Family Registry Research Articles

Q192R polymorphism in the PON1 gene and familial hypercholesterolemia in a Saudi population.

BACKGROUNDFamilial hypercholesterolemia (FH) is an autosomal dominant condition characterized by abnormal levels of low-density lipoprotein (LDL) in the blood. FH is a risk factor for atherosclerosis and cardiovascular disease. The relationship between the paraoxonase 1 (PON1) gene, atherosclerosis and coronary artery disease has not been studied in Saudi patients.OBJECTIVETo investigate the genetic associations of the Q192R polymorphism in the PON1 gene with FH in Saudi patients.DESIGNCase-control study.SETTINGTertiary care center, Riyadh.METHODSTwo hundred Saudi patients were enrolled in this study, including 100 patients with FH and 100 healthy controls, during the period from January 2012 to March 2013. Serum was separated from coagulated blood (3 mL) and used for analysis of lipid profiles. Genomic DNA was isolated from anticoagulant-treated blood (2 mL). Genotyping for the Q192R polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism analysis, followed by 3% agarose gel electrophoresis.MAIN OUTCOME MEASUREThe strength of association between the Q192R polymorphism and FH in the Saudi population.RESULTSWe confirmed that QR versus QQ (odds ratio [OR]: 1.55; 95% confidence interval [CI]: 1.05–3.43; P=.03), QR+RR versus QQ (OR: 1.98; 95% CI: 1.13–3.49; P=.01), and R versus Q (OR: 1.68; 95% CI: 1.09–2.59; P=.01) in the Q192R polymorphism were associated with FH in the Saudi population.CONCLUSIONIn conclusion, the Q192R polymorphism in the PON1 gene is associated with FH in the Saudi population. Our results confirmed that the R allele, QR, and dominant model genotypes were associated with FH.LIMITATIONOnly a single variant (Q192R) was analyzed, and the medical and family histories of the patients were not known.

Long-term weight loss after colorectal cancer diagnosis is associated with lower survival: The Colon Cancer Family Registry.

Body weight is associated with colorectal cancer (CRC) risk and survival, but to the authors' knowledge, the impact of long-term postdiagnostic weight change is unclear. Herein, the authors investigated whether weight change over the 5 years after a diagnosis of CRC is associated with survival. CRC cases diagnosed from 1997 to 2008 were identified through 4 population-based cancer registry sites. Participants enrolled within 2 years of diagnosis and reported their height and weight 2 years prior. Follow-up questionnaires were administered approximately 5 years after diagnosis. Associations between change in weight (in kg) or body mass index (BMI) with overall and CRC-specific survival were estimated using Cox regression analysis adjusted for age, sex, American Joint Committee on Cancer stage of disease, baseline BMI, nonsteroidal anti-inflammatory drug use, smoking, time between diagnosis and enrollment, and study site. At the 5-year postdiagnostic survey, 2049 participants reported higher (53%; median plus 5 kg), unchanged (12%), or lower (35%; median -4 kg) weight. Over a median of 5.1 years of subsequent follow-up (range, 0.3-9.9 years), 344 participants died (91 of CRC). Long-term weight loss (per 5 kg) was found to be associated with poorer overall survival (hazard ratio, 1.13; 95% confidence interval, 1.07-1.21) and CRC-specific survival (hazard ratio, 1.25; 95% confidence interval, 1.13-1.39). Significantly lower survival was similarly observed for relative weight loss (>5% vs ≤5% change), BMI reduction (per 1 unit), or BMI category change (overweight to normal vs remaining overweight). Weight loss 5 years after a diagnosis of CRC was found to be significantly associated with decreased long-term survival, suggesting the importance of avoiding weight loss in survivors of CRC. Future research should attempt to further evaluate this association, accounting for whether this weight change was intentional or represents a marker of declining health. Cancer 2017;123:4701-4708. © 2017 American Cancer Society.

Clinical verification of genetic results returned to research participants: findings from a Colon Cancer Family Registry.

BackgroundThe extent to which participants act to clinically verify research results is largely unknown. This study examined whether participants who received Lynch syndrome (LS)‐related findings pursued researchers’ recommendation to clinically verify results with testing performed by a CLIA‐certified laboratory.MethodsThe Fred Hutchinson Cancer Research Center site of the multinational Colon Cancer Family Registry offered non‐CLIA individual genetic research results to select registry participants (cases and their enrolled relatives) from 2011 to 2013. Participants who elected to receive results were counseled on the importance of verifying results at a CLIA‐certified laboratory. Twenty‐six (76.5%) of the 34 participants who received genetic results completed 2‐ and 12‐month postdisclosure surveys; 42.3% of these (11/26) participated in a semistructured follow‐up interview.ResultsWithin 12 months of result disclosure, only 4 (15.4%) of 26 participants reported having verified their results in a CLIA‐certified laboratory; of these four cases, all research and clinical results were concordant. Reasons for pursuing clinical verification included acting on the recommendation of the research team and informing future clinical care. Those who did not verify results cited lack of insurance coverage and limited perceived personal benefit of clinical verification as reasons for inaction.ConclusionThese findings suggest researchers will need to address barriers to seeking clinical verification in order to ensure that the intended benefits of returning genetic research results are realized.

Association between the Lynch syndrome gene MSH2 and breast cancer susceptibility in a Canadian familial cancer registry

BackgroundPrevious studies assessing breast cancer risk in families with Lynch syndrome (LS) have yielded conflicting results. Furthermore, conclusions are limited by small sample size and few breast cancer outcomes. This...

Abstract 1304: The contribution of rare and low-frequency variants to colorectal cancer heritability

Abstract Studies that estimate complex disease heritability based on genome-wide common SNP array data have shown that a large fraction of heritability is contributed from variants that do not reach genome-wide significance at current genome-wide association study (GWAS) sample sizes. The contribution of rare variants to heritability has yet to be explored for many complex diseases. Despite the decreasing cost of sequencing, it still remains prohibitively expensive to sequence sufficient samples for well-powered genetic association studies of rare variants. However, with increasingly large and denser imputation reference panels it has become feasible to accurately impute variants with minor allele frequencies (MAFs) as low as 0.1%, enabling study of a subset of rare risk variants. In previous work, we used restricted maximum likelihood (REML) to estimate the total additive heritability of colorectal cancer (CRC) based on common SNP array genotypes. Here, we expand this work using imputed genotype data and a larger sample size. We performed whole-genome sequencing of 1,961 CRC cases and 981 controls, and subsequently imputed these haplotypes into 11,895 unrelated CRC cases and 14,659 unrelated controls that are part of the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). We estimated heritability from individual-level imputed genotype data using LD- and MAF-stratified GREML, as implemented in GCTA. In total, we analyzed 17,649,167 imputed genetic variants with minor allele count >3. Published heritability estimates for CRC from family-based studies vary from 12% to 35%. Based on common genotyped SNPs, we previously estimated heritability to be 7.42% (95% CI: 4.71-10.12%) on the underlying liability scale, assuming a population prevalence of 0.004. For imputed genotypes, we estimate the total heritability to be 12.0% (95% CI: 9.65-14.35). Using a likelihood ratio test, we demonstrate a significant contribution of variants with MAF ≤1% to CRC genetic risk (P=0.003). Because of the imperfect imputation accuracy for very rare variants, their contribution is likely higher. These results suggest that with additional sequencing, improved imputation accuracy, and larger GWAS, we should expect to start discovering rare variant associations for CRC risk. Citation Format: Jeroen R. Huyghe, Sai Chen, Hyun M. Kang, Tabitha Harrison, Sonja I. Berndt, Stephane Bézieau, Hermann Brenner, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Steven J. Gallinger, Stephen B. Gruber, Andrea Gsur, Michael Hoffmeister, Thomas Hudson, Mark A. Jenkins, Loic Le Marchand, Polly A. Newcomb, John D. Potter, Conghui Qu, Martha L. Slattery, Joshua D. Smith, Emily White, Goncalo R. Abecasis, Li Hsu, Deborah A. Nickerson, Ulrike Peters, on behalf of CCFR and GECCO. The contribution of rare and low-frequency variants to colorectal cancer heritability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1304. doi:10.1158/1538-7445.AM2017-1304

Abstract 1286: Targeted deep sequencing of colorectal tumor tissues to study associations of tumor subtypes with germline genetic, lifestyle, and environmental risk factors

Abstract The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) in collaboration with the Colorectal Cancer Family Registry (CCFR) aims to identify genetic variants and environmental risk factors that impact colorectal cancer (CRC). Over 30 studies from North America, Europe, and Australia participate in GECCO. These studies have collected clinical, epidemiological, and survival data, as well as blood and tumor biospecimens, for over 80,000 CRC cases and controls. The current study aims to conduct targeted deep sequencing of tumors and matching normal DNA to identify recurrent and novel somatic and germline variants in 4,200 CRC cases. To achieve this goal, an AmpliSeq targeted sequencing panel of 1.12 Mbp was constructed to sequence the coding regions of 190 significantly mutated genes identified from whole exome sequencing datasets generated by the Nurses’ Health Study and Health Professional’s Follow-up Study, and The Cancer Genome Atlas. The panel also covers coding regions of 15 genes with germline high penetrance mutations in CRC, 54 regions to detect CRC-related copy number alterations (CNAs), and microsatellite and homopolymer repeat regions to identify defective DNA mismatch repair. Primers were also included to detect Fusobacterium nucleatum DNA in tumor biopsies, as F. nucleatum is thought to promote CRC carcinogenesis. Sequencing of the DNA libraries on Illumina HiSeq 2500 produced a mean coverage of greater than 500X for tumor DNA and 100X for normal DNA, with >85% of the bases covered at the target at 50x. So far, targeted sequencing of >1,500 DNA samples from CRC tumors and normal tissues has identified recurrent and novel somatic mutations, germline genetic variants, and hypermutation status of the tumors due to defective DNA mismatch repair or pathogenic mutations in the POLE gene. Targeted sequencing has also allowed quantification of the F. nucleatum DNA in tumor biopsies; the results were validated by a multiplex QPCR assay. At the AACR annual meeting, we will present targeted sequencing results generated from the first two GECCO-participating studies (n=1,300 cases). These data will be valuable for future association testing of somatic mutations, CNAs, hypermutation status, and F. nucleatum with germline genetic variants, lifestyle, and environmental risk factors and survival. This large study will allow development of better strategies for diagnosis, treatment, and prevention of CRC. Citation Format: Syed H. Zaidi, Wei Sun, Jeroen Huyghe, Catherine S. Grasso, Quang Trinh, Charles Connolly, Amy French, Jasmine Mu, Marios Giannakis, Eve Shinbrot, Ivan Borozan, Michael J. Quist, Hermann Brenner, Daniel Buchanan, Peter Campbell, Andrew Chan, Jenny Chang-Claude, Vincent Ferretti, Charles Fuchs, Andrea Gsur, Marc Gunter, Tabitha Harrison, Michael Hoffmeister, Wen-Yi Huang, Paul Krzyzanowski, Stephen Lee, Mathieu Lemire, Jessica Miller, Danielle Pasternack, Cherie Teney, Elaine Mardis, Polly Newcomb, Lincoln Stein, Lee Timms, David Wheeler, Christina Yung, Niha Zubair, Levi Garraway, Shuji Ogino, Li Hsu, Steven Gallinger, Stephen Thibodeau, Thomas Hudson, Ulrike Peters. Targeted deep sequencing of colorectal tumor tissues to study associations of tumor subtypes with germline genetic, lifestyle, and environmental risk factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1286. doi:10.1158/1538-7445.AM2017-1286

Abstract 2271: DNMT1 expression is peripheral mononuclear cells is associated with increased breast cancer risk

Abstract Loss of global DNA methylation in peripheral tissue has been identified as a biomarker of breast cancer susceptibility in several studies. DNA methyl-transferases or DNMTs are the enzymes in charge of catalyzing the addition of the methyl group to the DNA molecule. Of the different DNMTs described in humans, only DNMT1 has been found to be in charge of adding methyl groups to the newly synthesized DNA strand. Therefore, compromised levels of this enzyme might lead to a loss of global DNA methylation and concomitantly an increase in breast cancer risk. However, to date no study has examined the association between peripheral levels of DNMT1 and breast cancer. To investigate this relation, we conducted a case-control study including sisters in the New York site of the Breast Cancer Family Registry. We extracted mRNA from peripheral mononuclear cells (PMNC) in 196 sister sets, a total of 479 female participants, and assayed DNMT1 gene expression levels using Taqman expression assays. The results were analyzed using generalized estimating equations (GEE). We found that there were no large differences between the mean levels of DNMT1 expression levels of women with breast cancer and controls; mean level in cases was 0.46 ± 0.71 versus 0.63 ± 1.42 in controls (p=0.10). When examining expression levels as a continuous variable, there also were no associations in GEE regression models adjusting for age at blood drawn and smoking status Odds Ratio (OR) = 1.17 (95% confidence interval (CI) = 0.97 - 1.40 per one unit increase in expression levels), p=0.11). However, when results were analyzed by categorizing DNMT1 expression in tertiles, lower DNMT1 expression (≤ 0.17%) was associated with statistically significantly higher odds of breast cancer (OR = 1.47 (95%CI = 1.02 - 2.10), p=0.04). If replicated in other studies, these findings suggest that low DNMT1 expression in PBMC has the potential to be used as a biomarker of breast cancer risk in women at high risk of the disease. Citation Format: Lissette Delgado-Cruzata, Xinran Ma, Yuyan Liao, Maya Kappil, Regina M. Santella, Mary Beth Terry. DNMT1 expression is peripheral mononuclear cells is associated with increased breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2271. doi:10.1158/1538-7445.AM2017-2271

Abstract 240: Dietary patterns and risk of colorectal neoplasia in Puerto Rican Hispanics: A case control study

Abstract Colorectal cancer (CRC) is the leading cause of cancer death in Puerto Rico and second cause of death in the US. It is well accepted that modifiable lifestyle habits such as diet, contribute to CRC development. Diet could reduce up to 70% of CRC cases. Dietary patterns vary according to race/ethnicity. Puerto Rican Hispanics (PRH) have been shown to have a distinct diet compared to US non-Hispanic Whites (NHW). According to the BRFSS, only 17.7% of PRH and 23.4% of NHW consume fruit and vegetables five times per day. The objective of this study was to describe the association of specific food groups consumption with the risk of colorectal neoplasia (CRN: polyps and/or CRC) in PRH. The validated Colon Cancer Family Registry food frequency questionnaire was administered to healthy individuals (controls) and individuals with CRN (cases) recruited through the Puerto Rico Colorectal Cancer Registry (PURIFICAR). Models adjusted by age, gender, educational attainment and family history of CRC were fitted to estimate the odds ratios (OR) with 95% confidence intervals (CI) through a polytomous logistic regression models comparing cases and controls. A total of 577 subjects were included in the study (controls=254; polyps=50; and CRC=273). The frequency of consumption of fruits, low fat dairy products, eggs, pasta/rice, non-fried chicken, and seafood were significantly different between controls and CRN cases (p<0.05). Adjusted models showed that a higher consumption of fruits (OR≥once per day=0.29) and full-fat dairy products (OR≥once per day=0.22) were associated with decreased risk of polyps (p<0.05). A frequency of consumption of 2-4 times per week, when compared to ≤ 1 per week, of full-fat dairy products (OR2-4 times per week=0.51), seafood (OR2-4 times per week=0.49), and red meats (OR2-4 times per week=0.56) was associated with a decreased risk of CRC (p<0.05). Our results showed that a higher consumption of fruits and full-fat dairy products significantly reduce the risk of polyps in PRH. In addition, consumption of seafood, full-fat dairy, and red meats up to 4 times per week may reduce the risk of CRC in PRH. Educational interventions for cancer prevention in PRH should incorporate nutritional information tailor to our community. Citation Format: Julyann Perez-Mayoral, Sachelly Julian, Marievelisse Soto-Salgado, Michael J. Gonzalez, Marcia Cruz-Correa. Dietary patterns and risk of colorectal neoplasia in Puerto Rican Hispanics: A case control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 240. doi:10.1158/1538-7445.AM2017-240

Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort.

The underlying genetic cause of colorectal cancer (CRC) can be identified for 5-10% of all cases, while at least 20% of CRC cases are thought to be due to inherited genetic factors. Screening for highly penetrant mutations in genes associated with Mendelian cancer syndromes using next-generation sequencing (NGS) can be prohibitively expensive for studies requiring large samples sizes. The aim of the study was to identify rare single nucleotide variants and small indels in 40 established or candidate CRC susceptibility genes in 1,046 familial CRC cases (including both MSS and MSI-H tumor subtypes) and 1,006 unrelated controls from the Colon Cancer Family Registry Cohort using a robust and cost-effective DNA pooling NGS strategy. We identified 264 variants in 38 genes that were observed only in cases, comprising either very rare (minor allele frequency <0.001) or not previously reported (n=90, 34%) in reference databases, including six stop-gain, three frameshift, and 255 non-synonymous variants predicted to be damaging. We found novel germline mutations in established CRC genes MLH1, APC, and POLE, and likely pathogenic variants in cancer susceptibility genes BAP1, CDH1, CHEK2, ENG, and MSH3. For the candidate CRC genes, we identified likely pathogenic variants in the helicase domain of POLQ and in the LRIG1, SH2B3, and NOS1 genes and present their clinicopathological characteristics. Using a DNA pooling NGS strategy, we identified novel germline mutations in established CRC susceptibility genes in familial CRC cases. Further studies are required to support the role of POLQ, LRIG1, SH2B3 and NOS1 as CRC susceptibility genes.

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. BRCA1/2 mutations, family cancer history, and mutation location. Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

Somatic mutations of the coding microsatellites within the beta-2-microglobulin gene in mismatch repair-deficient colorectal cancers and adenomas.

In colorectal cancers (CRCs) with tumour mismatch repair (MMR) deficiency, genes involved in the host immune response that contain microsatellites in their coding regions, including beta-2-microglobulin (B2M), can acquire mutations that may alter the immune response, tumour progression and prognosis. We screened the coding microsatellites within B2M for somatic mutations in MMR-deficient CRCs and adenomas to determine associations with tumour subtypes, clinicopathological features and survival. Incident MMR-deficient CRCs from Australasian Colorectal Cancer Family Registry (ACCFR) and the Melbourne Collaborative Cohort Study participants (n = 144) and 63 adenomas from 41 MMR gene mutation carriers from the ACCFR were screened for somatic mutations within five coding microsatellites of B2M. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival by B2M mutation status were estimated using Cox regression, adjusting for age at CRC diagnosis, sex, AJCC stage and grade. B2M mutations occurred in 30 (20.8%) of the 144 MMR-deficient CRCs (29% of the MLH1-methylated, 17% of the Lynch syndrome and 9% of the suspected Lynch CRCs). No B2M mutations were identified in the 63 adenomas tested. B2M mutations differed by site, stage, grade and lymphocytic infiltration although none reached statistical significance (p > 0.05). The HR for overall survival for B2M mutated CRC was 0.65 (95% CI 0.29-1.48) compared with B2M wild-type. We observed differences in B2M mutation status in MMR-deficient CRC by tumour subtypes, site, stage, grade, immune infiltrate and for overall survival that warrant further investigation in larger studies before B2M mutation status can be considered to have clinical utility.

Inflammatory diet and risk for colorectal cancer: A population-based case-control study in Newfoundland, Canada.

Chronic inflammation is implicated in causing cancer. Diet plays an important role in regulating chronic inflammation by altering circulating levels of inflammatory biomarkers. Effect of single food or nutrient on cancer often is inconclusive; perhaps due to dietary interactions and multicolinearity. The aim of this study was to determine prediagnostic inflammatory potential of overall diet in relation to risk for colorectal cancer (CRC). In all, 547 patients with CRC from Newfoundland Familial Colorectal Cancer Registry and 685 controls from the general population were identified. Data on sociodemographic, medical history, lifestyle, and a 169-item food frequency questionnaire were collected retrospectively from both groups. Energy-adjusted Dietary Inflammatory Index (DII) score was calculated and used as both categorical and continuous variables for analysis. Odds ratio was estimated using multivariable logistic regression after adjusting potential confounders. A linear test for trend was performed using the median value in each quartile. Overall energy-adjusted mean DII score was -0.81 (range -5.19 to 6.93). Cases (-0.73±1.5) had slightly higher DII scores than controls (-0.89±1.6; P=0.04). After adjusting the potential confounders, a statistically significant association was found between DII score and CRC risk. Using DII as a continuous variable (odds ratio [OR]continuous 1.10, 95% confidence interval [CI] 1.01-1.20) and categorical variable (ORquartile 1 versus 4 1.65, 95% CI 1.13-2.42; Ptrend=0.02). Our findings indicate that proinflammatory diets are associated with an increased risk for CRC in the Newfoundland population.

Psychometric characteristics of the mental health crisis assessment scale in youth with autism spectrum disorder.

Youth with autism spectrum disorder (ASD) exhibit high rates of psychopathology. These symptoms can pose a risk of injury to self or others when the child is in crisis. Despite this danger, there are no instruments available to identify those with ASD who are at risk or actively in crisis. This study examined the psychometric properties of the Mental Health Crisis Assessment Scale (MCAS), a 28 item parent report measure. The MCAS was administered to the parents of 606 children and young adults (aged 3-25years, M age=13years, SD=5years) enrolled in the Interactive Autism Network, an online registry of families raising a child with ASD. The MCAS asks parents to rate the severity of various emotional and behavioral symptoms exhibited by their child. The parent then selects the behavior they perceive as the most dangerous behavior and rates the acuity of as well as their efficacy in managing this behavior. The MCAS was tested for internal consistency, construct validity, criterion validity, and convergent validity. The MCAS demonstrated strong internal consistency (Total Scale Cronbach's α=.88). The exploratory and confirmatory factor analyses suggested that a two factor (acuity and behavioral efficacy) model fit the data well, providing evidence of construct validity. Criterion validity, which was assessed by comparing the MCAS to clinician determination of crisis, indicated high levels of agreement (ROC=.85). Strong positive relationships emerged between the MCAS and measures of family distress (r=.56), parental stress, and frustration (r=.48), and use of emergency psychiatric services (OR=24.2, 95% CI: 8.6-68.2), indicating convergent validity of the measure (all p<.05). Results of the psychometric analyses suggest the MCAS appears to be a promising tool that can measure mental health crises in youth with ASD.

Abstract PR05: Does a comprehensive family history of colorectal cancer improve risk prediction?

Abstract Background: Family history of colorectal cancer (CRC) is a strong and well-established risk factor for CRC. To date, however, family history (FH) of the disease is generally only broadly categorized (usually as present or absent) in most risk prediction models (Freedman et al. 2009). These approaches fail to fully utilize information on family history and may lead to suboptimal predictive performance of CRC risk. We investigated the utility of a CRC risk model that incorporates a comprehensive family history of CRC as well as information on known genetic and environmental risk factors and personal characteristics. Methods: We used data from the Colon Cancer Family Registry (CCFR), a large, international consortium of six study centers. Prediction models were developed based on incident invasive CRC cases (N = 4445) and population-based controls (N = 3967) that were recruited from three study sites (Seattle, USA; Ontario, Canada; and Melbourne, Australia). A familial risk profile (FRP) score, a probability index of absolute risk for lifetime CRC was estimated based on family structure, age of onset for affected relatives and the polygenic effect of MLH1, MSH2, MSH6, PMS2 and MUTYH using modified segregation analysis, an approach adapted from Antoniou et al (2002)). Two sets of gender-specific logistic regression models were built: (I) the FRP models, which included FRP and other known risk factors (e.g., BMI, consumption of red meat, calcium and NSAID use duration, smoking amount (pack-years), a history of polyps, and history of FOBT, sigmoidoscopy, colonoscopy, fruit intake, and use of hormone replacement therapy for female); and (II) binary FH models, which replaced FRP with a binary indicator (yes/no) for any self-reported first-degree family member with CRC. 5-year absolute risks were calculated based on the estimated odds ratios (OR), country-, sex- and age-specific CRC incidence rate and mortality due to causes other than CRC. Model validation was conducted with unaffected relatives (N=12,120) and population-based controls (N=1,899) from five study sites based on the follow-up information on incident CRC and death status. The primary endpoint was CRC diagnosis within 5-year after baseline. We used calibration plots to compare the predicted 5-year absolute risks with the observed cumulative incidence rates. Receiver Operating Characteristic (ROC) curve analyses were conducted and areas under the ROC curve (AUC) were used to assess the discriminatory capacity for separating subjects with and without a CRC diagnosis within 5 years, accounting for censoring and competing risk. Results: The ORs (95% confidence interval [CI]) using the FRP per 10% increase were 1.16 (1.11-1.20) for males, and 1.09 (1.06-1.12) for females in the FRP models, while the ORs for the binary FH model were 2.32 (1.88- 2.85) for men and 1.70 (1.38-2.09) for women. The FRP models provided slightly better calibration, with average predicted risks falling within the 95% CIs of the empirical cumulative rates. The binary FH models, by comparison, tended to yield higher estimated CRC risks compared with the observed risks among individuals whose risks were above the top10% of the risk distribution. Both models yielded comparable AUCs using the full validation set. Among individuals with at least one first-degree family member affected with CRC, the FRP model performed significantly better (AUC = 0.71) than the FH model (AUC = 0.63) for male participants; difference equaled 0.09 (95% CI: 0.02, 0.16). The models were comparable for females. Conclusion: Our CRC prediction model that incorporates more comprehensive family history of CRC can provide improved calibration and discrimination of risks compared with the simple FH model, especially in populations with higher underlying risk. The models developed may potentially further improve screening decision making among subgroups with elevated CRC risk.

Mosaic trisomy 16: what are the obstetric and long-term childhood outcomes?

To evaluate obstetric and neonatal outcomes as well as long-term neurodevelopmental outcomes and quality of life among prenatally detected cases of mosaic trisomy (MT16) and confined placental mosaicism (CPM) for trisomy 16. We recruited participants for this cross-sectional study through an international registry of families with children diagnosed with MT16 or CPM. Parents were interviewed about expectations based on prenatal counseling as well as about actual perinatal outcomes, congenital anomalies, medical conditions, and school progress. Health-related quality of life (HRQOL) was assessed via the Pediatric Quality of Life Inventory 4.0 Generic Core Scales. Forty-four families were enrolled, and 68.2% of the children were female. Common complications were gestational hypertension (gHTN) or preeclampsia (38.1%), preterm delivery (PTD; 71.4%), cesarean delivery (CD; 73.8%), birth weight <10th percentile (73.8%), neonatal intensive care unit (NICU) admission (88.1%), and congenital anomalies (59.5%). However, 81.8% of school-aged children were entirely in mainstream classes, and median physical, psychosocial, and total HRQOL scores were high: 90.6 (34.4-100), 86.7 (35-100), and 84.8 (34.8-100), respectively (100 = optimal quality of life). Several obstetric and neonatal complications are common with pregnancies affected by MT16 or CPM. However, the majority of children demonstrate normal neurodevelopmental outcomes and high HRQOL.Genet Med advance online publication 06 April 2017.

The role of registries and genetic databases in familial hypercholesterolemia.

To review how leveraging familial hypercholesterolemia registries can impact molecular genetic research and precision medicine. Familial hypercholesterolemia is both much more common and more phenotypically heterogeneous than previously thought with some evidence for significant genotype to phenotype correlations. Genetic testing for familial hypercholesterolemia is becoming both more widely available and cheaper, spurring conversations about its clinical utility. In most countries, familial hypercholesterolemia is underdiagnosed and diagnosed later in life, often after the onset of coronary heart disease (CHD). Familial hypercholesterolemia is undertreated; low goal attainment and additional modifiable risk factors further increase CHD risk. Familial hypercholesterolemia epitomizes the goal of precision medicine to define a subset of individuals with a high risk of morbidity and mortality through genetic diagnosis to manage and treat the risk accordingly. Genetic cascade screening can be used to identify familial hypercholesterolemia patients at a younger age and start timely treatment to prevent CHD. Familial hypercholesterolemia registries are tools for clinical research and improving healthcare planning and patient care. As genotype and phenotype correlations in familial hypercholesterolemia become increasingly understood, this information will likely play a more important role in diagnosis and treatment especially as the cost of genetic testing continues to decline.

Longitudinal Study of Mammographic Density Measures That Predict Breast Cancer Risk.

Background: After adjusting for age and body mass index (BMI), mammographic measures-dense area (DA), percent dense area (PDA), and nondense area (NDA)-are associated with breast cancer risk. Our aim was to use longitudinal data to estimate the extent to which these risk-predicting measures track over time.Methods: We collected 4,320 mammograms (age range, 24-83 years) from 970 women in the Melbourne Collaborative Cohort Study and the Australian Breast Cancer Family Registry. Women had on average 4.5 mammograms (range, 1-14). DA, PDA, and NDA were measured using the Cumulus software and normalized using the Box-Cox method. Correlations in the normalized risk-predicting measures over time intervals of different lengths were estimated using nonlinear mixed-effects modeling of Gompertz curves.Results: Mean normalized DA and PDA were constant with age to the early 40s, decreased over the next two decades, and were almost constant from the mid-60s onward. Mean normalized NDA increased nonlinearly with age. After adjusting for age and BMI, the within-woman correlation estimates for normalized DA were 0.94, 0.93, 0.91, 0.91, and 0.91 for mammograms taken 2, 4, 6, 8, and 10 years apart, respectively. Similar correlations were estimated for the age- and BMI-adjusted normalized PDA and NDA.Conclusions: The mammographic measures that predict breast cancer risk are highly correlated over time.Impact: This has implications for etiologic research and clinical management whereby women at increased risk could be identified at a young age (e.g., early 40s or even younger) and recommended appropriate screening and prevention strategies. Cancer Epidemiol Biomarkers Prev; 26(4); 651-60. ©2017 AACR.

The Danish HD Registry-a nationwide family registry of HD families in Denmark.

The Danish Huntington's Disease Registry (DHR) is a nationwide family registry comprising 14 245 individuals from 445 Huntington's disease (HD) families of which the largest family includes 845 individuals in 8 generations. 1136 DNA and/or blood samples and 18 fibroblast cultures are stored in a local biobank. The birthplace of the oldest HD carrier in each of the 261 families of Danish origin was unevenly distributed across Denmark with a high number of families in the middle part of the peninsula Jutland and in Copenhagen, the capital. The prevalence of HD in Denmark was calculated to be 5-8:100 000. 1451 individuals in the DHR had the size of the HTT CAG repeat determined of which 975 had 36 CAG repeats or more (mean ± SD: 43,5 ± 4,8). Two unrelated individuals were compound heterozygous for alleles ≥36 CAGs, and 60 individuals from 34 independent families carried an intermediate allele.

Increased genomic burden of germline copy number variants is associated with early onset breast cancer: Australian breast cancer family registry

BackgroundWomen with breast cancer who have multiple affected relatives are more likely to have inherited genetic risk factors for the disease. All the currently known genetic risk factors for breast cancer account for less than half of the average familial risk. Furthermore, the genetic factor(s) underlying an increased cancer risk for many women from multiple-case families remain unknown. Rare genomic duplications and deletions, known as copy number variants (CNVs), cover more than 10% of a human genome, are often not assessed in studies of genetic predisposition, and could account for some of the so-called “missing heritability”.MethodsWe carried out a hypothesis-generating case-control study of breast cancer diagnosed before age 40 years (200 cases, 293 controls) using population-based cases from the Australian Breast Cancer Family Study. Genome-wide scanning for CNVs was performed using the Human610-Quad BeadChip and fine-mapping was conducted using PennCNV.ResultsWe identified deletions overlapping two known cancer susceptibility genes, (BRCA1 and BLM), and a duplication overlapping SMARCB1, associated with risk. The number of deletions across the genome was 1.5-fold higher for cases than controls (P = 10-16), and 2-fold higher when only rare deletions overlapping genes (frequency <1%) were assessed (P = 5 × 10-4). Association tests of CNVs, followed by experimental validation of CNV calls, found deletions overlapping the OR4C11 and OR4P4 genes were associated with breast cancer (P = 0.02 and P = 0.03, respectively).ConclusionThese results suggest rare CNVs might have a role in breast cancer susceptibility, at least for disease at a young age.

The dynamic DNA methylation landscape of the mutL homolog 1 shore is altered by MLH1-93G>A polymorphism in normal tissues and colorectal cancer

BackgroundColorectal cancers (CRCs) undergo distinct genetic and epigenetic alterations. Expression of mutL homolog 1 (MLH1), a mismatch repair gene that corrects DNA replication errors, is lost in up to 15% of sporadic tumours due to mutation or, more commonly, due to DNA methylation of its promoter CpG island. A single nucleotide polymorphism (SNP) in the CpG island of MLH1 (MLH1-93G>A or rs1800734) is associated with CpG island hypermethylation and decreased MLH1 expression in CRC tumours. Further, in peripheral blood mononuclear cell (PBMC) DNA of both CRC cases and non-cancer controls, the variant allele of rs1800734 is associated with hypomethylation at the MLH1 shore, a region upstream of its CpG island that is less dense in CpG sites.ResultsTo determine whether this genotype-epigenotype association is present in other tissue types, including colorectal tumours, we assessed DNA methylation in matched normal colorectal tissue, tumour, and PBMC DNA from 349 population-based CRC cases recruited from the Ontario Familial Colorectal Cancer Registry. Using the semi-quantitative real-time PCR-based MethyLight assay, MLH1 shore methylation was significantly higher in tumour tissue than normal colon or PBMCs (P < 0.01). When shore methylation levels were stratified by SNP genotype, normal colorectal DNA and PBMC DNA were significantly hypomethylated in association with variant SNP genotype (P < 0.05). However, this association was lost in tumour DNA. Among distinct stages of CRC, metastatic stage IV CRC tumours incurred significant hypomethylation compared to stage I–III cases, irrespective of genotype status. Shore methylation of MLH1 was not associated with MSI status or promoter CpG island hypermethylation, regardless of genotype. To confirm these results, bisulfite sequencing was performed in matched tumour and normal colorectal specimens from six CRC cases, including two cases per genotype (wildtype, heterozygous, and homozygous variant). Bisulfite sequencing results corroborated the methylation patterns found by MethyLight, with significant hypomethylation in normal colorectal tissue of variant SNP allele carriers.ConclusionsThese results indicate that the normal tissue types tested (colorectum and PBMC) experience dynamic genotype-associated epigenetic alterations at the MLH1 shore, whereas tumour DNA incurs aberrant hypermethylation compared to normal DNA.