946 research outputs found

    Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2 deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age

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    BACKGROUND: BRCA1 and BRCA2 mutations are found in a proportion of families with multiple early-onset breast cancers. There are a large number of different deleterious mutations in both genes, none of which would be detectable using standard genetic association studies. Single common variants and haplotypes of common variants may capture groups of deleterious mutations since some low prevalence haplotypes of common variants occur more frequently among chromosomes that carry rare, deleterious mutations than chromosomes that do not. METHODS: DNA sequence data for BRCA1 and BRCA2 was obtained from 571 participants from the Australian Breast Cancer Family Study. Genetic variants were classified as either deleterious mutations or common genetic variants. Variants tagging common polymorphisms were selected and haplotypes resolved using Haploview. Their frequency was compared to those with and without deleterious mutations using a permutation test. RESULTS: A common genetic variant in BRCA1 (3232A > G) was found to be over-represented in deleterious mutation carriers (p = 0.05), whereas a common genetic variant in BRCA2 (1342A > C) occurred less frequently in deleterious mutation carriers (p = 0.04). All four of the common BRCA1 variants used to form haplotypes occurred more frequently in the deleterious mutation carriers when compared to the non-carriers, but there was no evidence of a difference in the distributions between the two groups (p = 0.34). In BRCA2, all four common variants were found to occur less frequently in the deleterious mutation carriers when compared to non-carriers, but the evidence for difference in the distribution between the two groups was weak (p = 0.16). Several less common haplotypes of common BRCA1 variants were found to be over-represented among deleterious mutation carriers but there was no evidence for this at the population level. In BRCA2, only the most common haplotype was found to occur more frequently in deleterious mutation carriers, with again no evidence at the population level. CONCLUSIONS: We observed differences in the frequency of common genetic variants of the BRCA1 and BRCA2 and their haplotypes between early-onset breast cancer cases who did and did not carry deleterious mutations in these genes. Although our data provide only weak evidence for a difference in frequencies at the population level, the number of deleterious mutation carriers was low and the results may yet be substantiated in a larger study using pooled data

    Prospective Evaluation over 15 Years of Six Breast Cancer Risk Models.

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    Prospective validation of risk models is needed to assess their clinical utility, particularly over the longer term. We evaluated the performance of six commonly used breast cancer risk models (IBIS, BOADICEA, BRCAPRO, BRCAPRO-BCRAT, BCRAT, and iCARE-lit). 15-year risk scores were estimated using lifestyle factors and family history measures from 7608 women in the Melbourne Collaborative Cohort Study who were aged 50-65 years and unaffected at commencement of follow-up two (conducted in 2003-2007), of whom 351 subsequently developed breast cancer. Risk discrimination was assessed using the C-statistic and calibration using the expected/observed number of incident cases across the spectrum of risk by age group (50-54, 55-59, 60-65 years) and family history of breast cancer. C-statistics were higher for BOADICEA (0.59, 95% confidence interval (CI) 0.56-0.62) and IBIS (0.57, 95% CI 0.54-0.61) than the other models (p-difference ≤ 0.04). No model except BOADICEA calibrated well across the spectrum of 15-year risk (p-value < 0.03). The performance of BOADICEA and IBIS was similar across age groups and for women with or without a family history. For middle-aged Australian women, BOADICEA and IBIS had the highest discriminatory accuracy of the six risk models, but apart from BOADICEA, no model was well-calibrated across the risk spectrum.This work was primarily supported by grant 1129136 from the Australian National Health and Medical Research Council (NHMRC) (https://www.nhmrc.gov.au/). MCCS cohort recruitment was funded by Cancer Council Victoria (https://www.cancervic.org.au/) and VicHealth (https://www.vichealth.vic.gov.au/). The MCCS was further supported by Australian NHMRC grants 209057, 396414 and 1074383, and ongoing follow-up and data management has been funded by Cancer Council Victoria since 1995. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database.TN-D is a recipient of a Career Development Fellowship from the National Breast Cancer Foundation (Australia). JLH and MCS are Senior Principal and Senior Research Fellows of the National Health and Medical Research Council (Australia), respectively. ACA and AJL are supported by grants from Cancer Research UK (C12292/A20861 and PPRPGM19 Nov20\100002)

    Should the grading of colorectal adenocarcinoma include microsatellite instability status?

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    Adenocarcinomas of the colon and rectum are graded using a 2-tiered system into histologic low-grade and high-grade tumors based on the proportion of gland formation. The current grading system does not apply to subtypes of carcinomas associated with a high frequency of microsatellite instability (MSI), such as mucinous and medullary carcinomas. We investigated the combined effect of histologic grade and MSI status on survival for 738 patients with colorectal carcinoma (48% female; mean age at diagnosis 68.2 years). The proportion of high-grade adenocarcinoma was 18%. MSI was observed in 59 adenocarcinomas (9%), with higher frequency in high-grade tumors compared with low-grade tumors (20% versus 6%; P < .001). Using Cox regression models, adjusting for sex and age at diagnosis and stratifying by the American Joint Committee on Cancer stage, microsatellite stable (MSS) high-grade tumors were associated with increased hazard of all-cause and colorectal cancer specific mortality: hazard ratio 2.09 (95% confidence interval [CI], 1.58-2.77) and 2.54 (95% CI, 1.86-3.47), respectively, both P < .001. A new grading system separating adenocarcinoma into low grade (all histologic low grade and MSI high grade) and high grade (MSS histologic high grade) gave a lower Akaike information criterion value when compared with the current grading system and thus represented a better model fit to stratify patients according to survival. We found that patients with a high-grade adenocarcinoma had significantly shorter survival than patients with low-grade adenocarcinoma only if the tumor was MSS, suggesting that the grading of colorectal adenocarcinoma with high-grade histologic features should be made according to the MSI status of the tumor. (C) 2014 Elsevier Inc. All rights reserved

    Lifetime alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS- but not BRAF+ colorectal cancer.

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    Ethanol in alcoholic beverages is a causative agent for colorectal cancer. Colorectal cancer is a biologically heterogeneous disease, and molecular subtypes defined by the presence of somatic mutations in BRAF and KRAS are known to exist. We examined associations between lifetime alcohol intake and molecular and anatomic subtypes of colorectal cancer. We calculated usual alcohol intake for 10-year periods from age 20 using recalled frequency and quantity of beverage-specific consumption for 38,149 participants aged 40-69 years from the Melbourne Collaborative Cohort Study. Cox regression was performed to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between lifetime alcohol intake and colorectal cancer risk. Heterogeneity in the HRs across subtypes of colorectal cancer was assessed. A positive dose-dependent association between lifetime alcohol intake and overall colorectal cancer risk (mean follow-up = 14.6 years; n = 596 colon and n = 326 rectal cancer) was observed (HR = 1.08, 95% CI: 1.04-1.12 per 10 g/day increment). The risk was greater for rectal than colon cancer (phomogeneity  = 0.02). Alcohol intake was associated with increased risks of KRAS+ (HR = 1.07, 95% CI: 1.00-1.15) and BRAF-/KRAS- (HR = 1.05, 95% CI: 1.00-1.11) but not BRAF+ tumors (HR = 0.89, 95% CI: 0.78-1.01; phomogeneity  = 0.01). Alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS- tumors originating via specific molecular pathways including the traditional adenoma-carcinoma pathway but not with BRAF+ tumors originating via the serrated pathway. Therefore, limiting alcohol intake from a young age might reduce colorectal cancer originating via the traditional adenoma-carcinoma pathway

    The AIB1 glutamine repeat polymorphism is not associated with risk of breast cancer before age 40 years in Australian women

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    INTRODUCTION: AIB1, located at 20q12, is a member of the steroid hormone coactivator family. It contains a glutamine repeat (CAG/CAA) polymorphism at its carboxyl-terminal region that may alter the transcriptional activation of the receptor and affect susceptibility to breast cancer through altered sensitivity to hormones. METHODS: We evaluated this repeat polymorphism in the context of early-onset disease by conducting a case-control study of 432 Australian women diagnosed with breast cancer before the age of 40 years and 393 population-based control individuals who were frequency matched for age. Genotyping was performed using a scanning laser fluorescence imager. RESULTS: There were no differences in genotype frequencies between cases and control individuals, or between cases categorized by family history or by BRCA1 and BRCA2 germline mutation status. There was no evidence that the presence of one or two alleles of 26 glutamine repeats or fewer was associated with breast cancer (odds ratio = 1.03, 95% confidence interval = 0.73–1.44), or that women with alleles greater than 29 repeats were at increased risk of breast cancer. Exclusion of women who carried a BRCA1 or BRCA2 mutation (24 cases) and non-Caucasian women (44 cases) did not alter the risk estimates or inferences. We present raw data, including that on mutation carriers, to allow pooling with other studies. CONCLUSION: There was no evidence that risk of breast cancer depends on AIB1 CAG/CAA polymorphism status, even if affected women carry a mutation in BRCA1 or BRCA2

    Association of Markers of Inflammation, the Kynurenine Pathway and B Vitamins with Age and Mortality, and a Signature of Inflammaging

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    Under embargo until: 2022-06-12Background Inflammation is a key feature of aging. We aimed to (i) investigate the association of 34 blood markers potentially involved in inflammatory processes with age and mortality and (ii) develop a signature of “inflammaging.” Methods Thirty-four blood markers relating to inflammation, B vitamin status, and the kynurenine pathway were measured in 976 participants in the Melbourne Collaborative Cohort Study at baseline (median age = 59 years) and follow-up (median age = 70 years). Associations with age and mortality were assessed using linear and Cox regression, respectively. A parsimonious signature of inflammaging was developed and its association with mortality was compared with 2 marker scores calculated across all markers associated with age and mortality, respectively. Results The majority of markers (30/34) were associated with age, with stronger associations observed for neopterin, cystatin C, interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), several markers of the kynurenine pathway and derived indices KTR (kynurenine/tryptophan ratio), PAr index (ratio of 4-pyridoxic acid and the sum of pyridoxal 5′-phosphate and pyridoxal), and HK:XA (3-hydroxykynurenine/xanthurenic acid ratio). Many markers (17/34) showed an association with mortality, in particular IL-6, neopterin, C-reactive protein, quinolinic acid, PAr index, and KTR. The inflammaging signature included 10 markers and was strongly associated with mortality (hazard ratio [HR] per SD = 1.40, 95% CI: 1.24–1.57, p = 2 × 10−8), similar to scores based on all age-associated (HR = 1.38, 95% CI: 1.23–1.55, p = 4 × 10−8) and mortality-associated markers (HR = 1.43, 95% CI: 1.28–1.60, p = 1 × 10−10), respectively. Strong evidence of replication of the inflammaging signature association with mortality was found in the Hordaland Health Study. Conclusion Our study highlights the key role of the kynurenine pathway and vitamin B6 catabolism in aging, along with other well-established inflammation-related markers. A signature of inflammaging based on 10 markers was strongly associated with mortality.acceptedVersio

    The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers.

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    INTRODUCTION: The androgen receptor (AR) gene exon 1 CAG repeat polymorphism encodes a string of 9-32 glutamines. Women with germline BRCA1 mutations who carry at least one AR allele with 28 or more repeats have been reported to have an earlier age at onset of breast cancer. METHODS: A total of 604 living female Australian and British BRCA1 and/or BRCA2 mutation carriers from 376 families were genotyped for the AR CAG repeat polymorphism. The association between AR genotype and disease risk was assessed using Cox regression. AR genotype was analyzed as a dichotomous covariate using cut-points previously reported to be associated with increased risk among BRCA1 mutation carriers, and as a continuous variable considering smaller allele, larger allele and average allele size. RESULTS: There was no evidence that the AR CAG repeat polymorphism modified disease risk in the 376 BRCA1 or 219 BRCA2 mutation carriers screened successfully. The rate ratio associated with possession of at least one allele with 28 or more CAG repeats was 0.74 (95% confidence interval 0.42-1.29; P = 0.3) for BRCA1 carriers, and 1.12 (95% confidence interval 0.55-2.25; P = 0.8) for BRCA2 carriers. CONCLUSION: The AR exon 1 CAG repeat polymorphism does not appear to have an effect on breast cancer risk in BRCA1 or BRCA2 mutation carriers
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