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Obermair A.,University of Queensland | Youlden D.R.,Viertel Center for Research in Cancer Control | Young J.P.,University of Queensland | Young J.P.,Familial Cancer Laboratory | And 7 more authors.
International Journal of Cancer | Year: 2010

The risk of endometrial cancer (EC) subsequent to a diagnosis of colorectal cancer in women with a germline mutation in a mismatch repair gene [Lynch syndrome or hereditary non-polyposis colon cancer (HNPCC)] is unknown. We estimated the risk of EC following a diagnosis of colorectal carcinoma (CRC) for women with Lynch syndrome. A retrospective cohort study was performed on women diagnosed with CRC with a germline mutation in a mismatch repair (MMR) gene (Lynch syndrome cases), and women with microsatellite stable (MSS) CRC who were not known to carry a germline mutation (non-Lynch cases), identified from the Colon Cancer Family Registry. The incidence of EC following CRC was estimated and compared for women with and without Lynch syndrome, using adjusted hazards ratios calculated for time at risk among each group. A total of 112 women with Lynch syndrome and a previous diagnosis of CRC were compared with 908 women without Lynch and with a MSS CRC diagnosis. The estimated 10-year cumulative risk of EC subsequent to CRC was 23.4% [95% confidence interval (CI): 15-36%] for Lynch syndrome women compared with 1.6% (95% CI: 0.7-3.8%) for non-Lynch women. After adjusting for ascertainment, age at diagnosis and diagnosis of other cancers, risk of subsequent diagnosis with EC was elevated sixfold in women with Lynch syndrome compared with non-Lynch women (HR 6.2; 95% CI 2.2-17.3; p = 0.001). Approximately one quarter of women diagnosed with Lynch syndrome-associated CRC developed EC within 10 years. This supports the sentinel cancer concept and suggests that active and early management is important for these women. Copyright © 2010 UICC. Source

Rosty C.,Anatomical Pathology | Rosty C.,Center for Clinical Research | Rosty C.,Familial Cancer Laboratory | Buchanan D.D.,Familial Cancer Laboratory | And 5 more authors.
Human Pathology | Year: 2011

Benign serrated polyps are commonly found in the colorectum but have rarely been described in other parts of the gastrointestinal tract. We report a series of 9 serrated polyps arising in the duodenum with clinicopathologic features, immunohistochemical expression profile of mucins (MUC2, MUC5AC, MUC6), and molecular analysis for BRAF and KRAS. The polyps were diagnosed as incidental endoscopy findings in 9 different patients, comprising 3 male and 6 female patients, with a mean age of 52.2 years (range, 21-72 years). The second part of the duodenum was the most common site (n = 5), followed by the ampulla (n = 1) and the distal duodenum (n = 1), with the location of the 2 remaining polyps unspecified. Other upper gastrointestinal tract pathology features included Barrett esophagus for 5 patients, Helicobacter gastritis for 1 patient, and mild chronic gastritis for 1 patient. The histologic appearance of the polyps was similar to microvesicular hyperplastic polyp in the colorectum. Immunostaining for mucins showed MUC6 expression in the crypt bases of all polyps, MUC5AC expression in 8 cases (89%), and mucin 2 expression in 6 cases (67%). Molecular testing was successful in 6 polyps, showing BRAF mutation (V600E) in 2 polyps, KRAS mutation in 2 polyps, and no mutation for either gene in 2 polyps. Colonoscopy reports were available for 6 patients, of whom 4 were diagnosed with hyperplastic polyps or sessile serrated polyps in the colorectum. However, no patient met the criteria for serrated polyposis. Although probably rare and of uncertain malignant potential, hyperplastic polyp should be considered in the differential diagnosis of benign duodenal polyp. © 2011 Elsevier Inc. All rights reserved. Source

Buchanan D.D.,Familial Cancer Laboratory | Buchanan D.D.,University of Queensland | Sweet K.,Ohio State University | Drini M.,Canberra Hospital | And 37 more authors.
PLoS ONE | Year: 2010

Background: Patients with multiple serrated polyps are at an increased risk for developing colorectal cancer (CRC). Recent reports have linked cigarette smoking with the subset of CRC that develops from serrated polyps. The aim of this work therefore was to investigate the association between smoking and the risk of CRC in high-risk genetics clinic patients presenting with multiple serrated polyps. Methods and Findings: We identified 151 Caucasian individuals with multiple serrated polyps including at least 5 outside the rectum, and classified patients into non-smokers, current or former smokers at the time of initial diagnosis of polyposis. Cases were individuals with multiple serrated polyps who presented with CRC. Controls were individuals with multiple serrated polyps and no CRC. Multivariate logistic regression was performed to estimate associations between smoking and CRC with adjustment for age at first presentation, sex and co-existing traditional adenomas, a feature that has been consistently linked with CRC risk in patients with multiple serrated polyps. CRC was present in 56 (37%) individuals at presentation. Patients with at least one adenoma were 4 times more likely to present with CRC compared with patients without adenomas (OR = 4.09; 95%CI 1.27 to 13.14; P = 0.02). For females, the odds of CRC decreased by 90% in current smokers as compared to never smokers (OR = 0.10; 95%CI 0.02 to 0.47; P =0.004) after adjusting for age and adenomas. For males, there was no relationship between current smoking and CRC. There was no statistical evidence of an association between former smoking and CRC for both sexes. Conclusion: A decreased odds for CRC was identified in females with multiple serrated polyps who currently smoke, independent of age and the presence of a traditional adenoma. Investigations into the biological basis for these observations could lead to non-smoking-related therapies being developed to decrease the risk of CRC and colectomy in these patients. © 2010 Buchanan et al. Source

Buchanan D.D.,Familial Cancer Laboratory | Roberts A.,Familial Cancer Laboratory | Walsh M.D.,Familial Cancer Laboratory | Parry S.,Auckland City Hospital | Young J.P.,Familial Cancer Laboratory
Future Oncology | Year: 2010

Colorectal cancer (CRC) develops within precursor lesions in the single-celled epithelial lining of the gut. The two most common epithelial lesions are the adenoma and the serrated polyp. CRC is also one of the most familial of the common cancers, and just as there are syndromes associated with increased risk of CRC arising in adenomas, there are also syndromes with increased CRC risk associated with serrated polyps. In this article, we describe the features of such a syndrome, familial serrated neoplasia, which distinguish it from the well-characterized condition Lynch syndrome (or hereditary nonpolyposis CRC), and show that the molecular pathology of tumors forms the basis for this distinction. Lynch syndrome CRC arises almost exclusively within adenomatous precursor lesions, in contrast with familial serrated neoplasia where at least half of the cancers develop in serrated polyps. Finally, rare families exist in which both conditions segregate independently, producing a difficult diagnostic picture. © 2010 Future Medicine Ltd. Source

Buchanan D.D.,Familial Cancer Laboratory | Buchanan D.D.,University of Queensland | Sweet K.,Ohio State University | Drini M.,Royal Melbourne Hospital | And 37 more authors.
International Journal of Colorectal Disease | Year: 2010

Objective: Hyperplastic polyposis is a colonic polyposis condition of unknown aetiology. The purpose of this study was to examine the spectrum of phenotypic variation in patients with multiple serrated polyps as a basis for gene discovery. Methods: One hundred and twenty-six patients with multiple (≥5) serrated polyps were recruited to the study. Polyp counts were extracted from histology and colonoscopy reports. Ethnicity was self-reported. Family history of cancer data were derived from pedigrees. Ascertainment status was classified as either index case or identified by screening. Results: The average reported polyp count was 39. Patients with highest polyp numbers were more likely to be male (P =0.02). Colorectal cancer (CRC) was identified in 49 of 119 patients (41%) and 28% of these patients had multiple CRC. Young onset patients had higher polyp numbers (P =0.03) and were more likely to have their CRC in the distal colon (P =0.02). CRC was significantly associated with the presence of adenomas (P =0.03). Patients were divided into moderate polyposis (5-79 serrated polyps) and dense polyposis (80 or more) categories. The dense polyposis category was associated with a lack of family history for CRC (P =0.034) and male gender (P =0.014), independent of ascertainment status and recruitment site. Conclusion: Multiple serrated polyps were associated with an increased personal risk of CRC. A subset of patients with the highest polyp numbers was more likely to be male and to have no family history of CRC. This result suggests heterogeneous modes of inheritance and has implications for studies investigating the genetic basis of multiple serrated polyps. © 2010 The Author(s). Source

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