Mark Clendenning

Publications (37)212.79 Total impact

• Article: Identification of Novel Variants in Colorectal Cancer Families by High-Throughput Exome Sequencing.

  Melissa S Derycke, Shanaka R Gunawardena, Sumit Middha, Yan A Asmann, Dan J Schaid, Shannon K McDonnell, Shaun M Riska, Bruce W Eckloff, Julie M Cunningham, Brooke L Fridley, [......], Robert Haile, Michael O Woods, Steven Gallinger, Graham Casey, John D Potter, Polly A Newcomb, Loic Le Marchand, Noralane M Lindor, Stephen N Thibodeau, Ellen L Goode
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  ABSTRACT: BACKGROUND: Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants. METHODS: We completed exome sequencing on 40 affected cases from 16 multi-case pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single nucleotide variants (SNVs) predicted to be benign. RESULTS: We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or non-coding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively. CONCLUSIONS: Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in colorectal cancer susceptibility. Impact: Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk.
  Cancer Epidemiology Biomarkers &amp Prevention 05/2013; · 4.12 Impact Factor
• Article: Germline HOXB13 p.Gly84Glu mutation and risk of colorectal cancer.

  Mohammad R Akbari, Laura N Anderson, Daniel D Buchanan, Mark Clendenning, Mark A Jenkins, Aung Ko Win, John L Hopper, Graham G Giles, Robert Nam, Steven Narod, Steven Gallinger, Sean P Cleary
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  ABSTRACT: Introduction: The HOXB13 pGly84Glu mutation has recently been associated with an increased risk of prostate cancer but the association of other cancer sites with this allele has not been assessed. Data has suggested that HOXB13 expression levels are decreased in colorectal cancer (CRC) cell lines indicating this gene may be involved in colorectal tumourigenesis. Methods: To evaluate a potential association of this mutation with CRC, we genotyped the mutation in 2695 CRC cases and 4593 controls from population-based registries in Canada and Australia. Results: The HOXB13 pGly84Glu mutation was more common in CRC cases than controls (0.48% vs. 0.17%, P=0.02) indicating a significant association between the HOXB13 variant and CRC risk (OR=2.8; 95%CI: 1.2-6.8). This association was attenuated but remained significant with the inclusion of previously published and publicly available genotype data. Pedigree analysis of cases and controls revealed that 7/21 HOXB13 mutation carriers had a family history of prostate cancer. Discussion: This report is the first to suggest a risk of CRC associated with mutations in the HOXB13 gene. These findings require further validation but may be of importance in the screening and genetic counseling of families known to carry the HOXB13 pGly84Glu mutation.
  Cancer epidemiology. 03/2013;
• Article: Family History of Colorectal Cancer in BRAF p.V600E mutated Colorectal Cancer Cases.

  Daniel D Buchanan, Aung Ko Win, Michael D Walsh, Rhiannon J Walters, Mark Clendenning, Belinda N Nagler, Sally-Ann Pearson, Finlay Macrae, Susan Parry, Julie Arnold, Ingrid Winship, Graham G Giles, Noralane M Lindor, John D Potter, John L Hopper, Christophe Rosty, Joanne P Young, Mark A Jenkins
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  ABSTRACT: BACKGROUND: Previous reports suggest that relatives of CRC-affected probands carrying the BRAF p.V600E mutation are at an increased risk of colorectal (CRC) and extracolonic cancers (ECCs). In this study, we estimated the association between a family history (FH) of either CRC or ECC and risk of CRC with a BRAF p.V600E mutation. METHODS: Population-based CRC cases (probands; aged 18-59years at diagnosis), recruited irrespective of family cancer history, were characterised for BRAF p.V600E mutation and mismatch repair (MMR) status. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. RESULTS: The 690 eligible probands demonstrated a mean age at CRC diagnosis of 46.9±7.8years, with 313 (47.9%) reporting a FH of CRC and 53 (7.7%) that were BRAF-mutated. Probands with BRAF-mutated, MMR-proficient CRCs were less likely to have a FH of CRC than probands that were BRAF-wildtype (OR=0.46, 95%CI=0.24-0.91; p=0.03). For probands with a BRAF-mutated CRC, the mean age at diagnosis was older for those with a CRC-affected first- or second-degree relative (49.3±6.4 years) compared with those without a FH (43.8±10.2 years; p=0.04). The older the age at diagnosis of CRC with the BRAF p.V600E mutation, the more likely these probands demonstrated a FH of CRC (OR=1.09 per year of age; 95%CI=1.00-1.18; p=0.04). CONCLUSIONS: Probands with early-onset, BRAF-mutated and MMR-proficient CRC were less likely to have a FH of CRC than probands that were BRAF-wildtype. Impact: These findings provide useful insights for cancer risk assessment in families and suggest that familial factors are more important in early-onset, BRAF-wildtype CRC.
  Cancer Epidemiology Biomarkers &amp Prevention 03/2013; · 4.12 Impact Factor
• Article: Lynch syndrome-associated breast cancers do not overexpress chromosome 11-encoded mucins.

  Michael D Walsh, Margaret C Cummings, Sally-Ann Pearson, Mark Clendenning, Rhiannon J Walters, Belinda Nagler, John L Hopper, Mark A Jenkins, Graeme K Suthers, Jack Goldblatt, Kathy Tucker, Michael R Gattas, Julie L Arnold, Susan Parry, Finlay A Macrae, Michael A McGuckin, Joanne P Young, Daniel D Buchanan
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  ABSTRACT: Mismatch repair-deficient breast cancers may be identified in Lynch syndrome mutation carriers, and have clinicopathological features in common with mismatch repair-deficient colorectal and endometrial cancers such as tumour-infiltrating lymphocytes and poor differentiation. Mismatch repair-deficient colorectal cancers frequently show mucinous differentiation associated with upregulation of chromosome 11 mucins. The aim of this study was to compare the protein expression of these mucins in mismatch repair-deficient and -proficient breast cancers. Cases of breast cancer (n=100) were identified from families where (1) both breast and colon cancer co-occurred and (2) families met either modified Amsterdam criteria or had at least one early-onset (<50 years) colorectal cancer. Tumour sections were stained for the epithelial mucins, MUC2, MUC5AC, MUC5B and MUC6, and the homeobox protein CDX2, a regulator of MUC2 expression. In all, 16 mismatch repair-deficient Lynch syndrome breast cancers and 84 non-Lynch breast cancers were assessed for altered mucin expression. No significant difference in the expression of MUC2, MUC5AC or MUC6 was observed between the mismatch repair-deficient and mismatch repair-proficient breast cancers; however, there was a trend for mismatch repair-deficient tumours to express high levels of MUC5B less frequently (P=0.07, OR=0.2 (0.0-1.0)). Co-expression of two or more gel-forming mucins was common. Ectopic expression of CDX2 was associated with expression of MUC2 (P=0.035, OR=8.7 (1.3-58.4)). Mismatch repair-deficient breast cancers do not show differential expression of the mucins genes on chromosome 11 when compared with mismatch repair-proficient breast cancers, in contrast with mismatch repair-deficient colorectal and endometrial cancers, which frequently have increased mucin protein expression when compared with their mismatch repair-proficient counterparts. In addition, ectopic CDX2 expression is positively associated with de novo MUC2 expression.Modern Pathology advance online publication, 1 February 2013; doi:10.1038/modpathol.2012.232.
  Modern Pathology 02/2013; · 4.79 Impact Factor
• Article: Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features.

  Christophe Rosty, Joanne P Young, Michael D Walsh, Mark Clendenning, Rhiannon J Walters, Sally Pearson, Erika Pavluk, Belinda Nagler, David Pakenas, Jeremy R Jass, Mark A Jenkins, Aung Ko Win, Melissa C Southey, Susan Parry, John L Hopper, Graham G Giles, Elizabeth Williamson, Dallas R English, Daniel D Buchanan
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  ABSTRACT: KRAS-mutated carcinomas comprise 35-40% of all colorectal carcinomas but little is known about their characteristics. The aim of this study was to examine the pathological and molecular features of KRAS-mutated colorectal carcinomas and to compare them with other carcinoma subgroups. KRAS mutation testing was performed in 776 incident tumors from the Melbourne Collaborative Cohort Study. O(6)-methylguanine DNA methyltransferase (MGMT) status was assessed using both immunohistochemistry and MethyLight techniques. Microsatellite instability (MSI) phenotype and BRAF V600E mutation status were derived from earlier studies. Mutation in KRAS codon 12 or codon 13 was present in 28% of colorectal carcinomas. Compared with KRAS wild-type carcinomas, KRAS-mutated carcinomas were more frequently observed in contiguity with a residual polyp (38 vs 21%; P<0.001), demonstrated mucinous differentiation (46 vs 31%; P=0.001) and were associated with different MSI status (P<0.001) and with MGMT methylation (47 vs 21%; P=0.001). Compared with tumors demonstrating neither BRAF nor KRAS mutation, KRAS-mutated carcinomas showed more frequent location in the proximal colon (41 vs 27%; P=0.001), mucinous differentiation (46 vs 25%; P<0.001), presence of a contiguous polyp (38 vs 22%; P<0.001), MGMT methylation (47 vs 26%; P=0.01) and loss of MGMT immunohistochemical expression (27 vs 19%; P=0.02). KRAS-mutated carcinomas were distributed in a bimodal pattern along the proximal-distal axis of the colorectum. Compared with male subjects, female subjects were more likely to have KRAS-mutated carcinoma in the transverse colon and descending colon (39 vs 15%; P=0.02). No difference in overall survival was observed in patients according to their tumor KRAS mutation status. In summary, KRAS-mutated carcinomas frequently develop in contiguity with a residual polyp and show molecular features distinct from other colorectal carcinomas, in particular from tumors with neither BRAF nor KRAS mutation.Modern Pathology advance online publication, 25 January 2013; doi:10.1038/modpathol.2012.240.
  Modern Pathology 01/2013; · 4.79 Impact Factor
• Article: Detection of large scale 3' deletions in the PMS2 gene amongst Colon-CFR participants: have we been missing anything?

  Mark Clendenning, Michael D Walsh, Judith Balmana Gelpi, Stephen N Thibodeau, Noralane Lindor, John D Potter, Polly Newcomb, Loic Lemarchand, Robert Haile, Steve Gallinger, John L Hopper, Mark A Jenkins, Christophe Rosty, Joanne P Young, Daniel D Buchanan
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  ABSTRACT: Current screening practices have been able to identify PMS2 mutations in 78 % of cases of colorectal cancer from the Colorectal Cancer Family Registry (Colon CFR) which showed solitary loss of the PMS2 protein. However the detection of large-scale deletions in the 3' end of the PMS2 gene has not been possible due to technical difficulties associated with pseudogene sequences. Here, we utilised a recently described MLPA/long-range PCR-based approach to screen the remaining 22 % (n = 16) of CRC-affected probands for mutations in the 3' end of the PMS2 gene. No deletions encompassing any or all of exons 12 through 15 were identified; therefore, our results suggest that 3' deletions in PMS2 are not a frequent occurrence in such families.
  Familial Cancer 01/2013; · 1.30 Impact Factor
• Article: Cancer risks for MLH1 and MSH2 mutation carriers.

  James G Dowty, Aung K Win, Daniel D Buchanan, Noralane M Lindor, Finlay A Macrae, Mark Clendenning, Yoland C Antill, Stephen N Thibodeau, Graham Casey, Steve Gallinger, [......], Barbara A Leggett, Michael Gattas, Alex Boussioutas, Dennis J Ahnen, John A Baron, Susan Parry, Jack Goldblatt, Joanne P Young, John L Hopper, Mark A Jenkins
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  ABSTRACT: 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 to age 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 to age 70 years estimated to follow U-shaped distributions. For example 17% of male MSH2 mutation carriers have estimated lifetime risks of 0-10% while 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.
  Human Mutation 12/2012; · 5.69 Impact Factor
• Article: Multiplicity and Molecular Heterogeneity of Colorectal Carcinomas in Individuals With Serrated Polyposis.

  Christophe Rosty, Michael D Walsh, Rhiannon J Walters, Mark Clendenning, Sally-Ann Pearson, Mark A Jenkins, Aung Ko Win, John L Hopper, Kevin Sweet, Wendy L Frankel, [......], Jack Goldblatt, Kathy Tucker, Sian Greening, Michael R Gattas, Sonja Woodall, Julie Arnold, Neal I Walker, Susan Parry, Joanne P Young, Daniel D Buchanan
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  ABSTRACT: 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.
  The American journal of surgical pathology 12/2012; · 4.06 Impact Factor
• Article: A Multifactorial Likelihood Model for MMR Gene Variant Classification Incorporating Probabilities Based on Sequence Bioinformatics and Tumor Characteristics: A Report from the Colon Cancer Family Registry.

  Bryony A Thompson, David E Goldgar, Carol Paterson, Mark Clendenning, Rhiannon Walters, Sven Arnold, Michael T Parsons, D Michael, Steven Gallinger, Robert W Haile, John L Hopper, Mark A Jenkins, Loic Lemarchand, Noralane M Lindor, Polly A Newcomb, Stephen N Thibodeau, Joanne P Young, Daniel D Buchanan, Sean V Tavtigian, Amanda B Spurdle
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  ABSTRACT: Mismatch repair (MMR) gene sequence variants of uncertain clinical significance are often identified in suspected Lynch syndrome families, and this constitutes a challenge for both researchers and clinicians. Multifactorial likelihood model approaches provide a quantitative measure of MMR variant pathogenicity, but first require input of likelihood ratios (LRs) for different MMR variation-associated characteristics from appropriate, well-characterized reference datasets. Microsatellite instability (MSI) and somatic BRAF tumor data for unselected colorectal cancer probands of known pathogenic variant status were used to derive LRs for tumor characteristics using the Colon Cancer Family Registry (CFR) resource. These tumor LRs were combined with variant segregation within families, and estimates of prior probability of pathogenicity based on sequence conservation and position, to analyze 44 unclassified variants identified initially in Australasian Colon CFR families. In addition, in vitro splicing analyses were conducted on the subset of variants based on bioinformatic splicing predictions. The LR in favor of pathogenicity was estimated to be ∼12-fold for a colorectal tumor with a BRAF mutation-negative MSI-H phenotype. For 31 of the 44 variants, the posterior probabilities of pathogenicity were such that altered clinical management would be indicated. Our findings provide a working multifactorial likelihood model for classification that carefully considers mode of ascertainment for gene testing.
  Human Mutation 09/2012; · 5.69 Impact Factor
• Article: Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome.

  Aung Ko Win, Noralane M Lindor, Joanne P Young, Finlay A Macrae, Graeme P Young, Elizabeth Williamson, Susan Parry, Jack Goldblatt, Lara Lipton, Ingrid Winship, [......], Mark Clendenning, Christophe Rosty, Julie Arnold, A Joan Levine, Robert W Haile, Steven Gallinger, Loïc Le Marchand, Polly A Newcomb, John L Hopper, Mark A Jenkins
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  ABSTRACT: Background Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers. Methods We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan-Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period-specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population. Results Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97). Conclusion Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.
  CancerSpectrum Knowledge Environment 08/2012; 104(18):1363-72. · 14.07 Impact Factor
• Article: Recurrent and founder mutations in the PMS2 gene.

  J Tomsic, L Senter, S Liyanarachchi, M Clendenning, C P Vaughn, M A Jenkins, J L Hopper, J Young, W Samowitz, A de la Chapelle
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  ABSTRACT: Germline mutations in PMS2 are associated with Lynch syndrome (LS), the most common known cause of hereditary colorectal cancer. Mutation detection in PMS2 has been difficult due to the presence of several pseudogenes, but a custom-designed long-range PCR strategy now allows adequate mutation detection. Many mutations are unique. However, some mutations are observed repeatedly across individuals not known to be related due to the mutation being either recurrent, arising multiple times de novo at hot spots for mutations, or of founder origin, having occurred once in an ancestor. Previously, we observed 36 distinct mutations in a sample of 61 independently ascertained Caucasian probands of mixed European background with PMS2 mutations. Eleven of these mutations were detected in more than one individual not known to be related and of these, six were detected more than twice. These six mutations accounted for 31 (51%) ostensibly unrelated probands. Here, we performed genotyping and haplotype analysis in four mutations observed in multiple probands and found two (c.137G>T and exon 10 deletion) to be founder mutations and one (c.903G>T) a probable founder. One (c.1A>G) could not be evaluated for founder mutation status. We discuss possible explanations for the frequent occurrence of founder mutations in PMS2.
  Clinical Genetics 05/2012; · 3.13 Impact Factor
• Article: Cancer risks for relatives of patients with serrated polyposis.

  Aung Ko Win, Rhiannon J Walters, Daniel D Buchanan, Mark A Jenkins, Kevin Sweet, Wendy L Frankel, Albert de la Chapelle, Diane M McKeone, Michael D Walsh, Mark Clendenning, [......], Sian Greening, Steve Gallinger, Melyssa Aronson, Renee Perrier, Michael O Woods, Jane S Green, Neal Walker, Christophe Rosty, Susan Parry, Joanne P Young
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  ABSTRACT: Serrated polyposis (hyperplastic polyposis) is characterized by multiple polyps with serrated architecture in the colorectum. Although patients with serrated polyposis are known to be at increased risk of colorectal cancer (CRC) and possibly extracolonic cancers, cancer risk for their relatives has not been widely explored. The aim of this study was to estimate the risks of CRC and extracolonic cancers for relatives of patients with serrated polyposis. A cohort of the 1,639 first- and second-degree relatives of 100 index patients with serrated polyposis recruited regardless of a family history of polyps or cancer from genetic clinics in Australia, New Zealand, Canada, and the USA, were retrospectively analyzed to estimate the country-, age-, and sex-specific standardized incidence ratios (SIRs) for relatives compared with the general population. A total of 102 CRCs were observed in first- and second-relatives (SIR 2.25, 95% confidence interval (CI) 1.75-2.93; P<0.001), with 54 in first-degree relatives (SIR 5.16, 95% CI 3.70-7.30; P<0.001) and 48 in second-degree relatives (SIR 1.38, 95% CI 1.01-1.91; P=0.04). Six pancreatic cancers were observed in first-degree relatives (SIR 3.64, 95% CI 1.70-9.21; P=0.003). There was no statistical evidence of increased risk for cancer of the stomach, brain, breast, or prostate. Our finding that relatives of serrated polyposis patients are at significantly increased risk of colorectal and pancreatic cancer adds to the accumulating evidence that serrated polyposis has an inherited component.
  The American Journal of Gastroenterology 04/2012; 107(5):770-8. · 7.28 Impact Factor
• Article: Phenotype and polyp landscape in serrated polyposis syndrome: a series of 100 patients from genetics clinics.

  Christophe Rosty, Daniel D Buchanan, Michael D Walsh, Sally-Ann Pearson, Erika Pavluk, Rhiannon J Walters, Mark Clendenning, Kevin J Spring, Mark A Jenkins, Aung K Win, [......], Wendy L Frankel, Melyssa Aronson, Steve Gallinger, Jack Goldblatt, Sonja Woodall, Julie Arnold, Neal I Walker, Jeremy R Jass, Susan Parry, Joanne P Young
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  ABSTRACT: Serrated polyposis syndrome (SPS), also known as hyperplastic polyposis, is a syndrome of unknown genetic basis defined by the occurrence of multiple serrated polyps in the large intestine and associated with an increased risk of colorectal cancer (CRC). There are a variety of SPS presentations, which may encompass a continuum of phenotypes modified by environmental and genetic factors. To explore the phenotype of SPS, we recorded the histologic and molecular characteristics of multiple colorectal polyps in patients with SPS recruited between 2000 and 2010 from genetics clinics in Australia, New Zealand, Canada, and the United States. Three specialist gastrointestinal pathologists reviewed the polyps, which they classified into conventional adenomas or serrated polyps, with various subtypes, according to the current World Health Organization criteria. Mutations in BRAF and KRAS and mismatch repair protein expression were determined in a subset of polyps. A total of 100 patients were selected for the study, of whom 58 were female and 42 were male. The total polyp count per patient ranged from 6 to 150 (median 30). The vast majority of patients (89%) had polyposis affecting the entire large intestine. From this cohort, 406 polyps were reviewed. Most of the polyps (83%) were serrated polyps: microvesicular hyperplastic polyps (HP) (n=156), goblet cell HP (n=25), sessile serrated adenoma/polyps (SSA/P) (n=110), SSA/P with cytologic dysplasia (n=28), and traditional serrated adenomas (n=18). A further 69 polyps were conventional adenomas. BRAF mutation was mainly detected in SSA/P with dysplasia (95%), SSA/P (85%), microvesicular HP (76%), and traditional serrated adenoma (54%), whereas KRAS mutation was present mainly in goblet cell HP (50%) and in tubulovillous adenoma (45%). Four of 6 SSA/Ps with high-grade dysplasia showed loss of MLH1/PMS2 expression. CRC was diagnosed in 39 patients who were more often found to have a conventional adenoma compared with patients without CRC (P=0.003). Patients with SPS referred to genetics clinics had a pancolonic disease with a high polyp burden and a high rate of BRAF mutation. The occurrence of CRC was associated with the presence of conventional adenoma.
  The American journal of surgical pathology 04/2012; 36(6):876-82. · 4.06 Impact Factor
• Article: Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study.

  Aung Ko Win, Joanne P Young, Noralane M Lindor, Katherine M Tucker, Dennis J Ahnen, Graeme P Young, Daniel D Buchanan, Mark Clendenning, Graham G Giles, Ingrid Winship, [......], Shanaka R Gunawardena, Bharati Bapat, John A Baron, Graham Casey, Steven Gallinger, Loïc Le Marchand, Polly A Newcomb, Robert W Haile, John L Hopper, Mark A Jenkins
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  ABSTRACT: To determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population. We prospectively followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161; MSH2, n = 222; MSH6, n = 47; and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country-, age-, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers. Over a median follow-up of 5 years, mutation carriers had an increased risk of colorectal cancer (CRC; SIR, 20.48; 95% CI, 11.71 to 33.27; P < .001), endometrial cancer (SIR, 30.62; 95% CI, 11.24 to 66.64; P < .001), ovarian cancer (SIR, 18.81; 95% CI, 3.88 to 54.95; P < .001), renal cancer (SIR, 11.22; 95% CI, 2.31 to 32.79; P < .001), pancreatic cancer (SIR, 10.68; 95% CI, 2.68 to 47.70; P = .001), gastric cancer (SIR, 9.78; 95% CI, 1.18 to 35.30; P = .009), urinary bladder cancer (SIR, 9.51; 95% CI, 1.15 to 34.37; P = .009), and female breast cancer (SIR, 3.95; 95% CI, 1.59 to 8.13; P = .001). We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (SIR, 1.02; 95% CI, 0.33 to 2.39; P = .97). We confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives.
  Journal of Clinical Oncology 02/2012; 30(9):958-64. · 18.37 Impact Factor
• Article: Immunohistochemical testing of conventional adenomas for loss of expression of mismatch repair proteins in Lynch syndrome mutation carriers: a case series from the Australasian site of the colon cancer family registry.

  Michael D Walsh, Daniel D Buchanan, Sally-Ann Pearson, Mark Clendenning, Mark A Jenkins, Aung Ko Win, Rhiannon J Walters, Kevin J Spring, Belinda Nagler, Erika Pavluk, [......], John L Hopper, Jeremy R Jass, John A Baron, Dennis J Ahnen, Stephen N Thibodeau, Noralane Lindor, Susan Parry, Neal I Walker, Christophe Rosty, Joanne P Young
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  ABSTRACT: Debate continues as to the usefulness of assessing adenomas for loss of mismatch repair protein expression to identify individuals with suspected Lynch syndrome. We tested 109 polyps from 69 proven mutation carriers (35 females and 34 males) belonging to 49 Lynch syndrome families. All polyps were tested by immunohistochemistry for four mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. Detailed pathology review was performed by specialist gastrointestinal pathologists. The majority of polyps (86%) were conventional adenomas (n=94), with 65 tubular and 28 tubulovillous adenomas and a single villous adenoma. The remaining 15 lesions (14%) were serrated polyps. Overall, loss of mismatch repair expression was noted for 78/109 (72%) of polyps. Loss of mismatch repair expression was seen in 74 of 94 (79%) conventional adenomas, and 4 of 15 (27%) serrated polyps from mismatch repair gene mutation carriers. In all instances, loss of expression was consistent with the underlying germline mutation. Mismatch repair protein expression was lost in 27 of 29 adenomas with a villous component compared with 47 of 65 adenomas without this feature (93 vs 73%; P=0.028). A strong trend was observed for high-grade dysplasia. Mismatch repair deficiency was observed in 12 of 12 conventional adenomas with high-grade dysplasia compared with 60 of 79 with low-grade dysplasia (100 vs 76%; P=0.065). We were unable to demonstrate a significant association between conventional adenoma size or site and mismatch repair deficiency. All (4/4 or 100%) of the serrated polyps demonstrating mismatch repair deficiency were traditional serrated adenomas from a single family. Diagnostic testing of adenomas in suspected Lynch syndrome families is a useful alternative in cases where cancers are unavailable. The overwhelming majority of conventional adenomas from mutation carriers show loss of mismatch repair protein expression concordant with the underlying germline mutation.
  Modern Pathology 02/2012; 25(5):722-30. · 4.79 Impact Factor
• Article: Determining the frequency of de novo germline mutations in DNA mismatch repair genes.

  Aung Ko Win, Mark A Jenkins, Daniel D Buchanan, Mark Clendenning, Joanne P Young, Graham G Giles, Jack Goldblatt, Barbara A Leggett, John L Hopper, Stephen N Thibodeau, Noralane M Lindor
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  ABSTRACT: Carriers of a germline mutation in a DNA mismatch repair (MMR) gene--that is, persons with Lynch syndrome--have substantially high risks of colorectal (CRC), endometrial, and several other cancers. The proportion of carriers who have de novo mutations (not inherited from either parent) is not known. This study reports a case series of de novo mutations in MMR genes and estimates the frequency of de novo mutation in MMR genes using the Colon Cancer Family Registry. Screening for germline MLH1, MSH2, MSH6, and PMS2 mutations was performed for all incident CRC cases recruited from cancer registries (population based probands) displaying microsatellite instability (MSI) or loss of expression of MMR genes by immunohistochemistry (IHC) and probands with CRC in multi-case families recruited from clinics (clinic based probands), regardless of MSI or IHC status. All relatives of probands with a pathogenic mutation who donated a blood sample underwent testing for the mutation identified in the proband. Of 261 probands (202 clinic based, 59 population based) with MMR gene mutations for whom it was possible to determine the origin of the mutation, six (2.3%, 95% CI 0.9% to 5.0%) were confirmed as de novo, and the remaining 255 (97.7%, 95% CI 95.0% to 99.1%) were inherited. Of the de novo mutation carriers, three were clinic based probands (1.5%, 95% CI 0.3% to 4.5%) and three were population based probands (5.1%, 95% CI 1.2% to 14.5%). Two were in MLH1, three in MSH2, and one in MSH6. De novo MMR gene mutations are uncommon causes of Lynch syndrome.
  Journal of Medical Genetics 06/2011; 48(8):530-4. · 6.36 Impact Factor
• Article: Mutation deep within an intron of MSH2 causes Lynch syndrome.

  Mark Clendenning, Daniel D Buchanan, Michael D Walsh, Belinda Nagler, Christophe Rosty, Bryony Thompson, Amanda B Spurdle, John L Hopper, Mark A Jenkins, Joanne P Young
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  ABSTRACT: Lynch syndrome, a heritable form of cancer predisposition, is caused by germline mutations within genes of the DNA mismatch repair family, and can be rapidly identified in young onset cancer patients through the detection of loss of expression of at least one of these genes in tumour samples. To date, such causative mutations have only been identified within exonic and splice site regions. Though this approach has been successful in the majority of families, a considerable number remain in which no mutation has been found. To address this situation, we used an alternative mutation discovery procedure which involved haplotype analysis of the locus containing the gene lost in the tumour and delineation of segregating haplotypes, followed by an investigation of splicing aberrations to uncover cryptic splice sites which lay outside the genomic regions routinely examined for mutations. In this report, we show that an intronic mutation 478 bp upstream of exon 2 in the MSH2 gene causes Lynch syndrome through creation of a novel splice donor site with subsequent pseudoexon activation, thus highlighting the need for more extensive sequencing approaches in families where routine procedures fail to find a mutation.
  Familial Cancer 03/2011; 10(2):297-301. · 1.30 Impact Factor
• Article: Hepatic adenomas caused by somatic HNF1A mutations in children with biallelic mismatch repair gene mutations.

  Spring Holter, Aaron Pollett, George Zogopoulos, Hyeja Kim, Frank Schwenter, Kengo Asai, Steven Gallinger, Mark Clendenning, Gideon Steinbach, Angela Jacobson, Kym M Boycott
  Gastroenterology 02/2011; 140(2):735-6. · 11.68 Impact Factor
• Source

  Available from: Michael Gattas

  Article: Linkage to chromosome 2q32.2-q33.3 in familial serrated neoplasia (Jass syndrome).

  Aedan Roberts, Derek Nancarrow, Mark Clendenning, Daniel D Buchanan, Mark A Jenkins, David Duggan, Darin Taverna, Diane McKeone, Rhiannon Walters, Michael D Walsh, [......], Julie Arnold, Kathy Tucker, Amanda Muir, Musa Drini, Finlay Macrae, Polly Newcomb, John D Potter, Erika Pavluk, Annika Lindblom, Joanne P Young
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  ABSTRACT: Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.
  Familial Cancer 12/2010; 10(2):245-54. · 1.30 Impact Factor
• Article: Erratum to: Phenotypic diversity in patients with multiple serrated polyps: a genetics clinic study.

  Daniel D Buchanan, Kevin Sweet, Musa Drini, Mark A Jenkins, Aung Ko Win, Michael Gattas, Michael D Walsh, Mark Clendenning, Diane McKeone, Rhiannon Walters, [......], Sian Greening, Steven Gallinger, Jane Green, Michael O Woods, Renee Spaetgens, Albert de la Chapelle, Finlay Macrae, Neal I Walker, Jeremy R Jass, Joanne P Young
  International Journal of Colorectal Disease 10/2010; · 2.38 Impact Factor