Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Although genome-wide association studies have identified over 100 risk loci that explain ~33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa

FGF receptor genes and breast cancer susceptibility : results from the Breast Cancer Association Consortium

Background: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02–1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2

Responses to provision of personalised cancer risk information: a qualitative interview study with members of the public.

Background It is estimated that nearly 600,000 cancer cases in the UK could have been avoided in the past five years if people had healthier lifestyles. A number of theories of behaviour change suggest that before people will change health behaviours, they must accept that a risk applies to them. This study aimed to explore the views of the public on receiving personalised cancer risk information and the potential for that information to motivate behaviour change. Methods We conducted 27 interviews with members of the public (mean age 49 ± 23 years). Each participant completed a questionnaire to allow calculation of their risk of developing the most common cancers (10 for women, 8 for men). During the interviews we presented their risk using a web-based tool developed for the study and discussions covered their views on receiving that information. Each interview was audio-recorded and then analysed using thematic analysis. Results Participants generally viewed the concept of personalised cancer risk positively. The first reaction of almost all when presented with their 10-year risk of an individual cancer without any further context was that it was low and not concerning. Views on what constituted a high risk ranged widely, from 0.5 to 60%. All felt seeing the impact of changes in lifestyle was helpful. For some this led to intentions to change behaviour, but reductions in risk were not always motivating as the risks were considered low and differences small. Conclusions Provision of personalised cancer risk was well received and may be a useful addition to other cancer prevention initiatives. Further work is needed in particular to develop ways to present cancer risk that reflect the general perception of what constitutes a risk high enough to motivate behaviour change and help patients contextualise a less well known health risk by providing a frame of reference

Trends and outcome from radical therapy for primary non-metastatic prostate cancer in a UK population.

BACKGROUND: Increasing proportions of men diagnosed with prostate cancer in the UK are presenting with non-metastatic disease. We investigated how treatment trends in this demographic have changed. PATIENT AND METHODS: Non-metastatic cancers diagnosed from 2000-2010 in the UK Anglian Cancer network stratified by age and risk group were analysed [n = 10,365]. Radiotherapy [RT] and prostatectomy [RP] cancer specific survival [CSS] were further compared [n = 4755]. RESULTS: Over the decade we observed a fall in uptake of primary androgen deprivation therapy but a rise in conservative management [CM] and radical therapy [p<0.0001]. CM in particular has become the primary management for low-risk disease by the decade end [p<0.0001]. In high-risk disease however both RP and RT uptake increased significantly but in an age dependent manner [p<0.0001]. Principally, increased RP in younger men and increased RT in men ≥ 70y. In multivariate analysis of radically treated men both high-risk disease [HR 8.0 [2.9-22.2], p<0.0001] and use of RT [HR 1.9 [1.0-3.3], p = 0.024] were significant predictors of a poorer CSM. In age-stratified analysis however, the trend to benefit of RP over RT was seen only in younger men [≤ 60 years] with high-risk disease [p = 0.07]. The numbers needed to treat by RP instead of RT to save one cancer death was 19 for this group but 67 for the overall cohort. CONCLUSION: This study has identified significant shifts in non-metastatic prostate cancer management over the last decade. Low-risk disease is now primarily managed by CM while high-risk disease is increasingly treated radically. Treatment of high-risk younger men by RP is supported by evidence of better CSM but this benefit is not evident in older men

Improving Clinical Risk Stratification at Diagnosis in Primary Prostate Cancer: A Prognostic Modelling Study.

INTRODUCTION: Over 80% of the nearly 1 million men diagnosed with prostate cancer annually worldwide present with localised or locally advanced non-metastatic disease. Risk stratification is the cornerstone for clinical decision making and treatment selection for these men. The most widely applied stratification systems use presenting prostate-specific antigen (PSA) concentration, biopsy Gleason grade, and clinical stage to classify patients as low, intermediate, or high risk. There is, however, significant heterogeneity in outcomes within these standard groupings. The International Society of Urological Pathology (ISUP) has recently adopted a prognosis-based pathological classification that has yet to be included within a risk stratification system. Here we developed and tested a new stratification system based on the number of individual risk factors and incorporating the new ISUP prognostic score. METHODS AND FINDINGS: Diagnostic clinicopathological data from 10,139 men with non-metastatic prostate cancer were available for this study from the Public Health England National Cancer Registration Service Eastern Office. This cohort was divided into a training set (n = 6,026; 1,557 total deaths, with 462 from prostate cancer) and a testing set (n = 4,113; 1,053 total deaths, with 327 from prostate cancer). The median follow-up was 6.9 y, and the primary outcome measure was prostate-cancer-specific mortality (PCSM). An external validation cohort (n = 1,706) was also used. Patients were first categorised as low, intermediate, or high risk using the current three-stratum stratification system endorsed by the National Institute for Health and Care Excellence (NICE) guidelines. The variables used to define the groups (PSA concentration, Gleason grading, and clinical stage) were then used to sub-stratify within each risk category by testing the individual and then combined number of risk factors. In addition, we incorporated the new ISUP prognostic score as a discriminator. Using this approach, a new five-stratum risk stratification system was produced, and its prognostic power was compared against the current system, with PCSM as the outcome. The results were analysed using a Cox hazards model, the log-rank test, Kaplan-Meier curves, competing-risks regression, and concordance indices. In the training set, the new risk stratification system identified distinct subgroups with different risks of PCSM in pair-wise comparison (p < 0.0001). Specifically, the new classification identified a very low-risk group (Group 1), a subgroup of intermediate-risk cancers with a low PCSM risk (Group 2, hazard ratio [HR] 1.62 [95% CI 0.96-2.75]), and a subgroup of intermediate-risk cancers with an increased PCSM risk (Group 3, HR 3.35 [95% CI 2.04-5.49]) (p < 0.0001). High-risk cancers were also sub-classified by the new system into subgroups with lower and higher PCSM risk: Group 4 (HR 5.03 [95% CI 3.25-7.80]) and Group 5 (HR 17.28 [95% CI 11.2-26.67]) (p < 0.0001), respectively. These results were recapitulated in the testing set and remained robust after inclusion of competing risks. In comparison to the current risk stratification system, the new system demonstrated improved prognostic performance, with a concordance index of 0.75 (95% CI 0.72-0.77) versus 0.69 (95% CI 0.66-0.71) (p < 0.0001). In an external cohort, the new system achieved a concordance index of 0.79 (95% CI 0.75-0.84) for predicting PCSM versus 0.66 (95% CI 0.63-0.69) (p < 0.0001) for the current NICE risk stratification system. The main limitations of the study were that it was registry based and that follow-up was relatively short. CONCLUSIONS: A novel and simple five-stratum risk stratification system outperforms the standard three-stratum risk stratification system in predicting the risk of PCSM at diagnosis in men with primary non-metastatic prostate cancer, even when accounting for competing risks. This model also allows delineation of new clinically relevant subgroups of men who might potentially receive more appropriate therapy for their disease. Future research will seek to validate our results in external datasets and will explore the value of including additional variables in the system in order in improve prognostic performance.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pmed.100206

Risk Factors of Pancreatic Cancer: A Literature Review

Objective: To identify and compare current modifiable and non-modifiable risk factors for pancreatic cancer (PaCa) that may have potential application in PaCa risk stratification, prevention, and early detection. / Material: All articles in this literature review were identified through systematic searches of PubMed, Medline, and Embase databases. All articles were published in the English language, between January 2000 to December 2021 and with an abstract. In this review study, we judge the evidence level of different PaCa risk factors through the criteria of grading evidence for cancer prevention. / Results: The modifiable risk factors identified included cigarette smoking, heavy alcohol consumption, increased Body Mass Index (BMI) and abdominal obesity, chronic pancreatitis, diabetes, hepatitis B virus (HBV) infection, periodontal disease, cholecystectomy and chemicals and asbestos exposure. The non-modifiable risk factors included age, gender, ethnicity, blood type, family history, inherited syndromes, germline mutation, and single nucleotide polymorphisms (SNPs). However, there are still some ambiguous risk factors for which the current evidence is inconclusive such as low physical activity, increased consumption of red/processed meat and dairy products, vitamin D insufficiency, and some medical-related conditions including gut microbiota such as Helicobacter Pylori infection, long-term usage of Proton-pump inhibitors (PPI), and Systemic Lupus Erythematosus (SLE) history. / Conclusions: This literature review summarizes the modifiable and non-modifiable risk factors of PaCa with strong evidence, which could be used to further establish PaCa predictive model as an application of PaCa risk stratification, raise public awareness and educate the public as a prevention program. Further studies are needed to investigate other potential risk factors

Association between an inflammatory biomarker score and future dementia diagnosis in the population-based UK Biobank cohort of 500,000 people

This study was designed to investigate the relationship between a systematic inflammatory biomarker measure, concurrent and later cognitive performance, and future dementia risk. The literature has reported the potential involvement of inflammation in cognitive performance as well as Alzheimer’s Disease, but not consistently. We used a population-based cohort of 500,000 people in the UK and assessed the association between a composite inflammatory biomarker and cognitive performance measures across five domains measured concurrently and 4–13 years later, taking advantage of the large sample size. We also assessed the same biomarker’s association with dementia diagnosis 3–11 years later in the initially dementia-free sample. We report small but significant associations between elevated biomarker levels and worsened cognitive performance at baseline for four cognitive tasks (OR = 1.204, p<0.001 for Prospective memory, β = -0.366, p<0.001 for Fluid intelligence, β = 8.819, p<0.001 for Reaction time, and β = -0.224, p<0.001 for Numeric memory), comparing the highest quartile of the biomarker to the lowest. We also found that for one measure (Pairs matching) higher biomarker levels were associated with fewer errors, i.e. better performance (β = -0.096, p<0.001). We also report that the 4th quartiles of the baseline biomarker levels were significantly associated with cognitive task scores assessed years later on the p< = 0.002 level, except for the Pair matching test, for which none of the quartiles remained a significant predictor. Finally, the highest biomarker quartile was significantly associated with increased dementia risk compared to the lowest quartile (HR = 1.349, p<0.001). A case-only analysis to assess disease subtype heterogeneity suggested probable differences in the association with the highest biomarker quartile between vascular dementia and Alzheimer disease subtypes (OR = 1.483, p = 0.055). Our results indicate that systemic inflammation may play a small but significant part in dementia pathophysiology, especially in vascular dementia