Family Registry Research Articles

Population-based estimates of age-specific cumulative risk of breast cancer for pathogenic variants in ATM

BackgroundMultigene panel tests for breast cancer predisposition routinely include ATM as it is now a well-established breast cancer predisposition gene.MethodsWe included ATM in a multigene panel test applied to the Australian Breast Cancer Family Registry (ABCFR), a population-based case–control–family study of breast cancer, with the purpose of estimating the prevalence and penetrance of heterozygous ATM pathogenic variants from the family data, using segregation analysis.ResultsThe estimated breast cancer hazard ratio for carriers of pathogenic ATM variants in the ABCFR was 1.32 (95% confidence interval 0.45–3.87; P = 0.6). The estimated cumulative risk of breast cancer to age 80 years for heterozygous ATM pathogenic variant carriers was estimated to be 13% (95% CI 4.6–30).ConclusionsAlthough ATM has been definitively identified as a breast cancer predisposition gene, further evidence, such as variant-specific penetrance estimates, are needed to inform risk management strategies for carriers of pathogenic variants to increase the clinical utility of population testing of this gene.

Characteristics of the autism spectrum disorder gastrointestinal and related behaviors inventory in children.

Gastrointestinal (GI) symptoms are one of the prevalent co‐occurring issues in autism spectrum disorder (ASD), though the range of symptom frequency estimates varies dramatically across studies, which can limit the further research of GI issues in ASD as well as potential treatment strategies. The wide range of prevalence estimates is partly due to the lack of standardized, validated measures of GI symptoms among people with ASD. The goal of this study was to (1) develop a measure, which included non‐verbal and mealtime behaviors, to assess for GI symptoms and (2) evaluate its psychometric characteristics. This was accomplished by drawing on two existing tools, Autism Treatment Network Gastrointestinal Inventory and the Brief Autism Mealtime Behavior Inventory, and deriving new items, to create the “ASD Gastrointestinal and Related Behaviors Inventory” (ASD‐GIRBI). The ASD‐GIRBI was piloted in an online registry of families with a child with ASD. A psychometric analysis was carried out in a sample of 334 children aged 6–17 years with ASD, resulting in a 36‐item tool. The Cronbach's alpha for the overall scale was 0.88. Exploratory factor analysis identified a seven‐factor model (1. Bowel movement pain; 2. Aggressive or disruptive during mealtimes; 3. Particular with foods; 4. Abdominal pain and upset stomach; 5. Refusing food; 6. Constipation and encopresis; 7. Motor or other behaviors). Following validation in an independent sample with clinical evaluation of GI symptoms, this tool will be helpful for both research and clinical purposes.

Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region.

Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1-28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose-response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06-1.17; OR for AA genotype = 1.22; 95% CI, 1.14-1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. The study identifies multifaceted evidence of a possible functional effect for rs1318920.

Opinions and experiences of recontacting patients: a survey of Australasian genetic health professionals.

The issue of recontacting past genetics patients is increasingly relevant, particularly with the introduction of next-generation sequencing. Improved testing can provide additional information on the pathogenicity and prevalence of genetic variants, often leading to a need to recontact patients. Some international genetics societies have position statements and recommendations to guide genetic health professionals (GHPs) navigating the legal, ethical and practical issues of recontacting. In the absence of a standardised Australasian protocol, we explored the experiences and opinions of Australasian GHPs regarding patient follow-up and recontacting practices. Forty-five respondents completed an online survey. Most respondents indicated that recontacting occurred on an ad hoc basis, but most genetic services relied on patients (or family) initiating recontact. Implementation of a routine recontacting system was widely dismissed by 73% of respondents, citing lack of resources, limited information on legal responsibility and setting unrealistic expectations as common barriers. If recontact was contemplated, e-communication was an acceptable first step. This study identified the need for integrated familial cancer registries to assist under-resourced genetic services to maintain up-to-date patient records. Developing a standard recontacting protocol with flexibility to account for patient individuality and circumstances might enable provision of equitable service within Australasia.

Marital Surname System in Japan - Fūfubessei Issues and Disparate Impact of Civil Code Article 750 and Koseki (Family Registry) Law

Marital Surname System in Japan - Fūfubessei Issues and Disparate Impact of Civil Code Article 750 and Koseki (Family Registry) Law

Endoplasmic stress-inducing variants in CPB1 and CPA1 and risk of pancreatic cancer: A case-control study and meta-analysis.

Gene variants that encode pancreatic enzymes with impaired secretion can induce pancreatic acinar endoplasmic reticulum (ER) stress, cellular injury and pancreatitis. The role of such variants in pancreatic cancer risk has received little attention. We compared the prevalence of ER stress-inducing variants in CPA1 and CPB1 in patients with pancreatic ductal adenocarcinoma (PDAC cases), enrolled in the National Familial Pancreas Tumor Registry, to their prevalence in noncancer controls in the Genome Aggregation Database (gnomAD). Variants of unknown significance were expressed and variants with reduced secretion assessed for ER stress induction. In vitro assessments were compared with software predictions of variant function. Protein variant software was used to assess variants found in only one gnomAD control ("n-of-one" variants). A meta-analysis of prior PDAC case/control studies was also performed. Of the 1385 patients with PDAC, 0.65% were found to harbor an ER stress-inducing variant in CPA1 or CPB1, compared to 0.17% of the 64 026 controls (odds ratio [OR]: 3.80 [1.92-7.51], P=.0001). ER stress-inducing variants in the CPA1 gene were identified in 4 of 1385 PDAC cases vs 77 of 64 026 gnomAD controls (OR: 2.4 [0.88-6.58], P=.087), and variants in CPB1 were detected in 5 of 1385 cases vs 33 of 64 026 controls (OR: 7.02 [2.74-18.01], P=.0001). Meta-analysis demonstrated strong associations for pancreatic cancer and ER-stress inducing variants for both CPA1 (OR: 3.65 [1.58-8.39], P < .023) and CPB1 (OR: 9.51 [3.46-26.15], P < .001). Rare variants in CPB1 and CPA1 that induce ER stress are associated with increased odds of developing pancreatic cancer.

A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO.

Identifying families with an underlying inherited cancer predisposition is a major goal of cancer prevention efforts. Mendelian risk models have been developed to better predict the risk associated with a pathogenic variant of developing breast/ovarian cancer (with BRCAPRO) and the risk of developing pancreatic cancer (PANCPRO). Given that pathogenic variants involving BRCA2 and BRCA1 predispose to all three of these cancers, we developed a joint risk model to capture shared susceptibility. We expanded the existing framework for PANCPRO and BRCAPRO to jointly model risk of pancreatic, breast, and ovarian cancer and validated this new model, BRCAPANCPRO on three data sets each reflecting the common target populations. BRCAPANCPRO outperformed the prior BRCAPRO and PANCPRO models and yielded good discrimination for differentiating BRCA1 and BRCA2 carriers from non-carriers (AUCs 0.79, 95% CI: 0.73-0.84 and 0.70, 95% CI: 0.60-0.80) in families seen in high-risk clinics and pancreatic cancer family registries, respectively. In addition, BRCAPANCPRO was reasonably well calibrated for predicting future risk of pancreatic cancer (observed-to-expected (O/E) ratio = 0.81 [0.69, 0.94]). The BRCAPANCPRO model provides improved risk assessment over our previous risk models, particularly for pedigrees with a co-occurrence of pancreatic cancer and breast and/or ovarian cancer.

Risk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the ATM Gene

Pathogenic germline variants in the ATM gene have been associated with pancreatic cancer risk. Although genetic testing identifies these variants in approximately 1% to 3% of unselected patients with pancreatic cancer, the lifetime risk of pancreatic cancer among individuals with pathogenic ATM variants has not been well estimated. To estimate age-specific penetrance of pancreatic cancer in individuals with a pathogenic variant in the ATM gene. This was a multicenter cohort study of pancreatic cancer family registries in the US and Canada using pedigree data from 130 pancreatic cancer kindreds with a pathogenic germline ATM variant. Data analyses were performed from January 2020 to February 2021. Observational age-specific risk of pancreatic cancer. Penetrance was estimated using modified segregation analysis. The study population of 130 families (123 [95%] White families) comprised 2227 family members (mean age [SD], 58 [22] years; 1096 [49%] women) with complete records (ie, including familial relationships, pancreatic cancer diagnosis, ATM status, proband status, and age), of which 155 individuals had positive results for an ATM pathogenic variant, 16 had a negative result, and the remainder did not have a test result. In these 130 families, 217 individuals had pancreatic cancer: 78 families had 1 such member; 34 families had 2 such members; and 18 families had 3 or more members with pancreatic cancer. The average (range) age at diagnosis was 64 (31-98) years. The cumulative risk of pancreatic cancer among individuals with a germline pathogenic ATM variant was estimated to be 1.1% (95% CI, 0.8%-1.3%) by age 50 years; 6.3% (95% CI, 3.9%-8.7%) by age 70 years; and 9.5% (95% CI, 5.0%-14.0%) by age 80 years. Overall, the relative risk of pancreatic cancer was 6.5 (95% CI, 4.5-9.5) in ATM variant carriers compared with noncarriers. This multicenter cohort study found that individuals with a germline pathogenic ATM variant were at an increased lifetime risk of pancreatic cancer. These risk estimates can help guide decision-making when evaluating the risks and benefits of enhanced early detection surveillance.

Загальний аналіз клініко-лабораторних характеристик пацієнтів, які увійшли до Українського реєстру хворих із сімейною гіперхолестеринемією

The aim – to evaluate clinical and laboratory characteristics of patients of the Ukrainian familial hypercholesterolemia registry taking into account gender differences. Materials and methods. 231 patients with familial hypercholesterolemia were included to the Ukrainian Familial Hypercholesterolemia Registry: 8 children (under 18 years of age) and 223 adult patients (68 men (30.5 %), mean age 43.4±1.3 and 155 women) 69.5 %) – 45.5±1.0 years) with familial hypercholesterolemia verified according to the DLCN criteria. General clinical, laboratory, instrumental examinations and genetic testing were performed.Results and discussion. In the general registry among the patients with familial hypercholesterolemia in the setting of early manifestation of atherosclerosis the male patients with familial hypercholesterolemia were more likely to have coronary artery disease, premature coronary artery disease, cerebral and peripheral atherosclerosis, xanthoma, hypertriglyceridemia, diabetes mellitus, smoking and a history of MI, which caused a higher DLCN score (9.3 points in men against 7.8 points in women, p&lt;0.05). Female patients with familial hypercholesterolemia had a higher percentage of obesity and hypertension, which corresponds to the main gender trends of the Ukrainian population study.Conclusions. Since 2017, for the first time in Ukraine, the register of patients with familial hypercholesterolemia has been initiated. In December 2019 the most severe form – homozygous familial hypercholesterolemia – was first included in the list of orphan diseases by the Order of the Ministry of Health of Ukraine. According to the analysis of the data of the Ukrainian familial hypercholesterolemia registry, this pathology is diagnosed rather late and insufficiently in Ukraine. In patients with familial hypercholesterolemia, against the background of an earlier manifestation of atherosclerotic lesions, gender features of the cardiovascular risk factors profile, which are characteristic of the entire adult population of Ukraine, are preserved. The lower severity of familial hypercholesterolemia clinical manifestations in women according to the general Ukrainian familial hypercholesterolemia registry may be due to the predominance of heterozygous forms in the registry and inclusion of women of reproductive age against the background of preserved antiatherogenic effects of estrogen to the registry.

MP16-11 PATHOLOGICAL FEATURES AND CLINICAL BEHAVIOR OF LYNCH SYNDROME-ASSOCIATED BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Non-invasive II (MP16)1 Sep 2021MP16-11 PATHOLOGICAL FEATURES AND CLINICAL BEHAVIOR OF LYNCH SYNDROME-ASSOCIATED BLADDER CANCER Karla Rebullar, Sean Skeldon, Katherine Lajkosz, Kara Semotiuk, Melyssa Aronson, Cynthia Kuk, Otto Hemminki, Steven Gallinger, Zane Cohen, and Alexandre R. Zlotta Karla RebullarKarla Rebullar More articles by this author , Sean SkeldonSean Skeldon More articles by this author , Katherine LajkoszKatherine Lajkosz More articles by this author , Kara SemotiukKara Semotiuk More articles by this author , Melyssa AronsonMelyssa Aronson More articles by this author , Cynthia KukCynthia Kuk More articles by this author , Otto HemminkiOtto Hemminki More articles by this author , Steven GallingerSteven Gallinger More articles by this author , Zane CohenZane Cohen More articles by this author , and Alexandre R. ZlottaAlexandre R. Zlotta More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002001.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Lynch syndrome (LS) is an autosomal dominant disorder caused by mutations in DNA mismatch repair (MMR) genes that predisposes affected individuals to a variety of cancers. LS is currently believed to occur in about 1 in 300 people in the general population. An increased risk of upper tract urothelial carcinoma (UTUC) in LS has been well described in the literature, specifically in those with MSH2 gene mutation. Our group and others have also described an increased risk of bladder urothelial cancer (UC) in this population. However, little is known about the pathological features and clinical behavior of LS associated bladder cancer. METHODS: Bladder UC data between 1980 to 2019 were evaluated in MMR gene (MSH2, MLH1, MSH6, PMS2, EPCAM) mutation carriers within the Familial Gastrointestinal Cancer Registry (FGICR) in Toronto, Canada. Pathology, recurrences, and progression data were obtained. The American Urological Association (AUA) risk stratification for non-muscle invasive bladder cancer (NMIBC) was used to risk-stratify cases. RESULTS: Among 32 bladder UC patients with confirmed MMR mutations, 28 patients after an initial transurethral resection of bladder tumor (TURBT) had available data for review only. All cases were found with NMIBC on pathology, none with muscle invasive or metastatic disease. 12 cases (43%) were classified as low-risk, 6 (21%) were intermediate, and 10 (36%) were high-risk. 12/28 cases were high grade (HG) (5 TaHG and 7 T1HG). Eleven (39%) patients had recurrences, and 6 of these patients had worse pathology (grade and/or stage) on recurrence. Median time to recurrence was 28.5 months (IQR38.5). With a median follow up time of 5.3 years, 5 (18%) patients progressed to muscle invasive bladder cancer (2 from the low-risk group, 1 from the intermediate group, and 2 from the high-risk group). Median time to progression was 36 months (IQR 42.3). CONCLUSIONS: At the time of the initial presentation, NMIBC accounted for 100% of all LS-associated UC, in sharp contrast with the 25-30% of muscle-invasive disease expected in most series of sporadic tumors. Ta was observed in 75%, of tumors, similar to what would be expected for sporadic cases, although over half of these patients had either intermediate or high-risk NMIBC as per the AUA risk stratification. A worrisome 18% of NMIBC patients progressed to muscle-invasive disease. Interestingly, 20% of these came from a low-risk group, which is intriguing and unexpected. Our finding suggests a possible more aggressive clinical behavior of bladder UC in the LS population. Source of Funding: N/A © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e300-e300 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Karla Rebullar More articles by this author Sean Skeldon More articles by this author Katherine Lajkosz More articles by this author Kara Semotiuk More articles by this author Melyssa Aronson More articles by this author Cynthia Kuk More articles by this author Otto Hemminki More articles by this author Steven Gallinger More articles by this author Zane Cohen More articles by this author Alexandre R. Zlotta More articles by this author Expand All Advertisement Loading ...

32Do the risks of Lynch syndrome-related cancers depend on the parent-of-origin of the mutation?

Abstract Background Individuals who carry pathogenic mutations in DNA mismatch repair (MMR) genes have high risks of cancer, and small studies have suggested that these risks depend on the sex of the parent from whom the mutation was inherited. We have conducted the first large study of such a parent-of-origin effect (POE). Methods Our study was based on all MMR gene mutation carriers and their relatives in the Colon Cancer Family Registry, comprising 18,226 people. The POE was estimated as a hazard ratio (HR) using a segregation analysis approach that adjusted for ascertainment. HR = 1 corresponds to no POE and HR &amp;gt; 1 corresponds to higher risks for maternal mutations. Results For all MMR genes combined, the estimated POE HRs were 1.02 (95% confidence interval (CI) 0.75-1.39, p = 0.9) for male colorectal cancer, 1.12 (95% CI 0.81-1.54, p = 0.5) for female colorectal cancer and 0.84 (95% CI 0.52-1.36, p = 0.5) for endometrial cancer. Separate results for each MMR gene were similar. Conclusions Despite being well-powered, our study did not find any evidence that cancer risks for MMR gene mutation carriers depend on the parent-of-origin of the mutation. Based on current evidence, we don’t recommend that POEs be incorporated into the clinical guidelines or advice for such carriers. Key messages MMR gene mutations inherited from the maternal and paternal side confer similar risks of developing colorectal and endometrial cancer.

Not Entirely Married: Resisting the Hegemonic Patrilineal Family in Japan's Household Registry

Abstract The koseki 戸籍 (family or household registry) has long served as a material representation of the conceptual structure of Japanese family relations. Membership in a family has been stipulated and proved through registration in a koseki document defined through a shared surname and address. Evidence of family membership for purposes of legal transactions and social interactions has rested in the koseki document. However, during the past several decades some women have questioned the social pressure and legal requirement to change their names in marriage, choosing instead to maintain their surname by refusing to register their marriages to their “husbands.” Claiming themselves “married” but not legally registering their marriages, this growing group of name-change resisters defines their nonregistered marriages as jijitsukon 事実婚 (common-law or real marriage). Drawing on ethnographic research with women in jijitsukon marriages in Tokyo who refuse to share a koseki with their “husbands,” this article explores the implications of marital registration resistance in a marriage-centric society and the concurrent critique of the koseki system (the Koseki Law, koseki document, and the broader system of registration) and the legal marriage structure at the core of women's claims to be married when they do not meet Japan's legal criteria for marriage.

Sex differences in HoFH patients of the Ukrainian familial hypercholesterolemia registry

Background and Aims: Homozygous Familial hypercholesterolemia (HoFH)- is a rare genetic lipid disorder associated with increased LDL-C and premature atherosclerotic cardiovascular disease (ASCVD), but gender specificities are not sufficiently studied.

Parental Rights and the Temporality of Attachment: Law, Kinship, and Child Welfare in Japan

AbstractThis article explores the legal norms and regulatory mechanisms in Japan that structure child welfare placement decisions, focusing specifically on the legal category of “parental rights.” It is suggested that the ways child welfare officers and caregivers understand the concept of “rights”—both those of the biological parent(s) and the child—construe kinship relationships as problems to be managed, but with a particular orientation toward what is called in the article the temporality of attachment. Child welfare caseworkers’ understandings of legal categories, processes, and forms of documentation (such as the Japanese family registry) produce particular forms of kinship that prioritize a child's possible future relationship with an absent parent, above and beyond the day-to-day relationships children might develop with alternative caregivers such as foster parents. Despite the fact that the author's Japanese interlocutors often described kinship as an immutable relationship of blood ties, the author shows how kinship is in fact produced through specific encounters between (mostly absent) parents and their children, child welfare caseworkers, and foster and institutional caregivers, scaffolded by their engagement with legal and bureaucratic regimes. The article explores what parenthood means within Japanese child welfare, both as a temporalized form of relationality and as a set of legally structured claims to the right to care.

Hospital-based traceback program for prior ovarian cancer patients results in minimal uptake of genetic counseling and testing

<h3>Objectives:</h3> Objective: To determine the feasibility of a hospital-based approach to implementation of a genetic testing traceback program for ovarian cancer patients <h3>Methods:</h3> The Division of Cancer Prevention and the Division of Cancer Control and Population Sciences, National Cancer Institute (NCI) recognized the opportunity lost by the lack of genetic counseling and/or testing (GC/T) for <i>BRCA1</i> and <i>BRCA2</i> in previously diagnosed women with ovarian cancer (OC). During a 2016 workshop, they coined the term ‘traceback' to describe the concept of offering GC/T to these patients and families that should have been offered services previously. We identified traceback-eligible patients and patient-designated surrogates (emergency contacts, medical power-of-attorney designees, family members) using tumor registry and electronic medical record data. Eligible patients had histology-confirmed epithelial malignancies of ovarian, fallopian tube, or peritoneal origin. All living patients were sent a letter explaining the availability of GC/T and surrogates of deceased patients were called on the telephone. Outcomes of contact attempts were systematically recorded and statistically described. <h3>Results:</h3> We identified 176 presumed-living and 441 deceased trace-back-eligible OC patients diagnosed between 2006-2016. For living patients, 6% (n=11) of letters were returned without forwarding address and 1% (n=2) contacted our office upon receipt of the letter and scheduled genetic counseling visits. Telephone numbers but no other contact information details were available for at least one surrogate for 91% (n=401) of deceased patients. The most commonly listed primary surrogates were spouses (41%) followed by daughters (21%). Approximately 20% (n=.77) of contact attempts to primary surrogates have resulted in a phone conversation about the availability of GC/T. More than half (64%) have required more than one call. Of the primary surrogates successfully contacted, 40% have previously heard of GC/T for OC before, 28% have discussed GC/T with their healthcare providers, 9% had already had GC/T and 13% were interested in GC/T at this time. Phone numbers were invalid for 20% of primary contacts. Overall, hospital-based traceback resulted in GC/T for 2% of those patients and surrogates contacted. <h3>Conclusions:</h3> While feasible, telephone-based contact of patient-designated surrogates is time-intensive and results in minimal uptake of GC/T. To practically execute this type of outreach program, health systems should consider collection of alternative contact information details like email addresses for surrogates and should consider the development of family registries for future contact.

Adopting in the Shadows: False Registration as a Method of Adoption in Postcolonial South Korea

AbstractThis article examines false registration as a method of domestic adoption in South Korea. The article argues that the practice of falsely registering adoptees as natural births in the family registry emerged in response to the highly restrictive adoption laws in South Korea. As adopting agnatic kin for the purpose of family succession was deemed the only legitimate form of adoption, significant hurdles existed for other kinds of adoption in Korea. This article examines the history of domestic adoption in Korea and highlights the legal hurdles to domestic adoption. These restrictive adoption customs first originated during the Chosŏn dynasty (1392–1910) as a prescription for yangban elite; they were then codified as customary law for all Koreans under Japanese colonial rule (1910–45). The ban on non-agnatic adoption continued in the postcolonial period when it was codified in the new Civil Code of 1960. Multiple legal reforms were attempted since the 1970s to promote domestic adoptions, but change was slow. This article argues that the highly restrictive nature of adoption laws in South Korea produced an adoption regime that existed largely outside of the legal realm.

A competing risks model with binary time varying covariates for estimation of breast cancer risks in BRCA1 families.

Mammographic screening and prophylactic surgery such as risk-reducing salpingo oophorectomy can potentially reduce breast cancer risks among mutation carriers of BRCA families. The evaluation of these interventions is usually complicated by the fact that their effects on breast cancer may change over time and by the presence of competing risks. We introduce a correlated competing risks model to model breast and ovarian cancer risks within BRCA1 families that accounts for time-varying covariates. Different parametric forms for the effects of time-varying covariates are proposed for more flexibility and a correlated gamma frailty model is specified to account for the correlated competing events.We also introduce a new ascertainment correction approach that accounts for the selection of families through probands affected with either breast or ovarian cancer, or unaffected. Our simulation studies demonstrate the good performances of our proposed approach in terms of bias and precision of the estimators of model parameters and cause-specific penetrances over different levels of familial correlations. We applied our new approach to 498 BRCA1 mutation carrier families recruited through the Breast Cancer Family Registry. Our results demonstrate the importance of the functional form of the time-varying covariate effect when assessing the role of risk-reducing salpingo oophorectomy on breast cancer. In particular, under the best fitting time-varying covariate model, the overall effect of risk-reducing salpingo oophorectomy on breast cancer risk was statistically significant in women with BRCA1 mutation.

Association between post-treatment circulating biomarkers of inflammation and survival among stage II-III colorectal cancer patients.

Biomarker studies on colorectal cancer (CRC) prognosis are limited to pre-diagnostic or pre-operative measures. Post-treatment biomarkers are not well understood for their associations with CRC survival. We included 306 eligible incident stage II-III CRC cases from the population-based Seattle Colon Cancer Family Registry. Concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), adiponectin, and leptin were measured using post-treatment plasma samples. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and CRC-specific mortality were calculated using Cox proportional hazard models. Elevated levels of CRP, IL-6, MCP-1, and adiponectin were significantly associated with a higher risk of all-cause mortality within 10 years post blood draw with HRs (95% CI) of 1.32 (1.10-2.59), 2.72 (2.07-3.56), 1.97 (1.18-3.28) and 1.71 (1.14-2.58), respectively. IL-6 and adiponectin had a dose-response effect (Ptrend < 0.0001). For CRC-specific mortality, we observed positive associations for CRP (HR = 1.75, 95% CI: 1.2-2.56), IL-6 (HR = 5.02, 95% CI: 2.92-8.59), MCP-1 (HR = 3.78, 95% CI: 1.41-10.08), and adiponectin (HR = 3.16, 95% CI: 1.27-7.86), and inverse association for leptin (HR = 0.44, 95% CI: 0.29-0.68) within the first year of blood draw, whereas the association for IL-6 remained statistically significant over 10 years. Our results support the role of chronic inflammation in CRC progression and suggested several post-treatment inflammatory biomarkers, particularly IL-6, are promising prognostic markers for stage II-III CRC patients.

Abstract 885: A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO

Abstract Introduction: Identifying families with an underlying inherited cancer predisposition is a major goal of cancer prevention efforts. Mendelian risk models have been developed to better predict the risk associated with a pathogenic variant of developing breast/ovarian cancer (with BRCAPRO), and the risk of developing pancreatic cancer (PANCPRO). Given that pathogenic variants involving BRCA2 and BRCA1 predispose to all three of these cancers, we developed a joint risk model to capture shared susceptibility. Methods: We expanded the existing framework for PANCPRO and BRCAPRO to model underlying risk of pancreatic, breast, and ovarian cancer. We then validated this model on three datasets each reflecting the target populations for these models, including patients referred to a high-risk genetics clinic, patients with multiple family members with pancreatic cancer who underwent genetic testing for BRCA1/2, as well as a prospective registry of pancreatic cancer families. The new model is designated BRCAPANCPRO. Results: BRCAPANCPRO yielded good discrimination for differentiating BRCA1 and BRCA2 carriers from non-carriers (AUC = 0.84, 95% CI: 0.78, 0.87) and was reasonably well-calibrated for predicting future risk of pancreatic cancer (observed-to-expected (O/E) ratio = 0.82 [0.69, 0.94]). In these families, BRCAPANCPRO outperformed both the prior BRCAPRO and PANCPRO models. Discussion: The BRCAPANCPRO model improves the identification of families with a pathogenic variant in BRCA2 or BRCA1, particularly for families where there is the co-occurrence of pancreatic cancer in addition to breast and/or ovarian cancer. The model also improves the prediction of pancreatic cancer among families with a pancreatic cancer family history, with or without breast and/or ovarian cancer. Citation Format: Amanda L. Blackford, Erica J. Childs, Nancy Porter, Gloria Petersen, Kari Rabe, Steven Gallinger, Ayelet Borgida, Sapna Syngal, Ann Schwartz, Michele Cote, Ralph Hruban, Michael Goggins, Alison P. Klein, Giovanni Parmigiani. A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 885.

Abstract 819: Consumption of fruits, vegetables and fiber and risk of colorectal cancer: A gene environment interaction analysis

Abstract Introduction: Consumption of fruits, vegetables and fiber has been associated with lower colorectal cancer (CRC) risk however, it is unclear if genetic variants can modify these associations. Methods: Within three genetic CRC consortia including up to 76,157 participants (32,859 cases and 43,298 controls) of European descent: the Colorectal Cancer Family Registry (CCFR), the Colorectal Cancer Transdisciplinary (CORECT) Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), one-step [logistic regression case-control analysis and joint two- and three-degrees of freedom (DF) tests] and two-step methods were implemented to identify novel and biologically plausible gene-environment interactions. Results: Fruits, vegetables and fiber consumption were inversely associated with CRC with odds ratios per quartile increase of 0.89 [95% confidence interval (CI): 0.86, 0.92], 0.91 (95% CI: 0.88, 0.94) and 0.86 (95% CI: 0.84, 0.89) respectively. The logistic regression analysis identified significant interaction effects between rs142981275 adjacent to the ACOT1 gene and fruits consumption (pval:1.91E-8) and the 2DF test, which jointly considers G and GxE effects, also identified this SNP. The 3DF test also considers G and GxE information and further revealed four loci associated with CRC risk, in the genes NEGR1(rs1620977), ZRANB3 (rs1561277), MCM6 (rs4988235), R3HDM1(rs12465802) (all pval:&amp;lt;5E-8) out of which rs1620977 and rs12465802 were the leading independent variants. For vegetables, the 3DF test identified significant interaction effects in the DCBLD1 gene (rs4946259; pval:1.44E-8). Finally, no significant interactions were observed for any genetic variant and fiber consumption. The 2-step approach did not identify additional interactions either. Conclusion: This study identified statistically significant interactions between several genetic variants and the consumption of fruits and vegetables with CRC risk. Further research is needed to elucidate the exact mechanisms through which these interactions might influence CRC risk. Citation Format: Nikos Papadimitriou, Akihisa Hidaka, Andre Kim, Niki Dimou, Neil Murphy, Sonja I. Berndt, David Conti, Peter T. Campbell, Graham Casey, Jane C. Figueiredo, Konstantinos K. Tsilidis, Stephen B. Gruber, Sophia Harlid, Yi Lin, Victor Moreno, Lori C. Sakoda, Virginia D. Obrero, Li Hsu, William J. Gauderman, Marc Gunter, Ulrike Peters. Consumption of fruits, vegetables and fiber and risk of colorectal cancer: A gene environment interaction analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 819.