Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

A nurse-led FibroScan® outreach clinic encourages socially deprived heavy drinkers to engage with liver services.

AIMS AND OBJECTIVES: To determine whether a portable FibroScan® device can be an acceptable screening tool for chronic liver disease in a community alcohol support service, through recording uptake, determining apparent prevalence of undiagnosed fibrosis/cirrhosis in participants and report engagement following referral to specialist liver services of those individuals referred because of a FibroScan® reading ≥ 7.1 kilopascals (kPa). BACKGROUND: Alcohol-related liver disease, including cirrhosis, is a major cause of death in the UK. Liver disease is silent and usually presents late. Socially deprived patients with alcohol-related liver disease are a "hard to engage" population and at higher risk of death than less deprived. A FibroScan® device is a non-invasive tool for measuring liver stiffness. A result of ≥7.1 kPa can indicate possible chronic liver disease. DESIGN: Prospective observational study. METHOD: Individuals who self-identified as harmful drinkers were recruited. Consented individuals attended for a liver FibroScan® . Those with a reading ≥7.1 kPa were referred to a nurse-led liver clinic for further investigations, results of which determined referral to a liver specialist in secondary care. Participants referred were monitored for compliance over a 6-month period. RESULTS: Seventy-nine consented individuals participated, an uptake of 67% of those informed of the study. Of the 79 scans performed, three were unreliable leaving 76 participants. After scanning, 20/76 (26%) had a FibroScan® ≥7.1 kPa requiring referral on to the nurse-led clinic. All 20 (100%) engaged in further assessment. Of those, 12 required onward referral to specialist services. Subsequent compliance with specialist services in this sample (n = 12) was ≥90%. CONCLUSION: A nurse-led FibroScan® outreach clinic encourages socially deprived drinkers to engage with liver services. RELEVANCE TO CLINICAL PRACTICE: A 67% uptake suggests a nurse-led FibroScan® service in a community alcohol service is acceptable. High engagement gives potential for early intervention and improved health outcomes.

Statin use and association with colorectal cancer survival and risk: case control study with prescription data linkage.

BACKGROUND: In Scotland colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer death. Epidemiological studies have reported conflicting associations between statins and CRC risk and there is one published report of the association between statins and CRC survival. METHODS: Analysis was carried out on 309 cases and 294 controls from the Scottish Study of Colorectal Cancer (SOCCS). Cox's hazard and logistic regression models were applied to investigate the association between statin use and CRC risk and survival. RESULTS: In an adjusted logistic regression model, statins were found to show a statistically significant association for three of the four statin variables and were found to not show a statistically significant association with either all-cause or CRC-specific mortality (OR 0.49; 95%CI 0.49-1.36; p-value = 0.17 and OR 0.33; 95%CI 0.08-1.35; P-value = 0.12, respectively). CONCLUSION: We did find a statistically significant association between statin intake and CRC risk but not statin intake and CRC-specific mortality. However, the study was insufficiently powered and larger scale studies may be advisable.

Diet, environmental factors, and lifestyle underlie the high prevalence of vitamin D deficiency in healthy adults in Scotland, and supplementation reduces the proportion that are severely deficient.

Vitamin D deficiency has recently been implicated as a possible risk factor in the etiology of numerous diseases, including nonskeletal conditions. In humans, skin synthesis following exposure to UVB is a potent source of vitamin D, but in regions with low UVB, individuals are at risk of vitamin D deficiency. Our objectives were to describe the prevalence of vitamin D deficiency and to investigate determinants of plasma 25-hydroxyvitamin D (25-OHD) concentrations in a high northern latitude country. Detailed dietary, lifestyle, and demographic data were collected for 2235 healthy adults (21-82 y) from Scotland. Plasma 25-OHD was measured by liquid chromatography-tandem MS. Among study participants, 34.5% were severely deficient (25-OHD <25 nmol/L) and 28.9% were at high risk of deficiency (25-40 nmol/L). Only 36.6% of participants were at low risk of vitamin D deficiency or had adequate levels (>40 nmol/L). Among participants who were taking supplements, 21.3% had a May-standardized 25-OHD concentration >50 nmol/L, 54.2% had 25-50 nmol/L, and 24.5% had <25 nmol/L, whereas this was 15.6, 43.3, and 41%, respectively, among those who did not take supplements (P < 0.0001). The most important sources of vitamin D were supplements and fish consumption. Vitamin D deficiency in Scotland is highly prevalent due to a combination of insufficient exposure to UVB and insufficient dietary intake. Higher dietary vitamin D intake modestly improved the plasma 25-OHD concentration (P = 0.02) and reduced the proportion of severely deficient individuals (P < 0.0001). In regions with low UVB exposure, dietary and supplement intake may be much more important than previously thought and consideration should be given to increasing the current recommended dietary allowance of 0-10 µg/d for adults in Scotland.

Effect of aspirin and NSAIDs on risk and survival from colorectal cancer.

BACKGROUND: Previous studies have shown that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) lower colorectal cancer (CRC) risk. However, the lowest effective NSAID dose, treatment duration, and effects on survival are not defined. In a large population-based case-control study, we have explored the relationship between NSAID dose and duration, CRC risk and overall CRC-specific survival. METHODS: The relationship between NSAID use and CRC risk was examined in 2279 cases and 2907 controls. Subjects completed food-frequency and lifestyle questionnaires. NSAID categories were low-dose aspirin (75 mg), non-aspirin NSAIDs (NA-NSAIDs) and any NSAID. Users were defined as taking >4 tablets/week for >1 month. ORs were calculated by logistic regression models and adjusted for potential confounding factors. Effect of NSAID use on all-cause and CRC-specific mortality was estimated using Logrank tests and Cox's hazard models. RESULTS: In all, 354 cases (15.5%) were taking low-dose aspirin compared to 526 controls (18.1%). Low-dose aspirin use was associated with decreased CRC risk (OR 0.78 95% CI 0.65 to 0.92, p=0.004), evident after 1 year and increasing with duration of use (p(trend)=0.004). NA-NSAID and any NSAID use were also inversely associated with CRC. There was no demonstrable effect of NSAIDS on all-cause (HR 1.11, p=0.22, 0.94-1.33) or CRC-specific survival (HR 1.01, p=0.93, 0.83-1.23). CONCLUSION: This is the first study to demonstrate a protective effect against CRC associated with the lowest dose of aspirin (75 mg per day) after only 5 years use in the general population. NSAID use prior to CRC diagnosis does not influence survival from the disease.

Creation and Worldwide Utilisation of New COVID-19 Online Information Hub for Genetics Health Professionals, Patients and Families.

The current COVID-19 pandemic has unfortunately resulted in many significant concerns for individuals with genetic disorders and their relatives, regarding the viral infection and, particularly, its specific implications and additional advisable precautions for individuals affected by genetic disorders. To address this, the resulting requirement for guidance and information for the public and for genetics professionals was discussed among colleagues nationally, on the ScotGEN Steering Committee, and internationally on the Education Committee of the European Society of Human Genetics (ESHG). It was agreed that the creation of an online hub of genetics-related COVID-19 information resources would be particularly helpful. The proposed content, divided into a web page for professionals and a page for patients, was discussed with, and approved by, genetics professionals. The hub was created and provided online at www.scotgen.org.uk and linked from the ESHG's educational website for genetics and genomics, at www.eurogems.org. The new hub provides links, summary information and representative illustrations for a wide range of selected international resources. The resources for professionals include: COVID-19 research related hubs provided by Nature, Science, Frontiers, and PubMed; clinical guidelines; the European Centre for Disease Prevention and Control; the World Health Organisation; and molecular data sources including coronavirus 3D protein structures. The resources for patients and families include links to many accessible sources of support and relevant information. Since the launch of the pages, the website has received visits from over 50 countries worldwide. Several genetics consultants have commented on usefulness, clarity, readability, and ease of navigation. Visits have originated most frequently in the United Kingdom, Kuwait, Hong Kong, Moldova, United States, Philippines, France, and Qatar. More links have been added since the launch of the hub to include additional international public health and academic resources. In conclusion, an up-to-date online hub has been created and made freely available for healthcare professionals, patients, relatives and the public, providing categorised easily navigated links to a range of worldwide resources related to COVID-19. These pages are receiving a rapidly growing number of return visits and the authors continue to maintain and update the pages' content, incorporating new developments in this field of enormous worldwide importance.

Association between common mtDNA variants and all-cause or colorectal cancer mortality.

Mutations in the mitochondrial DNA (mtDNA) have been found to be present in several types of tumours including tumours of the large bowel. However, their role in cancer development and prognosis is still to be resolved. We used 2838 cases from a large Scottish colorectal cancer (CRC) case-control study to examine whether inherited genetic variation at the mtDNA influenced all-cause and CRC-specific mortality. We examined 140 tagging mtDNA variants including nine haplotypes commonly found in European populations. After applying three Cox proportional hazard models adjusted for American Joint Committee on Cancer (AJCC) stage, age and sex, three single nucleotide polymorphisms, two located in the 12S ribosomal RNA region (G752A and G1440A) and one in the nicotinamide adenine dinucleotide dehydrogenase subunit 2 region (ND2) region (G4770A), were statistically significantly associated with all-cause (Model I P-values: 0.0001, 0.002 and 0.002, respectively) and CRC-specific mortality (Model I P-values: 5 x 10(-5), 0.0003 and 0.0006, respectively). The H and U haplogroups were associated with an increased and decreased CRC risk, respectively, but with P-values of borderline significance and only after AJCC stage adjustment. In conclusion, the findings of the current study suggest a link between three common mtDNA variants and CRC prognosis. These findings are interesting and consistent with other biological knowledge but need to be confirmed through replication in independent cohorts.

Characteristics of Early Paget's Disease in SQSTM1 Mutation Carriers: Baseline Analysis of the ZiPP Study Cohort.

Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB), but little is known about the clinical characteristics of those with early disease. Radionuclide bone scans, biochemical markers of bone turnover, and clinical characteristics were analyzed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. We studied 222 individuals, of whom 54.9% were female, with mean ± SE age of 50.1 ± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu, which was present in 141 of 222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%), ten of whom (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 versus 49.8 ± 8.9; p = .07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years versus 59 years, p = .17). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions (0.75 ± 0.69 versus 0.42 ± 0.29 arbitary units; p < .0001). Similar findings were observed for other biochemical markers of bone turnover, but the sensitivity of ALP and other markers in detecting lesions was poor. Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow-up of this cohort will provide important information on the natural history of early PDB and its response to treatment. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.

BACKGROUND: The identification of mutations in germ-line DNA mismatch-repair genes at the time of diagnosis of colorectal cancer is important in the management of the disease. METHODS: Without preselection and regardless of family history, we recruited 870 patients under the age of 55 years soon after they received a diagnosis of colorectal cancer. We studied these patients for germ-line mutations in the DNA mismatch-repair genes MLH1, MSH2, and MSH6 and developed a two-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes. Stage 1 of the model incorporated only clinical variables; stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability. The model was validated in an independent population of patients. We analyzed 2938 patient-years of follow-up to determine whether genotype influenced survival. RESULTS: There were 38 mutations among the 870 participants (4 percent): 15 mutations in MLH1, 16 in MSH2, and 7 in MSH6. Carrier frequencies in men (6 percent) and women (3 percent) differed significantly (P<0.04). The addition of immunohistochemical analysis in stage 2 of the model had a sensitivity of 62 percent and a positive predictive value of 80 percent. There were 35 mutations in the validation series of 155 patients (23 percent): 19 mutations in MLH1, 13 in MSH2, and 3 in MSH6. The performance of the model was robust among a wide range of cutoff probabilities and was superior to that of the Bethesda and Amsterdam criteria for hereditary nonpolyposis colorectal cancer. Survival among carriers was not significantly different from that among noncarriers. CONCLUSIONS: We devised and validated a method of identifying patients with colorectal cancer who are carriers of mutations in DNA repair genes. Survival was similar among carriers and noncarriers.

Zoledronate in the prevention of Paget's (ZiPP): protocol for a randomised trial of genetic testing and targeted zoledronic acid therapy to prevent SQSTM1-mediated Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget's disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry SQSTM1 mutations. METHODS AND ANALYSIS: People with a family history of PDB aged >30 years who test positive for SQSTM1 mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events. ETHICS AND DISSEMINATION: The study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals with SQSTM1 mutations can prevent or slow the development of bone lesions with an adverse event profile that is acceptable. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Modification of the associations between lifestyle, dietary factors and colorectal cancer risk by APC variants.

In a large Scottish case-control study, we investigated the effects of adenomatous polyposis coli (APC) Asp1822Val (rs459552) and APC Glu1317Gln substitutions on colorectal cancer (CRC) risk and whether these associations were influenced by lifestyle and dietary factors. We did not observe any associations between the variants and CRC risk in the whole population. Post-menopausal women taking hormone replacement therapy (HRT) and participants who consumed a diet low in total fat, saturated fatty acids, monounsaturated fatty acids (MUFAs) and trans fatty acids had a lower risk of CRC [odds ratio (95% confidence interval): 0.53 (0.41, 0.68); 0.84 (0.72, 0.98); 0.72 (0.62, 0.85); 0.85 (0.73, 1.00) and 0.78 (0.67, 0.92), respectively]. This risk reduction was stronger in those homozygous for the variant APC 1822 allele with significant interaction relationships for HRT, red meat and MUFA intakes (P for interaction case-only design: 0.02, 0.002 and 0.02, respectively). Low n3 polyunsaturated fatty acids intake was associated with an increased CRC risk for the wild-type and heterozygous APC 1822 individuals but with a decreased CRC risk in those homozygous for the variant allele (P for interaction case-only design: 0.09). The interaction relationships with the APC 1317 variant were of the same direction though not significant, possibly due to the low frequency of the variant allele. Our results confirm the findings of three recent case-control studies suggesting a number of possible biological mechanisms. However, further large-scale studies are necessary in order to replicate these findings and confirm the role of these APC gene variants and their interaction with dietary and lifestyle exposures in colorectal carcinogenesis.

Modification of the inverse association between dietary vitamin D intake and colorectal cancer risk by a FokI variant supports a chemoprotective action of Vitamin D intake mediated through VDR binding.

Vitamin D has anticarcinogenic properties and might influence colorectal cancer (CRC) risk, but the epidemiological evidence is inconsistent. Many mechanisms of action for vitamin D have been proposed, with some of them initiating via its binding to the vitamin D receptor (VDR). Using a large Scottish case-control study, we investigated (i) main associations between CRC, vitamin D and calcium dietary intake and 4 VDR single nucleotide polymorphisms (rs10735810, rs1544410, rs11568820, rs7975232) and (ii) interaction associations between the VDR variants, vitamin D and calcium intakes. Inverse and dose-dependent associations were found between CRC risk, dietary [Odds ratio (OR) = 0.77, 95% confidence intervals (CI) 0.63, 0.92, p-trend = 0.012] and total vitamin D (OR = 0.80, 95% CI 0.65, 0.98, p-trend = 0.014) intake in multivariable-adjusted logistic regression models, whereas neither calcium intake nor any of the VDR variants were associated with CRC. Additionally, we observed statistically significant interactions (case-control, case-only designs) between vitamin D and calcium intake and rs10735810 (p-interaction 0.02, 0.006, respectively). We conducted meta-analyses of cohort, case-control and serum studies that also showed an inverse association between dietary vitamin D intake and CRC (serum studies: combined OR = 0.70, 95% CI 0.56, 0.87). The evidence of interaction we report here further supports the inverse association between vitamin D mediated through binding to the VDR.

Dietary vitamin B6 intake and the risk of colorectal cancer.

Vitamin B6, a coenzyme in the folate metabolism pathway, may have anticarcinogenic effects. Laboratory and epidemiologic studies support the hypothesis of its protective effect against colorectal cancer (CRC). The aim of this large Scottish case-control study, including 2,028 hospital-based cases and 2,722 population-based controls, was to investigate the associations between dietary and supplementary intake of vitamin B6 and CRC. Three logistic regression models adjusted for several confounding factors, including energy, folate, and fiber intake, were applied in the whole sample and after age, sex, cancer site, folate, MTHFR C677T (rs1801133), MTHFR A1298C (rs1801131), MTR A2756G (rs1805087), and MTRR A66G (rs1801394) stratification (analysis on genotypes on 1,001 cases and 1,010 controls < or =55 years old). Moderately strong inverse and dose-dependent associations in the whole sample were found between CRC risk and the intake of dietary and total vitamin B6 in all three models [model III: odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.61-0.98; P for trend = 0.03; OR, 0.86; 95% CI, 0.69-1.07; P for trend = 0.12]. In addition, meta-analyses of published studies showed inverse associations between vitamin B6 and CRC (combined relative risk, 0.81; 95% CI, 0.68-0.96; test for overall effect P = 0.01; combined odds ratio, 0.67; 95% CI, 0.60-0.75; test for overall effect P < 0.00001). Analysis within the stratified subgroups showed similar associations apart from a stronger effect among < or =55-year-old individuals. Evidence from larger cohort and experimental studies is now required to confirm and define the anticarcinogenic actions of vitamin B6 and to explore the mechanisms by which this effect is mediated.

Inequality of use of cancer genetics services by members of breast, ovarian and colorectal cancer families in South East Scotland.

Some studies have found a deficiency of male, younger and more socially deprived individuals amongst referrals to and/or attendees at cancer genetics clinics. We investigated this inequality of use of genetics services from data on 4,178 Scottish patients with a family history of breast and/or ovarian cancer (BOC) or colorectal cancer (CRC) referred from 2000--2006. Some 98% BOC and 60% CRC referrals were female. Median age of female referrals was greater in the CRC than the BOC group (45.3 vs. 38.7 years, P < 0.001). Both groups of referrals were less socially deprived than the general population (P < 0.001) and the CRC less deprived than the BOC group (P < 0.001). Some 88% patients attended the first appointment offered. Attendance was greater in the CRC group (P < 0.001) and in older patients (P < 0.001) and in the BOC group was highly significantly lower in more socially deprived patients (P < 0.001). Male relatives may feel counselling is less relevant and relatives of both sexes may delay counselling until approaching the age of onset of cancer in a relative. We suggest that medical professionals and the general public may have more knowledge about the genetics of BOC than of CRC. Thus relatives in CRC families seeking counselling are likely to be those with access to more information. The lower attendance amongst more deprived relatives in BOC families may result from poor understanding of the reason for referral. These findings confirm the need to provide male, younger and more socially deprived relatives with more helpful information on cancer genetics.

Predicting breast cancer risk: implications of a "weak" family history.

Published guidelines adopted in many countries recommend that women whose family history of breast cancer places them at a risk>or=1.7 times that of the age-matched general population, should be considered for inclusion in special surveillance programmes. However validation of risk assessment models has been called for as a matter of urgency. The databases of the four Scottish Familial Breast Cancer clinics and the Scottish Cancer Registry have been searched to identify breast cancers occurring among 1,125 women aged 40-56, with family histories placing them below the "moderate" level of genetic risk. The observed incidence over 6 years was compared with age-specific data for the Scottish population. Our findings confirm that when there are two affected relatives (one first degree) the relative risk (RR) exceeds 1.7 regardless of their ages at diagnosis. When only one (first degree) relative was affected at any age from 40 to 55, the RR does not reach 1.7 if that relative was a mother but exceeds it if the relative was a sister. The probable explanation is that sisters are more likely than mother/daughter pairs to share homozygosity for a risk allele. Surveillance programmes might therefore accommodate sisters of women affected before age 55. Evidence that "low penetrance" alleles contributing to breast cancer risk may be recessive should be taken into account in strategies for identifying them.

Dietary flavonoids and the risk of colorectal cancer.

In vitro and in vivo laboratory data point to chemoprotective effects of flavonoids on colorectal cancer. However, there has been limited epidemiologic research on the dietary intake of flavonoids and risk of colorectal cancer. Recent expansions of dietary databases to include flavonoid data now make such studies feasible. Association between the six main classes of flavonoids and the risk of colorectal cancer was examined using data from a national prospective case-control study in Scotland, including 1,456 incident cases and 1,456 population-based controls matched on age, sex, and residence area. Dietary, including flavonoid data, were obtained from a validated, self-administered food frequency questionnaire. Risk of colorectal cancer was estimated using conditional logistic regression models in the whole sample and stratified by sex, smoking status, and cancer site and adjusted for established and putative risk factors. After energy adjustment, reductions in colorectal cancer risk associated with the highest quartiles of intake (versus the lowest quartile) were 27% for flavonols [odds ratio (OR), 0.73; P(trend) = 0.012], 32% for quercetin (OR, 0.68; P(trend) = 0.001), 32% for catechin (OR, 0.68; P(trend) < 0.0005); 26% for epicatechin (OR, 0.74; P(trend) = 0.019), and 22% for procyanidins (OR, 0.78; P(trend) = 0.031). The significant dose-dependent reductions in colorectal cancer risk that were associated with increased consumption of flavonols, quercetin, catechin, and epicatechin remained robust after controlling for overall fruit and vegetable consumption or for other flavonoid intake. The risk reductions were greater among nonsmokers, but no interaction beyond a multiplicative effect was present. Sex-specific or cancer-type differences were not observed. No risk reductions were associated with intake of flavones (P(trend) = 0.64), flavonones (P(trend) = 0.22), and phytoestrogens (P(trend) = 0.26). This was the first of several a priori hypotheses to be tested in this large study and showed strong and linear inverse associations of flavonoids with colorectal cancer risk.

Long-term attendance at follow-up of women assessed as being at increased risk of developing breast cancer in south-east Scotland.

BACKGROUND: Women with a family history of breast cancer increasingly seek genetic advice and screening. In the present study we investigated referral rates and factors associated with long-term attendance for screening in Scotland. METHODS: We investigated referral rates to the genetic service over a 21-month period and long-term attendance for screening amongst the 226 women at increased risk of developing breast cancer. RESULTS: The overall annual referral rate was 0.31 per 1,000 patients on general practitioners' lists. Some 98% of women for whom it was appropriate attended at least one screening appointment and 88% were continuing to attend appointments for surveillance up to 5 years later. Attendance was significantly lower among more socially deprived patients (p < 0.01). CONCLUSIONS: These results suggest that as increasing numbers of women with a positive family history seek risk assessment and screening, current facilities may be inadequate.

Referrals of patients to colorectal cancer genetics services in south-east Scotland.

The discovery that genetic factors are involved in the aetiology of colorectal cancer, has prompted many relatives of affected individuals to seek genetic counselling and screening. This paper describes the demand for genetic services by families with colorectal cancer in south-east Scotland, their expectations and views of the service offered. The annual referral rate over the 21-month study period, for patients with a family history of colorectal cancer, was 0.11 per 1000 patients on general practitioner lists. This is one third of the rate for patients with a family history of breast cancer and in comparison with the breast cancer group, relatives of colorectal cancer patients were significantly older and less socially deprived. Approximately one third were referred via a hospital specialist unit. One hundred patients were included in the study. Mean (+/- standard deviation) age was 43 (+/- 10.7 years), 75 were female and 31 were self referrals. Before the consultation, almost half the patients had an inflated perception of their risk and there was little change at follow-up. There was an improvement in objective understanding after counselling which was sustained up to 6 months but only two thirds remembered their objective risk accurately. Most patients were satisfied with the consultation. Our findings suggest the need to educate individuals, in particular men, younger people and the more socially deprived, about the relevance of a family history of colorectal cancer and to facilitate patients' comprehension of their risk status.

Associations between dietary and lifestyle risk factors and colorectal cancer in the Scottish population.

Colorectal cancer (CRC) accounts for 9.7% of all cancer cases and for 8% of all cancer-related deaths. Established risk factors include personal or family history of CRC as well as lifestyle and dietary factors. We investigated the relationship between CRC and demographic, lifestyle, food and nutrient risk factors through a case-control study that included 2062 patients and 2776 controls from Scotland. Forward and backward stepwise regression was applied and the stability of the models was assessed in 1000 bootstrap samples. The variables that were automatically selected to be included by the forward or backward stepwise regression and whose selection was verified by bootstrap sampling in the current study were family history, dietary energy, 'high-energy snack foods', eggs, juice, sugar-sweetened beverages and white fish (associated with an increased CRC risk) and NSAIDs, coffee and magnesium (associated with a decreased CRC risk). Application of forward and backward stepwise regression in this CRC study identified some already established as well as some novel potential risk factors. Bootstrap findings suggest that examination of the stability of regression models by bootstrap sampling is useful in the interpretation of study findings. 'High-energy snack foods' and high-energy drinks (including sugar-sweetened beverages and fruit juices) as risk factors for CRC have not been reported previously and merit further investigation as such snacks and beverages are important contributors in European and North American diets.

Ten common genetic variants associated with colorectal cancer risk are not associated with survival after diagnosis.

PURPOSE: To date, genomewide association studies have identified 10 genetic loci associated with colorectal cancer (CRC) susceptibility. We hypothesized that these loci might also affect cancer survival. EXPERIMENTAL DESIGN: To determine whether single-nucleotide polymorphisms tagging these 10 loci influenced all-cause and CRC-specific mortality, we prospectively followed survival outcomes for 2,838 Scottish patients recruited soon after a diagnosis of CRC. Survival analysis was conducted using Cox proportional hazard models adjusted for American Joint Committee on Cancer stage, age, and sex. RESULTS: None of the single-nucleotide polymorphisms were found to be statistically significantly associated with all-cause or CRC-specific mortality. CONCLUSIONS: We conclude that none of the 10 common genetic variants thus far shown to be associated with CRC risk are associated with survival from CRC.