97 research outputs found
First principles calculations of transition metal complexes for artificial photosynthesis
No full textNanoscale devices using transition metals have shown promise in the renewable energy context for their robustness and scalability. In artificial photosynthetic devices, light harvesting molecules drive reactions which create fuel (e.g by splitting water). For optimal fuel generation efficiency a long charge transfer excited state lifetime is necessary. Additionally, an absorption peak in the visible region is required for the molecule to absorb sunlight. To investigate the absorption peak and properties associated with the excited state lifetime of light harvesting molecules, a workflow has been developed using a combination of first principles techniques and analysis code. In the development of the workflow, this study focused on a vanadium(V) oxo compound VOLF which has been experimentally synthesized by collaborators. To fully understand the properties of this light absorbing molecule, it was studied using a variety of theoretical techniques and compared to experimental results obtained by collaborators.University of Ontario Institute of Technolog
Whatever Happened To . . . Tilden Rent-a-Car v. Clendenning
No full textAuthor has retained copyright on PDF of article. Article deposited after permission was obtained by CPLEA 01/30/15Ye
Aspirin, ibuprofen, and the risk of colorectal cancer in Lynch Syndrome
No full textBackground: Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 causes a high risk of colorectal and other cancers (Lynch Syndrome). Use of aspirin has been shown to be associated with a reduced risk of colorectal cancer for the general population as well as for MMR gene mutation carriers. The aim of this study was to determine whether use of aspirin and ibuprofen in a nontrial setting is associated with the risk of colorectal cancer risk for MMR gene mutation carriers. Methods: We included 1858 participants in the Colon Cancer Family Registry who had been found to have a pathogenic germline mutation in a MMR gene (carriers). We used weighted Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results: A total of 714 carriers (38%) were diagnosed with colorectal cancer at a mean age of 42.4 (standard deviation 10.6) years. A reduced risk of colorectal cancer was associated with aspirin use (for 1 month to 4.9 years: HR = 0.49, 95% CI = 0.27 to 0.90, P = .02; for ≥5 years: HR = 0.25, 95% CI = 0.10 to 0.62, P = .003) and ibuprofen use (for 1 month to 4.9 years: HR = 0.38, 95% CI = 0.18 to 0.79, P = .009; for ≥5 years: HR = 0.26, 95% CI = 0.10 to 0.69, P = .007), compared with less than one month of use. Conclusion: Our results provide additional evidence that, for MMR gene mutation carriers, use of aspirin and ibuprofen might be effective in reducing their high risk of colorectal cancer.Driss Ait Ouakrim, Seyedeh Ghazaleh Dashti, Rowena Chau, Daniel D. Buchanan, Mark Clendenning, Christophe Rosty, Ingrid M. Winship, Joanne P. Young, Graham G. Giles, Barbara Leggett, Finlay A. Macrae, Dennis J. Ahnen, Graham Casey, Steven Gallinger, Robert W. Haile, Loïc Le Marchand, Stephen N. Thibodeau, Noralane M. Lindor, Polly A. Newcomb, John D. Potter, John A. Baron, John L. Hopper, Mark A. Jenkins and Aung Ko Wi
Multivitamin, calcium and folic acid supplements and the risk of colorectal cancer in Lynch syndrome
No full textBackground: People with a DNA mismatch repair (MMR) gene mutation have a substantially elevated risk of colorectal cancer (CRC) but the modifiers of this risk are not well established. We investigated the association between dietary supplement intake and CRC risk for carriers. Methods: This study included 1966 (56% female) carriers of an MMR gene mutation (719 MLH1, 931 MSH2, 211 MSH6 and 105 PMS2) who were recruited from the USA, Canada, Australia and New Zealand into the Colon Cancer Family Registry between 1997 and 2012. Information on lifestyle factors including supplement intake was collected at the time of recruitment. Using Cox proportional hazards regression weighted to correct for ascertainment bias, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between self-reported multivitamin, calcium and folic acid supplement intake and CRC risk. Results: Of 744 carriers with CRC, 18%, 6% and 5% reported intake of multivitamin, calcium and folic acid supplements for at least 1 month, respectively, compared with 27%, 11% and 10% of 1222 carriers without CRC. After adjusting for identified confounding variables, a decreased CRC risk was associated with multivitamin intake for at least 3 years (HR 0.47, 95% CI 0.32-0.69) and calcium intake for at least 3 years(HR 0.42, 95% CI 0.23-0.74), compared with never users. There was no evidence of an association between folic acid supplement intake and CRC risk (P = 0.82). Conclusion: Intake of multivitamin and calcium supplements might be associated with a decreased risk of CRC for MMR gene mutation carriers.Rowena Chau, Seyedeh Ghazaleh Dashti, Driss Ait Ouakrim, Daniel D Buchanan, Mark Clendenning, Christophe Rosty, Ingrid M Winship, Joanne P Young, Graham G Giles, Finlay A Macrae, Alex Boussioutas, Susan Parry, Jane C Figueiredo, A Joan Levine, Dennis J Ahnen, Graham Casey, Robert W Haile, Steven Gallinger, Loïc C Le Marchand, Stephen N Thibodeau, Noralane M Lindor, Polly A Newcomb, John D Potter, John A Baron, John L Hopper, Mark A Jenkins, and Aung Ko Wi
Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer
No full textWe studied 2332 individuals with monoallelic mutations in MUTYH among 9504 relatives of 264 colorectal cancer (CRC) cases with a MUTYH mutation. We estimated CRC risks through 70 years of age of 7.2% for male carriers of monoallelic mutations (95% confidence interval [CI], 4.6%-11.3%) and 5.6% for female carriers of monoallelic mutations (95% CI, 3.6%-8.8%), irrespective of family history. For monoallelic MUTYH mutation carriers with a first-degree relative with CRC diagnosed by 50 years of age who does not have the MUTYH mutation, risks of CRC were 12.5% for men (95% CI, 8.6%-17.7%) and 10% for women (95% CI, 6.7%-14.4%). Risks of CRC for carriers of monoallelic mutations in MUTYH with a first-degree relative with CRC are sufficiently high to warrant more intensive screening than for the general population.Aung Ko Win, James G. Dowty, Sean P. Cleary, Hyeja Kim, Daniel D. Buchanan, Joanne P. Young, Mark Clendenning, Christophe Rosty, Robert J. MacInnis, Graham G. Giles, Alex Boussioutas, Finlay A. Macrae, Susan Parry, Jack Goldblatt, John A. Baron, Terrilea Burnett, Loïc Le Marchand, Polly A. Newcomb, Robert W. Haile, John L. Hopper, Michelle Cotterchio, Steven Gallinger, Noralane M. Lindor, Katherine M. Tucker, Ingrid M. Winship, Mark A. Jenkin
PIK3CA activating mutation in colorectal carcinoma: associations with molecular features and survival
No full textMutations in PIK3CA are present in 10 to 15% of colorectal carcinomas. We aimed to examine how PIK3CA mutations relate to other molecular alterations in colorectal carcinoma, to pathologic phenotype and survival. PIK3CA mutation testing was carried out using direct sequencing on 757 incident tumors from the Melbourne Collaborative Cohort Study. The status of O-6-methylguanine-DNA methyltransferase (MGMT) was assessed using both immunohistochemistry and methyLight techniques. Microsatellite instability, CpG island phenotype (CIMP), KRAS and BRAF V600E mutation status, and pathology review features were derived from previous reports. PIK3CA mutation was observed in 105 of 757 (14%) of carcinomas, characterized by location in the proximal colon (54% vs. 34%; P<0.001) and an increased frequency of KRAS mutation (48% vs. 25%; P<0.001). High-levels of CIMP were more frequently found in PIK3CA-mutated tumors compared with PIK3CA wild-type tumors (22% vs. 11%; P = 0.004). There was no difference in the prevalence of BRAF V600E mutation between these two tumor groups. PIK3CA-mutated tumors were associated with loss of MGMT expression (35% vs. 20%; P = 0.001) and the presence of tumor mucinous differentiation (54% vs. 32%; P<0.001). In patients with wild-type BRAF tumors, PIK3CA mutation was associated with poor survival (HR 1.51 95% CI 1.04-2.19, P = 0.03). In summary, PIK3CA-mutated colorectal carcinomas are more likely to develop in the proximal colon, to demonstrate high levels of CIMP, KRAS mutation and loss of MGMT expression. PIK3CA mutation also contributes to significantly decreased survival for patients with wild-type BRAF tumors.Christophe Rosty, Joanne P. Young, Michael D. Walsh, Mark Clendenning, Kristy Sanderson, Rhiannon J. Walters, Susan Parry, Mark A. Jenkins, Aung Ko Win, Melissa C. Southey, John L. Hopper, Graham G. Giles, Elizabeth J. Williamson, Dallas R. English, Daniel D. Buchana
Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene
No full textPublished online: 23 July 2015The base excision repair protein, MUTYH, functionally interacts with the DNA mismatch repair (MMR) system. As genetic testing moves from testing one gene at a time, to gene panel and whole exome next generation sequencing approaches, understandin g the risk associated with co-existence of germline mutations in these genes will be important for clinical interpretation and management. From the Colon Cancer Family Registry, we identified 10 carriers who had both a MUTYH mutation (6 with c.1187G>A p.(Gly396Asp), 3 with c.821G>A p.(Arg274Gln), and 1 with c.536A>G p.(Tyr179Cys)) and a MMR gene mutation (3 in MLH1, 6 in MSH2, and 1 in PMS2), 375 carriers of a single (monoallelic) MUTYH mutation alone, and 469 carriers of a MMR gene mutation alone. Of the 10 carriers of both gene mutations, 8 were diagnosed with colorectal cancer. Using a weighted cohort analysis, we estimated that risk of colorectal cancer for carriers of both a MUTYH and a MMR gene mutation was substantially higher than that for carriers of a MUTYH mutation alone [hazard ratio (HR) 21.5, 95% confidence interval (CI) 9.19-50.1; p < 0.001], but not different from that for carriers of a MMR gene mutation alone (HR 1.94, 95% CI 0.63-5.99; p = 0.25). Within the limited power of this study, there was no evidence that a monoallelic MUTYH gene mutation confers additional risk of colorectal cancer for carriers of a MMR gene mutation alone. Our finding suggests MUTYH mutation testing in MMR gene mutation carriers is not clinically informative.Aung Ko Win, Jeanette C. Reece, Daniel D. Buchanan, Mark Clendenning, Joanne P. Young, Sean P. Cleary, Hyeja Kim, Michelle Cotterchio, James G. Dowty, Robert J. MacInnis, Katherine M. Tucker, Ingrid M. Winship, Finlay A. Macrae, Terrilea Burnett, Loı, c Le Marchand, Graham Casey, Robert W. Haile, Polly A. Newcomb, Stephen N. Thibodeau, Noralane M. Lindor, John L. Hopper, Steven Gallinger, Mark A. Jenkin
Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH
No full textGermline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first- and 3,255 second-degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7-97) and ovarian cancer 17 (2.4-115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7-13); hepatobiliary cancer 4.5 (2.7-7.5); endometrial cancer 2.1 (1.1-3.9) and breast cancer 1.4 (1.0-2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5-77%) for males and 8% (2-33%) for females and ovarian cancer 14% (2-65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4-7%) for males and 2.3% (1.7-3.3%) for females; hepatobiliary cancer 3% (2-5%) for males and 1.4% (0.8-2.3%) for females; endometrial cancer 3% (2%-6%) and breast cancer 11% (8-16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.Aung Ko Win, Jeanette C. Reece, James G. Dowty, Daniel D. Buchanan, Mark Clendenning, Christophe Rosty, Melissa C. Southey, Joanne P. Young, Sean P. Cleary, Hyeja Kim, Michelle Cotterchio, Finlay A. Macrae, Katherine M. Tucker, John A. Baron, Terrilea Burnett, Loïc Le Marchand, Graham Casey, Robert W. Haile, Polly A. Newcomb, Stephen N. Thibodeau, John L. Hopper, Steven Gallinger, Ingrid M. Winship, Noralane M. Lindor, and Mark A. Jenkin
Role of tumour molecular and pathology features to estimate colorectal cancer risk for first-degree relatives
No full textOBJECTIVE: To estimate risk of colorectal cancer (CRC) for first-degree relatives of CRC cases based on CRC molecular subtypes and tumour pathology features. DESIGN: We studied a cohort of 33,496 first-degree relatives of 4853 incident invasive CRC cases (probands) who were recruited to the Colon Cancer Family Registry through population cancer registries in the USA, Canada and Australia. We categorised the first-degree relatives into four groups: 28,156 of 4095 mismatch repair (MMR)-proficient probands, 2302 of 301 MMR-deficient non-Lynch syndrome probands, 1799 of 271 suspected Lynch syndrome probands and 1239 of 186 Lynch syndrome probands. We compared CRC risk for first-degree relatives stratified by the absence or presence of specific tumour molecular pathology features in probands across each of these four groups and for all groups combined. RESULTS: Compared with first-degree relatives of MMR-proficient CRC cases, a higher risk of CRC was estimated for first-degree relatives of CRC cases with suspected Lynch syndrome (HR 2.06, 95% CI 1.59 to 2.67) and with Lynch syndrome (HR 5.37, 95% CI 4.16 to 6.94), but not with MMR-deficient non-Lynch syndrome (HR 1.04, 95% CI 0.82 to 1.31). A greater risk of CRC was estimated for first-degree relatives if CRC cases were diagnosed before age 50 years, had proximal colon cancer or if their tumours had any of the following: expanding tumour margin, peritumoral lymphocytes, tumour-infiltrating lymphocytes or synchronous CRC. CONCLUSIONS: Molecular pathology features are potentially useful to refine screening recommendations for first-degree relatives of CRC cases and to identify which cases are more likely to be caused by genetic or other familial factors.Aung Ko Win, Daniel D Buchanan, Christophe Rosty, Robert J MacInnis, James G Dowty, Gillian S Dite, Graham G Giles, Melissa C Southey, Joanne P Young, Mark Clendenning, Michael D Walsh, Rhiannon J Walters, Alex Boussioutas, Thomas C Smyrk, Stephen N Thibodeau, John A Baron, John D Potter, Polly A Newcomb, Loïc Le Marchand, Robert W Haile, Steven Gallinger, Noralane M Lindor, John L Hopper, Dennis J Ahnen, Mark A Jenkin
Abstract 4266: Double somatic mutations as a cause of tumor mismatch repair-deficiency in population-based colorectal and endometrial cancer with Lynch-like syndrome
No full textAbstract
Background: Tumour mismatch repair (MMR) deficiency, determined by immunohistochemical (IHC) loss of MMR protein expression, is used diagnostically to identify individuals with Lynch syndrome. A high proportion of colorectal cancers (CRCs) and endometrial cancers (ECs) that demonstrate tumor MMR-deficiency are categorised as having “Lynch-like syndrome” due to the absence of tumor MLH1 methylation or germline MMR gene mutations after standard screening approaches. The aim of this study was to investigate somatic causes of tumor MMR-deficiency in patients with Lynch-like syndrome.
Methods: Population-based participants with incident MMR-deficient colorectal (n=193; ACCFR and MCCS) or endometrial cancer (n=197; ANECS and MCCS) were categorised as either Lynch syndrome, MLH1 methylated or Lynch-like after screening for germline MMR gene mutations and for tumor MLH1 gene promoter hypermethylation. Lynch-like tumors were tested for somatic MMR gene mutations (point mutations and loss of heterozygosity) using AmpliSeq-Ion Proton custom capture sequencing and for MSH2 or MSH6 gene promoter methylation. Overall survival for molecularly defined subgroups of Lynch-like CRCs were compared to Lynch syndrome related CRCs using cox regression models to estimate hazard ratios (HR) and 95% confidence intervals adjusting for age at CRC diagnosis, sex, AJCC stage and grade.
Results: Lynch-like tumors comprised 32% (63/193) and 23% (45/197) of the MMR-deficient CRCs and ECs, respectively compared with 27% and 15% for Lynch syndrome and 41% and 62% for MLH1 methylated CRCs and ECs, respectively. Two somatic mutations were identified in the MMR gene indicated by the pattern of MMR IHC loss of expression were identified in 36.7% (18/49) and 47.8% (11/23) of the Lynch-like CRCs and ECs tested. The proportion of tumors with double somatic alterations was highest for both CRC and EC tumors showing MSH2-deficiency (40% and 64.3%). The mean age at diagnosis for the Lynch-like CRCs with double somatic mutations was 49.7 ± 15.8years which was not significantly different from the Lynch syndrome CRCs (n=52; 45.4 ± 11.3years; p=0.2) but was significantly different compared with the MLH1 methylated CRCs (n=83; 70 ± 8.9years; p=0.0001). The adjusted HR for double somatic Lynch-like CRCs was 2.58 (95% CI, 0.77-8.67) compared with Lynch syndrome CRCs (p=0.1). No evidence of tumor MSH2 or MSH6 gene promoter methylation was identified in either MSH2-deficient or MSH6-deficient Lynch-like CRCs or ECs tested (n=34 and n=12, respectively).
Conclusions: Double somatic mutations in the MMR genes represent a significant proportion of the unexplained Lynch-like MMR-deficient subtype for both population-based CRC and EC. Triaging strategies used to identify Lynch syndrome for both CRC and EC should include tumor testing for somatic mutations in the MMR genes.
Note: This abstract was not presented at the meeting.
Citation Format: Daniel D. Buchanan, Mark Clendenning, Harindra Jayasekara, Jihoon E. Joo, Ee M. Wong, Melissa C. Southey, Rhiannon J. Walters, Bernard J. Pope, Aung K. Win, John L. Hopper, Mark A. Jenkins, Roger L. Milne, Graham G. Giles, Dallas R. English, Finlay A. Macrae, Amanda B. Spurdle, Ingrid M. Winship, Christophe Rosty. Double somatic mutations as a cause of tumor mismatch repair-deficiency in population-based colorectal and endometrial cancer with Lynch-like syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4266. doi:10.1158/1538-7445.AM2017-4266</jats:p
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