Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers

Sharp characters of finite groups

AbstractIf χ is a virtual (generalized) character of a finite group G, with n=χ and L={χ(g)|g∈G, g≠1 {χ(g)¦gϵG, g ≠ 1}, then ¦G¦ dividesfL(n), where fL(x) is the monic polynomial of least degree having L as its set of roots. (This generalises a result of the second author for permutation characters.) We say that the pair ((G,χ)) is L-sharp if ¦G¦=fL(n). We characterise the L-sharp pairs for various sets L, sometimes under additional hypotheses, and give a number of examples

MSS0005. McCarthy family photographs finding aid

The collection comprises 33 black and white photographs and two Memphis, Tennessee, postcards. The photographs mostly feature accountant James T. McCarthy and his wife Anna L. Sharp McCarthy of Memphis

On sharp characters of rank 2 with rational values

AbstractFor a finite group G and its character χ, let L be the set of distinct values of χ on non-identity elements of G and fL(χ(1)) denote the monic polynomial of least degree having L as its set of roots. Blichfeldt [A theorem concerning the invariants of linear homogeneous groups with some applications to substitution groups, Trans. Amer. Math. Soc. 5 (1904) 461–466. [2]] showed that fL(χ(1))/|G| is a rational integer. Cameron and Kiyota [Sharp character of finite groups, J. Algebra 115 (1988) 125–143] called the pair (G,χ) L-sharp if |G|=fL(χ(1)) and posed the problem of determining all the L-sharp pairs (G,χ) for a given set L. For several cases those problems have already been studied by many authors. Our purpose is to determine the sharp pairs of types {−2,1} and {−1,2} having non-trivial center

Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women

<p>Abstract</p> <p>Background</p> <p>Several studies have determined that dietary intake of B vitamins may be associated with breast cancer risk as a result of interactions between <it>5,10-methylenetetrahydrofolate reductase (MTHFR) </it>and <it>methionine synthase </it>(<it>MTR</it>) in the one-carbon metabolism pathway. However, the association between B vitamin intake and breast cancer risk in Brazilian women in particular has not yet been investigated.</p> <p>Methods</p> <p>A case-control study was conducted in São Paulo, Brazil, with 458 age-matched pairs of Brazilian women. Energy-adjusted intakes of folate, vitamin B₆, and vitamin B₁₂were derived from a validated Food Frequency Questionnaire (FFQ). Genotyping was completed for <it>MTHFR </it>A1298C and C677T, and <it>MTR </it>A2756G polymorphisms. A logistical regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs).</p> <p>Results</p> <p>Neither dietary intake of folate, vitamin B₆, or vitamin B₁₂nor <it>MTHFR </it>polymorphisms were independently associated with breast cancer risk. Analysis stratified by menopausal status showed a significant association between placement in the highest tertile of folate intake and risk of breast cancer in premenopausal women (OR = 2.17, 95% CI: 1.23–3.83; <it>P</it>_{<it>trend </it>}= 0.010). The <it>MTR </it>2756GG genotype was associated with a higher risk of breast cancer than the 2756AA genotype (OR = 1.99, 95% CI = 1.01–3.92; <it>P</it>_{<it>trend </it>}= 0.801), and statistically significant interactions with regard to risk were observed between the <it>MTHFR </it>A1298C polymorphism and folate (P = 0.024) or vitamin B₆(P = 0.043), and between the <it>MTHFR </it>C677T polymorphism and folate (P = 0.043) or vitamin B₁₂(P = 0.022).</p> <p>Conclusion</p> <p><it>MTHFR </it>polymorphisms and dietary intake of folate, vitamin B₆, and vitamin B₁₂had no overall association with breast cancer risk. However, increased risk was observed in total women with the <it>MTR </it>2756GG genotype and in premenopausal women with high folate intake. These findings, as well as significant interactions between <it>MTHFR </it>polymorphisms and B vitamins, warrant further investigation.</p

The changing association between socioeconomic circumstances and the incidence of colorectal cancer: a population-based study

Background:There is emerging evidence to suggest that the association between socioeconomic circumstances and colorectal cancer incidence has changed over recent decades.Methods:We conducted a descriptive population-based study to describe the relationship between socioeconomic circumstances and the incidence of colorectal cancer in a pre-screened population. Incident cases of colorectal cancer from the West of Scotland were identified from the Scottish Cancer Registry and European age-standardised incidence rates (EASR) were calculated. Socioeconomic circumstances were measured using the area-based Scottish Index of Multiple Deprivation (SIMD).Results:In total, 14?051 incident cases of colorectal cancer were recorded from 1999 to 2007. Incidence of colorectal cancer was associated with increased deprivation in men but not among women; an association that became evident from 2005 onwards. From 2005 to 2007, the deprivation gap in incidence among men was 13.3 per 100?000 (95% confidence interval 3.2-23.4), with rates 19.5% lower among the least deprived compared with the most deprived. This deprivation gap now accounts for an estimated 75 excess cases per year of male colorectal cancer in the West of Scotland.Conclusion:Deprivation was associated with higher incidence rates of male, but not female, colorectal cancer before the implementation of a national bowel screening programme

Rural factors and survival from cancer: analysis of Scottish cancer registrations

In this survival study 63 976 patients diagnosed with one of six common cancers in Scotland were followed up. Increasing distance from a cancer centre was associated with less chance of diagnosis before death for stomach, breast and colorectal cancers and poorer survival after diagnosis for prostate and lung cancers. © 2000 Cancer Research Campaig

The utility and predictive value of combinations of low penetrance genes for screening and risk prediction of colorectal cancer

Despite the fact that colorectal cancer (CRC) is a highly treatable form of cancer if detected early, a very low proportion of the eligible population undergoes screening for this form of cancer. Integrating a genomic screening profile as a component of existing screening programs for CRC could potentially improve the effectiveness of population screening by allowing the assignment of individuals to different types and intensities of screening and also by potentially increasing the uptake of existing screening programs. We evaluated the utility and predictive value of genomic profiling as applied to CRC, and as a potential component of a population-based cancer screening program. We generated simulated data representing a typical North American population including a variety of genetic profiles, with a range of relative risks and prevalences for individual risk genes. We then used these data to estimate parameters characterizing the predictive value of a logistic regression model built on genetic markers for CRC. Meta-analyses of genetic associations with CRC were used in building science to inform the simulation work, and to select genetic variants to include in logistic regression model-building using data from the ARCTIC study in Ontario, which included 1,200 CRC cases and a similar number of cancer-free population-based controls. Our simulations demonstrate that for reasonable assumptions involving modest relative risks for individual genetic variants, that substantial predictive power can be achieved when risk variants are common (e.g., prevalence > 20%) and data for enough risk variants are available (e.g., ~140–160). Pilot work in population data shows modest, but statistically significant predictive utility for a small collection of risk variants, smaller in effect than age and gender alone in predicting an individual’s CRC risk. Further genotyping and many more samples will be required, and indeed the discovery of many more risk loci associated with CRC before the question of the potential utility of germline genomic profiling can be definitively answered