically defined syndrome characterized by the occurrence of multiple serrated polyps in the large intestine. Individuals with SP and their relatives are at increased risk of colorectal carcinoma (CRC). We aimed to determine the pathologic and molecular profiles of CRCs in individuals fulfilling World Health Organization criteria for SP. A total of 45 CRCs were obtained from 38 individuals with SP (27 female and 11 male patients; median age at CRC diagnosis, 58.5 y) attending genetics clinics. Tumor samples were pathologically reviewed, screened for somatic BRAF and KRAS mutations, and analyzed immunohistochemically for mismatch repair protein (MMR) expression. Tumors were spread throughout the large intestine, with 64% located in the proximal colon. Mutations in BRAF and KRAS and immunohistochemical evidence of MMR deficiency were found in 46%, 5%, and 38%, respectively. Nearly half of CRCs were BRAF/KRAS wild type, and these were associated with distal location (63%) and MMR proficiency (84%). Overexpression of p53 and/or evidence of β-catenin activation were identified in 13 CRCs. Ten patients (26%) had synchronous or metachronous CRCs. In conclusion, the majority of CRCs arising in individuals with SP do not harbor molecular hallmarks of serrated pathway CRCs but show a diverse range of molecular profiles. The high proportion of multiple CRCs suggests that individuals with SP would benefit from frequent colonoscopic surveillance and from a consideration of a more extensive colectomy at the time of CRC diagnosis. Copyright © 2013 by Lippincott Williams & Wilkins.
Menon S.,Griffith University |
Buteri J.,Griffith University |
Roy B.,Griffith University |
Murrell M.,Griffith University |
And 5 more authors.
Brain Research | Year: 2011
Migraine is a neurological disorder that is associated with increased levels of calcitonin gene-related peptide (CGRP) in plasma. CGRP, being one of the mediators of neurogenic inflammation and a phenomenon implicated in the pathogenesis of migraine headache, is thus suggested to have an important role in migraine pathophysiology. Polymorphisms of the CALCA gene have been linked to Parkinson's disease, ovarian cancer and essential hypertension, suggesting a functional role for these polymorphisms. Given the strong evidence linking CGRP and migraine, it is hypothesised that polymorphisms in the CALCA gene may play a role in migraine pathogenesis. Seemingly non functional intronic polymorphisms are capable of disrupting normal RNA processing or introducing a splice site in the transcript. A 16 bp deletion in the first intron of the CALCA gene has been reported to be a good match for the binding site for a transcription factor expressed strongly in neural crest derived cells, AP-2. This deletion also eliminates an intron splicing enhancer (ISE) that may potentially cause exon skipping. This study investigated the role of the 16 bp intronic deletion in the CALCA gene in migraineurs and matched control individuals. Six hundred individuals were genotyped for the deletion by polymerase chain reaction followed by fragment analysis on the 3130 Genetic Analyser. The results of this study showed no significant association between the intronic 16 bp deletion in the CALCA gene and migraine in the tested Australian Caucasian population. However, given the evidence linking CGRP and migraine, further investigation of variants with this gene may be warranted. © 2010 Elsevier B.V. All rights reserved.
Dowty J.G.,University of Melbourne |
Win A.K.,University of Melbourne |
Buchanan D.D.,Queensland Institute of Medical Research |
Lindor N.M.,Mayo Medical School |
And 24 more authors.
Human Mutation | Year: 2013
We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available. © 2012 Wiley Periodicals, Inc.
Bennett I.C.,University of Queensland |
Muller J.,Cancer Screening Services |
Cockburn L.,BreastScreen Queensland |
Joshua H.,BreastScreen Queensland |
And 7 more authors.
World Journal of Surgery | Year: 2010
Background While population-based breast screening for women over the age of 50 years is a generally accepted and proven health strategy, the role of breast screening specifically among women at high risk of familial breast cancer has remained controversial. Indeed, there are very few services specifically offering a breast-screening program for women at high risk of familial breast cancer. Methods In 1999 a Familial Breast Cancer Screening Clinic (FBCSC) was established at the North Brisbane BreastScreen Queensland Service to provide a regular multimodality screening program utilizing clinical breast examination, breast ultrasound, and mammography for women at higher risk of hereditary breast cancer and with entry into the program commencing from the age of 30 years. Results Since its inception, a total of 2440 women have participated in the FBCSC. A total 7051 breast-screening examinations have been performed on these participants, with 53 breast cancers being diagnosed, including 8 in situ ductal carcinomas, 38 invasive ductal carcinomas, and 7 invasive lobular carcinomas. The mean size of the cancers was 16 mm (range = 1-45 mm), and of the 45 invasive cancers, 60% were less than or equal to 15 mm in size. The overall axillary node positive rate was 24.5% (13/53). The invasive cancer detection rate for first-round screening was 8.3 cancers per 1000 women screened, with 5.2 cancers per 1000 women detected on subsequent round screening. Conclusions The results from this service demonstrate that multimodality screening for women at high risk of familial breast cancer and including women of younger age is effective and appropriate, with very acceptable cancer detection rates and pathological cancer characteristics being observed consistent with early-stage detection. The colocated siting of this service within a BreastScreen Queensland facility has proven to be efficient and cost effective. © Société Internationale de Chirurgie 2010.