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INDELs and CNVs are structural variations that may play roles in cancer susceptibility and patient outcomes. Our objectives were a) to computationally detect and examine the genome‐wide INDEL/CNV profiles in a cohort of colorectal cancer patients, and b) to examine the associations of frequent INDELs/CNVs with relapse‐free survival time. We also identified unique variants in 13 Familial Colorectal Cancer Type X (FCCX) cases. The study cohort consisted of 495 colorectal cancer patients. QuantiSNP and PennCNV algorithms were utilized to predict the INDELs/CNVs using genome‐wide signal intensity data. Duplex PCR was used to validate predictions for 10 variants. Multivariable Cox regression models were used to test the associations of 106 common variants with relapse‐free survival time. Score test and the multivariable Cox proportional hazards models with time‐varying coefficients were applied to identify the variants with time‐varying effects on the relapse‐free survival time. A total of 3486 distinct INDELs/CNVs were identified in the patient cohort. The majority of these variants were rare (83%) and deletion variants (81%). The results of the computational predictions and duplex PCR results were highly concordant (93–100%). We identified four promising variants significantly associated with relapse‐free survival time (P

As Newfoundland has the highest rate of familial CRC in the world, we started a population-based clinic to provide colonoscopic and Lynch syndrome (LS) screening recommendations to families of CRC patients based on family risk. Of 1091 incident patients 52% provided a family history. Seventy-two percent of families were at low or intermediate-low risk of CRC and colonoscopic screening recommendations were provided by letter. Twenty eight per cent were at high and intermediate-high risk and were referred to the genetic counsellor, but only 30% (N = 48) were interviewed by study end. Colonoscopy was recommended more frequently than every 5 years in 35% of families. Lower family risk was associated with older age of proband but the frequency of screening colonoscopy recommendations varied across all age groups, driven by variability in family history. Twenty four percent had a high MMR Predict score for a Lynch Syndrome mutation, and 23% fulfilled the Provincial Program criteria for LS screening. A population-based approach in the provision of colonoscopic screening recommendations to families at risk of CRC was limited by the relatively low response rate. A family history first approach to the identification of LS families was inefficient.

Among patients receiving hemodialysis, abnormalities in calcium regulation have been linked to an increased risk of cardiovascular events. Cinacalcet lowers serum calcium concentrations through its effect on parathyroid hormone secretion and has been hypothesized to reduce the risk of cardiovascular events. In observational cohort studies, prescriptions of low dialysate calcium concentration and larger observed serum-dialysate calcium gradients have been associated with higher risks of in-dialysis facility or peri-dialytic sudden cardiac arrest. We performed this study to examine the risks associated with dialysate calcium and serum-dialysate gradients among participants in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. In EVOLVE, 3883 hemodialysis patients were randomized 1:1 to cinacalcet or placebo. Dialysate calcium was administered at the discretion of treating physicians. We examined whether baseline dialysate calcium concentration or the serum-dialysate calcium gradient modified the effect of cinacalcet on the following adjudicated endpoints: (1) primary composite endpoint (death or first non-fatal myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular event); (2) cardiovascular death; and (3) sudden death. In EVOLVE, use of higher dialysate calcium concentrations was more prevalent in Europe and Latin America compared with North America. There was a significant fall in serum calcium concentration in the cinacalcet group; dialysate calcium concentrations were changed infrequently in both groups. There was no association between baseline dialysate calcium concentration or serum-dialysate calcium gradient and the endpoints examined. Neither the baseline dialysate calcium nor the serum-dialysate calcium gradient significantly modified the effects of cinacalcet on the outcomes examined. The effects of cinacalcet on cardiovascular death and major cardiovascular events are not altered by the dialysate calcium prescription and serum-dialysate calcium gradient.

Background Knowledge of molecular biology and genomics continues to expand rapidly, promising numerous opportunities for improving health. However, a key aspect of the success of genomic medicine is related to public understanding and acceptance. Design Using community consultations and an online survey, we explored public attitudes and expectations about genomics research. Results Thirty-three members of the general public in Newfoundland, Canada, took part in the community sessions, while 1024 Atlantic Canadians completed the online survey. Overall, many participants noted they lacked knowledge about genetics and associated research and took the opportunity to ask numerous questions throughout sessions. Participants were largely hopeful about genomics research in its capacity to improve health, not only for current residents, but also for future generations. However, they did not accept such research uncritically, and a variety of complex issues and questions arose during the community consultations and were reflected in survey responses. Discussion With the proliferation of biobanks and the rapid pace of discoveries in genomics research, public support will be crucial to realize health improvements. If researchers can engage the public in regular, transparent dialogue, this two-way communication could allow greater understanding of the research process and the design of efficient and effective genetic health services, informed by the public that will use them.

Lynch Syndrome (LS) families harbor mutated mismatch repair genes,which predispose them to specific types of cancer. Because individuals within LS families can experience multiple cancers over their lifetime, we developed a progressive three-state model to estimate the disease risk from a healthy (state 0) to a first cancer (state 1) and then to a second cancer (state 2). Ascertainment correction of the likelihood was made to adjust for complex sampling designs with carrier probabilities for family members with missing genotype information estimated using their family's observed genotype and phenotype information in a one-step expectation–maximization algorithm. A sandwich variance estimator was employed to overcome possible model misspecification. The main objective of this paper is to estimate the disease risk (penetrance) for age at a second cancer after someone has experienced a first cancer that is also associated with a mutated gene. Simulation study results indicate that our approach generally provides unbiased risk estimates and low root mean squared errors across different family study designs, proportions of missing genotypes, and risk heterogeneities. An application to 12 large LS families from Newfoundland demonstrates that the risk for a second cancer was substantial and that the age at a first colorectal cancer significantly impacted the age at any LS subsequent cancer. This study provides new insights for developing more effective management of mutation carriers in LS families by providing more accurate multiple cancer risk estimates. Copyright © 2013 John Wiley & Sons, Ltd.

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1-2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex-influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre-symptomatic diagnosis has the greatest clinical utility.

Lifetime risk of developing endometrial cancer in Lynch syndrome carriers is very high and females are also at an increased risk of developing ovarian cancer. The aim of the study was to determine the impact of gynecological screening in MSH2 mutation carriers. Gynecological cancer incidence and overall survival was compared in female mutation carriers who received gynecological screening (cases) and in matched controls. Controls were randomly selected from non-screened mutation carriers who were alive and disease-free at the age the case entered the screening program. Median age to diagnosis of gynecological cancer was 54 years in the screened group compared to 56 years in controls (p = 0.50). Stage I or II cancer was diagnosed in 92% of screened patients compared to 71% in the control group (p = 0.17). Two of three deaths in the screened group were the result of ovarian cancer. Mean survival in the screened group was 79 years compared to 69 years in the control group (p = 0.11), likely associated with concomitant colonoscopy screening. Gynecological screening did not result in earlier gynecologic cancer detection and despite screening two young women died from ovarian cancer suggesting that prophylactic hysterectomy with bilateral salpingo-oophorectomy be considered in female mutation carriers who have completed childbearing.

Hereditary non-polyposis colorectal cancer (HNPCC) may be the result of Lynch syndrome (LS) caused by mutations in mismatch repair (MMR) genes, a syndrome of unknown etiology called familial colorectal cancer type-X (FCCTX), or familial serrated neoplasia associated with the colorectal cancer (CRC) somatic BRAF mutation. To determine the cause of HNPCC in the founder population of the island of Newfoundland, we studied 37 families with LS and 29 families without LS who fulfilled the Amsterdam I criteria. In non-LS, four index CRCs were BRAF mutation positive, one of which was microsatellite instable. Geographic clustering of LS families caused by three different founder mutations in MSH2 was observed. Nine unique MMR mutations in four MMR genes were identified in single families distributed in different geographic isolates. The geographic distribution of non-LS was similar to LS. The coefficient of relatedness using genotype data was significantly higher for non-LS than for all CRC. Extensive genealogic investigation failed to connect non-LS families and in some clusters pathologic CRC heterogeneity was observed. We conclude that non-LS HNPCC may be a heterogeneous disorder with different pathogenic pathways, and that the geographic distribution is consistent with multiple different mutations in unknown CRC susceptibility gene(s).

Cancer risks for a person who has inherited a MUTYH mutation from only one parent (monoallelic mutation carrier) are uncertain. Using the Colon Cancer Family Registry and Newfoundland Familial Colon Cancer Registry, we identified 2,179 first- and second-degree relatives of 144 incident colorectal cancer (CRC) cases who were monoallelic or biallelic mutation carriers ascertained by sampling population complete cancer registries in the United States, Canada and Australia. Using Cox regression weighted to adjust for sampling on family history, we estimated that the country-, age- and sex-specific standardized incidence ratios (SIRs) for monoallelic mutation carriers, compared to the general population, were: 2.04 (95% confidence interval, CI 1.56-2.70; p < 0.001) for CRC, 3.24 (95%CI 2.18-4.98; p < 0.001) for gastric cancer, 3.09 (95%CI 1.07-12.25; p = 0.07) for liver cancer and 2.33 (95%CI 1.18-5.08; p = 0.02) for endometrial cancer. Age-specific cumulative risks to age 70 years, estimated using the SIRs and US population incidences, were: for CRC, 6% (95%CI 5-8%) for men and 4% (95%CI 3-6%) for women; for gastric cancer, 2% (95%CI 1-3%) for men and 0.7% (95%CI 0.5-1%) for women; for liver cancer, 1% (95%CI 0.3-3%) for men and 0.3% (95%CI 0.1-1%) for women and for endometrial cancer, 4% (95%CI 2-8%). There was no evidence of increased risks for cancers of the brain, pancreas, kidney, lung, breast or prostate. Monoallelic MUTYH mutation carriers with a family history of CRC, such as those identified from screening multiple-case CRC families, are at increased risk of colorectal, gastric, endometrial and possibly liver cancers.

Purpose To evaluate the indications, concurrence with prescribing guidelines and potential necessity for antibiotic (AB) prescriptions written in community practice. Methods We reviewed the charts of all patients with infection-related illnesses seen by family physicians during two random days of regular practice between 1 Oct 1997 and 30 Jan 1998. Guideline concurrence of AB prescribing was assessed using regional AB prescribing guidelines. Likelihood of AB indication for respiratory tract infections was assessed using published clinical practice guidelines for determination of likely viral versus bacterial etiology. Results Of 4218 visits captured, 949 (22%) were for newly acquired infections. Sixty four percent (n = 604) of consultations for newly acquired infections resulted in an AB prescription. Based on the doctors' diagnoses, 61% of AB prescriptions were concurrent with prescribing guidelines, 10% were for the wrong drug, 20% were not indicated and in 10% of cases a lower line AB was available. For respiratory tract infections, 12% of these infections were likely bacterial, whereas the physicians determined that 56% were bacterial. Conclusions A large proportion of ABs administered in community practices were not in concurrence with community AB prescribing guidelines. Improvements can be made in AB choice and in decisions about likely viral etiology for respiratory tract infections. Copyright © 2004 John Wiley & Sons, Ltd.

Hyporesponsiveness to erythropoietin stimulating agents occurs frequently, and may be observed at initiation of treatment or during maintenance therapy. An inverse relationship between hyporesponsiveness and incident cardiovascular events has been reported. It is related at least in part to co-morbidity and its occurrence requires a search for the cause. Treatment of anemia in hyporesponsive patients should be individualized, with consideration given to the indication for ESA therapy, the target hemoglobin for therapy, and maximal dose limitations.

There are at least five distinct Bardet-Biedl syndrome (BBS) loci, four of which have been mapped: 11q (BBS1), 16q (BBS2), 3p (BBS3), and 15q (BBS4). A comparative study of the three Arab-Bedouin kindreds used to map the BBS2, BBS3, and BBS4 loci suggests that the variability in the number and severity of clinical manifestations, particularly the pattern of polydactyly, reflects chromosome-specific subtypes of BBS [Carmi et al., 1995a; Am J Med Genet 59:199-203]. We describe a Newfoundland kindred of northern European descent and confirm the initial finding of a BBS locus on chromosome 3. However, the "BBS3 phenotype," which includes polydactyly of all four limbs and a progression to morbid obesity, was not observed. Rather, four of the five BBS patients in this family had polydactyly restricted to their feet. The obesity in these patients was reversible with caloric restriction and/or exercise. Mental retardation has been considered a major symptom of BBS. However, formal IQ testing shows that these patients are of average intelligence. Haplotype analysis reduces the BBS3 critical region to a 6-cM interval between D3S1595-D3S1753.

We evaluated the accuracy of ultrasonographic diagnosis of autosomal dominant polycystic kidney disease (ADPKD) and factors influencing its prognosis in members of 17 Newfoundland families originally described in 1984. In 10 families showing genetic linkage between ADPKD and markers for the PKD1 locus, rates of false negative ultrasonographic diagnosis are estimated as 36% below the age of 10 years and 8% or less thereafter, comparable with findings of genetic linkage studies of a subset of family members. At ages above 30 years, false negative ultrasonographic diagnosis of PKD1 disease is unlikely. In 2 families in which ADPKD is not co-inherited with PKD1 markers, only 11% of members aged less than 30 years had kidney cysts. The mean (SE) age of onset of ESRD is 56.3 (1.8) years for persons with the PKD1 form of ADPKD, and 68.7 (1.7) years for affected members of families in which ADPKD is not co-inherited with PKD1 markers (P = 0.01). In the PKD1 families, age of onset of end stage renal disease (ESRD) was unrelated to the sex of the affected individual but was earlier in persons inheriting the disease from their mothers than from their fathers (50.5 vs. 64.8 years, P = 0.004), consistent with an influence of genetic imprinting on disease progression. In females with a PKD1 mutation, onset of ESRD was not influenced by parity. In PKD1 families, resemblance in age of onset of ESRD was apparent; variation was less within than between families (F = 13.0, P less than 0.0001), and risk of false negative ultrasonographic diagnosis appears largely restricted to families in which ESRD occurs relatively late.