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Importance: Endometriosis has been associated with an increased risk of ovarian cancer; however, the associations between endometriosis subtypes and ovarian cancer histotypes have not been well-described., Objective: To evaluate the associations of endometriosis subtypes with incidence of ovarian cancer, both overall and by histotype., Design, Setting, and Participants: Population-based cohort study using data from the Utah Population Database. The cohort was assembled by matching 78 893 women with endometriosis in a 1:5 ratio to women without endometriosis., Exposures: Endometriosis cases were identified via electronic health records and categorized as superficial endometriosis, ovarian endometriomas, deep infiltrating endometriosis, or other., Main Outcomes and Measures: Estimated adjusted hazard ratios (aHRs), adjusted risk differences (aRDs) per 10 000 women, and 95% CIs for overall ovarian cancer, type I ovarian cancer, and type II ovarian cancer comparing women with each type of endometriosis with women without endometriosis. Models accounted for sociodemographic factors, reproductive history, and past gynecologic operations., Results: In this Utah-based cohort, the mean (SD) age at first endometriosis diagnosis was 36 (10) years. There were 597 women with ovarian cancer. Ovarian cancer risk was higher among women with endometriosis compared with women without endometriosis (aHR, 4.20 [95% CI, 3.59-4.91]; aRD, 9.90 [95% CI, 7.22-12.57]), and risk of type I ovarian cancer was especially high (aHR, 7.48 [95% CI, 5.80-9.65]; aRD, 7.53 [95% CI, 5.46-9.61]). Ovarian cancer risk was highest in women with deep infiltrating endometriosis and/or ovarian endometriomas for all ovarian cancers (aHR, 9.66 [95% CI, 7.77-12.00]; aRD, 26.71 [95% CI, 20.01-33.41]), type I ovarian cancer (aHR, 18.96 [95% CI, 13.78-26.08]; aRD, 19.57 [95% CI, 13.80-25.35]), and type II ovarian cancer (aHR, 3.72 [95% CI, 2.31-5.98]; aRD, 2.42 [95% CI, -0.01 to 4.85])., Conclusions and Relevance: Ovarian cancer risk was markedly increased among women with ovarian endometriomas and/or deep infiltrating endometriosis. This population may benefit from counseling regarding ovarian cancer risk and prevention and could be an important population for targeted screening and prevention studies.

Objective: To assess individual- and neighborhood-level sociodemographic factors associating with providers' ordering of nonpharmacologic treatments for patients with low back pain (LBP), specifically physical therapy, image-guided interventions, and lumbar surgery., Methods: Our cohort included all patients diagnosed with LBP from 2000 to 2017 in a statewide database of all hospitals and ambulatory surgical facilities within Utah. We compared sociodemographic and clinical characteristics of (1) patients with LBP who received any treatment with those who received none and (2) patients with LBP who received invasive LBP treatments with those who only received noninvasive LBP treatments using the Student's t test, Wilcoxon's rank-sum tests, and Pearson's χ 2 tests, as applicable, and two separate multivariate logistic regression models: (1) to determine whether sociodemographic characteristics were risk factors for receiving any LBP treatments and (2) risk factors for receiving invasive LBP treatments., Results: Individuals in the most disadvantaged neighborhoods were less likely to receive any nonpharmacologic treatment orders (odds ratio [OR] 0.74 for most disadvantaged, P < .001) and received fewer invasive therapies (0.92, P = .018). Individual-level characteristics correlating with lower rates of treatment orders were female sex, Native Hawaiian or other Pacific Islander race (OR 0.50, P < .001), Hispanic ethnicity (OR 0.77, P < .001), single or unmarried status (OR 0.69, P < .001), and no insurance or self-pay (OR 0.07, P < .001)., Conclusion: Neighborhood and individual sociodemographic variables associated with treatment orders for LBP with Area Deprivation Index, sex, race or ethnicity, insurance, and marital status associating with receipt of any treatment, as well as more invasive image-guided interventions and surgery., (Copyright © 2024 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Socially disadvantaged groups generally are more likely to reside in areas with less desirable conditions. We examined longitudinal relationships between neighborhood resident characteristics and amenities from 1990 to 2010 in an urban area of Utah, U.S. Four temporal patterns of social inequities are described using mixed-effects models: historical inequities; differential selection into amenity-rich tracts; differential investment in amenities; and simultaneous twenty-year change. Results indicate historical differences by neighborhood socioeconomic status, with lower status tracts having fewer green/natural amenities and higher air pollution in 1990 but also greater walkability and more food stores. Differences in amenities by neighborhood socioeconomic status widened over time as aggregate socioeconomic status disproportionately increased in tracts with more green/natural amenities, less air pollution, and lower walkability in 1990, consistent with differential selection. Tract percentage non-Hispanic White did not predict historical differences, but tracts that were less walkable and had fewer healthy food stores in 1990 experienced larger subsequent increases in racial/ethnic diversity. Tracts with higher relative to lower percentage non-Hispanic White in 1990 had larger decreases in air pollution but declining green/natural amenities. This study shows how social inequities in neighborhood amenities change over time, providing evidence of historical socioeconomic differences increasing from differential resident selection., Competing Interests: Declarations of interest: none.

Introduction: Acute extremity compartment syndrome ("CS") is an under-researched, highly morbid condition affecting trauma populations. The purpose of this study was to analyze incidence rates and risk factors for extremity compartment syndrome using a high-quality population database. Additionally, we evaluated heritable risk for CS using available genealogic data. We hypothesized that diagnosis of extremity compartment syndrome would demonstrate heritability., Materials and Methods: Adult patients with fractures of the tibia, femur, and upper extremity were retrospectively identified by ICD-9, ICD-10, and CPT codes from 1996 to 2020 in a statewide hospital database. Exposed and unexposed cohorts were created based on a diagnosis of CS. Available demographic data were analyzed to determine risk factors for compartment syndrome using logistic regression. Mortality risk at the final follow-up was evaluated using Cox proportional hazard modeling. Patients with a diagnosis of CS were matched with those without a diagnosis for heritability analysis., Results: Of 158,624 fractures, 931 patients were diagnosed with CS. Incidence of CS was 0.59% (tibia 0.83%, femur 0.31%, upper extremity 0.27%). Male sex (78.1% vs. 46.4%; p < 0.001; RR = 3.24), younger age at fracture (38.8 vs. 48.0 years; p < 0.001; RR = 0.74), Medicaid enrollment (13.2% vs. 9.3%; p < 0.001; RR = 1.58), and smoking (41.1% vs. 31.1%; p < 0.001; RR 1.67) were significant risk factors for CS. CS was associated with mortality (RR 1.61, p < 0.001) at mean follow-up 8.9 years in the CS cohort. No significant heritable risk was found for diagnosis of CS., Conclusions: Without isolating high-risk fractures, rates of CS are lower than previously reported in the literature. Male sex, younger age, smoking, and Medicaid enrollment were independent risk factors for CS. CS increased mortality risk at long-term follow-up. No heritable risk was found for CS., Level of Evidence: III., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To determine whether there is evidence of heritable risk for nonunion using a large, state-wide population database., Design: Database., Setting: Level 1 Trauma Center., Population: All Utah residents from 1996 to 2021 who sustained a long bone fracture and their family members were included., Outcomes: The primary outcome was nonunion and the prevalence of nonunion among the patients' first-, second-, and third-degree relatives. The secondary objective was to identify demographic, injury, and socioeconomic risk factors associated with nonunion., Results: In total, 150,263 fractures and 6577 nonunions (4.4%) were identified. This was highly refined to a 1:3 matched cohort of 4667 nonunions of 13,981 fractures for familial clustering analysis. Cox proportional hazards did not demonstrate excessive risk of nonunion among first- ( P = 0.863), second- ( P = 0.509), and third-degree relatives ( P = 0.252). Further analysis of the entire cohort demonstrated that male sex (relative risk [RR] = 1.15; P < 0.001), Medicaid enrollment (RR = 2.64; P < 0.001), open fracture (RR = 2.53; P < 0.001), age group 41-60 years (RR = 1.43; P < 0.001), and a history of obesity (RR = 1.20; P < 0.001) were independent risk factors for nonunion., Conclusions: Our results demonstrate no evidence of heritable risk for nonunion. Independent risk factors for nonunion were male sex, Medicaid enrollment, open fracture, middle age, and a history of obesity. Although it is important to identify modifiable and nonmodifiable risk factors, these results continue to support that the risk of nonunion is multifactorial, relating to injury characteristics, operative techniques, and patient-specific risk factors., Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Our goals were to identify individuals who required surgery for thumb carpometacarpal (CMC) joint osteoarthritis (OA), determine if CMC joint OA clusters in families, define the magnitude of familial risk of CMC joint OA, identify risk factors associated with CMC joint OA, and identify rare genetic variants that segregate with familial CMC joint OA., Methods: We searched the Utah Population Database to identify a cohort of CMC joint OA patients who required surgery. Affected individuals were mapped to pedigrees to identify high-risk families with excess clustering of CMC joint OA. Cox regression models were used to calculate familial risk of CMC joint OA in related individuals. Risk factors were evaluated using logistic regression models. Whole exome sequencing was used to identify rare coding variants associated with familial CMC joint OA., Results: We identified 550 pedigrees with excess clustering of severe CMC joint OA. The relative risk of CMC joint OA requiring surgical treatment was elevated significantly in first- and third-degree relatives of affected individuals, and significant associations with advanced age, female sex, obesity, and tobacco use were observed. We discovered candidate genes that dominantly segregate with severe CMC joint OA in 4 independent families, including a rare variant in Chondroitin Sulfate Synthase 3 (CHSY3)., Conclusions: Familial clustering of severe CMC joint OA was observed in a statewide population. Our data indicate that genetic and environmental factors contribute to the disease process, further highlighting the multifactorial nature of the disease. Genomic analyses suggest distinct biological processes are involved in CMC joint OA pathogenesis., Clinical Relevance: Awareness of associated comorbidities may guide the diagnosis of CMC joint OA in at-risk populations and help identify individuals who may not do well with nonoperative treatment. Further pursuit of the genes associated with severe CMC joint OA may lead to assays for detection of early stages of disease and have therapeutic potential., (Copyright © 2022. Published by Elsevier Inc.)

Objective: To define the live birth rates in a large, population-based study of the most common reproductive-age cancers in women., Design: Retrospective cohort study., Setting: Population-based study., Patients: Female cancer patients diagnosed with cancer at age 18 years old or older between 1952-2014 (n = 17,952) were compared to fertility of non-cancer controls (n = 89,436)., Interventions: Live births in cancer survivors were compared with those in healthy, age-matched controls. Cases and controls were matched in the ratio of 5:1 for birth year, birthplace (Utah, yes/no), and follow-up time in Utah., Main Outcome Measure: Rate of at least one live birth, reported as an incidence rate ratio (IRR)., Results: Of all cancer survivors, 3,127 (17.4%) had at least 1 live birth after treatment in comparison to 19,405 healthy, age-matched controls (21.7%) with the same amount of time exposure for attempting pregnancy. Breast cancer was the most common cancer type (23.1% of patients in cohort). Compared with age-matched, healthy controls, IRR of live birth was 0.69 (95% confidence interval [CI], 0.67-0.70) for all cancer types, 0.25 (95% CI, 0.20-0.33) for leukemia, 0.40 (95% CI, 0.28-0.59) for gastrointestinal cancers, 0.44 (95% CI, 0.41-0.48) for breast cancer, 0.53 (95% CI, 0.47-0.59) for central nervous system cancers, and 0.57 (95% CI, 0.44-0.73) for soft tissue cancers. With all cancer types stratified by age at diagnosis, IRR for live births in cancer survivors aged >41 years at diagnosis was 0.48 (95% CI, 0.44-0.52); IRR was 0.64 (95% CI, 0.61-0.67) in the group aged 31-40 years and 0.71 (95% CI, 0.69-0.74) in the group aged 18-30 years after their cancer treatment., Conclusions: Cancer and its treatment were associated with lower live birth rates when comparing women with cancer vs. age-matched, healthy controls., (© 2021 The Author(s).)

Objective: Erosive hand osteoarthritis (OA) is a severe and rapidly progressing subset of hand OA. Its etiology remains largely unknown, which has hindered development of successful treatments. This study was undertaken to test the hypothesis that erosive hand OA demonstrates familial clustering in a large statewide population linked to genealogical records, and to determine the association of potential risk factors with erosive hand OA., Methods: Patients diagnosed as having erosive hand OA were identified by searching 4,741,840 unique medical records from a comprehensive statewide database, the Utah Population Database (UPDB). Affected individuals were mapped to pedigrees to identify high-risk families with excess clustering of erosive hand OA as defined by a familial standardized incidence ratio (FSIR) of ≥2.0. The magnitude of familial risk of erosive hand OA in related individuals was calculated using Cox regression models. Association of potential erosive hand OA risk factors was analyzed using multivariate conditional logistic regression and logistic regression models., Results: We identified 703 affected individuals linked to 240 unrelated high-risk pedigrees with excess clustering of erosive hand OA (FSIR ≥2.0, P < 0.05). The relative risk of developing erosive hand OA was significantly elevated in first-degree relatives (P < 0.001). There were significant associations between a diagnosis of erosive hand OA and age, sex, diabetes, and obesity (all P < 0.05)., Conclusion: Familial clustering of erosive hand OA observed in a statewide database indicates a potential genetic contribution to the etiology of the disease. Age, sex, diabetes, and obesity are risk factors for erosive hand OA. Identification of causal gene variants in these high-risk families may provide insight into the genes and pathways that contribute to erosive hand OA onset and progression., (© 2020, American College of Rheumatology.)

Background: Periprosthetic joint infection (PJI) is a devastating complication after total joint arthroplasty, carrying significant economic and personal burden. The goal of this study is to use an established database to analyze socioeconomic variables and assess their relationship to PJI. Additionally, we sought to evaluate whether socioeconomic factors, along with other known risk factors of PJI, when controlled for in a statistical model affected the familial risk of PJI., Methods: With approval from our Institutional Review Board we performed a population-based retrospective cohort study on all primary total joint arthroplasty cases of the hip or knee (n = 85,332), within a statewide database, between January 1996 and December 2013. We excluded 9854 patients due to age <18 years, missing data, history of PJI prior to index procedure, and no evidence of 2-year follow-up (excluding those with PJI). Cases that developed PJI following the index procedure (n = 2282) were compared to those that did not (n = 73,196)., Results: After adjusting for covariates, patients with Medicaid as a primary payer were at greater risk for experiencing PJI (relative risk 1.40, 95% confidence interval [CI] 1.08-1.82, P = .01). There was no difference in risk between the groups associated with education level or median household income (all, P > .05). First-degree relatives of patients who develop PJI (hazard ratio 1.66, 95% CI 1.23-2.24, P = .001) and first-degree and second-degree relatives combined (hazard ratio 1.39, 95% CI 1.09-1.77, P = .007) were at greater risk despite controlling for the above socioeconomic factors., Conclusion: Our study provides further support that genetic factors may underlie PJI as we did observe significant familial risk even after accounting for socioeconomic factors and payer status. We did not find a correlation between education level or household income and PJI; however, Medicaid payees were at increased risk. Continued study is needed to define a possible heritable disposition to PJI in an effort to optimize treatment and possibly prevent this complication., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ageing may be due to mutation accumulation across the lifespan, leading to tissue dysfunction, disease, and death. We tested whether germline autosomal mutation rates in young adults predict their remaining survival, and, for women, their reproductive lifespans. Age-adjusted mutation rates (AAMRs) in 61 women and 61 men from the Utah CEPH (Centre d'Etude du Polymorphisme Humain) families were determined. Age at death, cause of death, all-site cancer incidence, and reproductive histories were provided by the Utah Population Database, Utah Cancer Registry, and Utah Genetic Reference Project. Higher AAMRs were significantly associated with higher all-cause mortality in both sexes combined. Subjects in the top quartile of AAMRs experienced more than twice the mortality of bottom quartile subjects (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.21-3.56; p = 0.008; median survival difference = 4.7 years). Fertility analyses were restricted to women whose age at last birth (ALB) was ≥ 30 years, the age when fertility begins to decline. Women with higher AAMRs had significantly fewer live births and a younger ALB. Adult germline mutation accumulation rates are established in adolescence, and later menarche in women is associated with delayed mutation accumulation. We conclude that germline mutation rates in healthy young adults may provide a measure of both reproductive and systemic ageing. Puberty may induce the establishment of adult mutation accumulation rates, just when DNA repair systems begin their lifelong decline.

Background: The effect of diabetes type on the risk of periprosthetic joint infection is not well documented. We hypothesized that patients with diabetes mellitus type 1 would be at greater risk for periprosthetic joint infection than those with diabetes mellitus type 2 and that a history of diabetic complications would be associated with an increased risk of periprosthetic joint infection., Methods: We performed a retrospective cohort study, within a statewide database, on all adult patients who underwent hip or knee arthroplasty, with follow-up of ≥2 years, from 1996 to 2013. Of the 75,478 patients included, 1,668 had type-1 diabetes and 18,186 had type-2 diabetes. Risk factors were calculated using Cox regression, adjusting for siblings and stratified by age. Logistic regression was used to analyze the effect of diabetic complications on the risk of periprosthetic joint infection, controlling for other known risks for periprosthetic joint infection., Results: There was no difference in age or sex between groups (p > 0.05). The frequency of periprosthetic joint infection in patients without diabetes was 2.6% compared with 4.3% in all patients with diabetes (relative risk, 1.47; p < 0.001). Patients with type-1 diabetes were at a 1.8 times greater risk for periprosthetic joint infection than patients with type-2 diabetes (7% compared with 4%; p < 0.001). The following diabetic complications increased the risk of periprosthetic joint infection: peripheral circulatory disorders (odds ratio [OR], 2.59 [95% confidence interval (CI), 1.70 to 3.94]), ketoacidosis (OR, 2.52 [95% CI, 1.51 to 4.19]), neurological manifestations (OR, 2.33 [95% CI, 1.96 to 2.78]), renal manifestations (OR, 2.15 [95% CI, 1.66 to 2.79]), and ophthalmic manifestations (OR, 1.76 [95% CI, 1.24 to 2.51]). The odds of periprosthetic joint infection increased with each added complication and patients with ≥4 complications were 9 times more likely to have a periprosthetic joint infection than patients with uncomplicated diabetes (OR, 9.47 [95% CI, 4.97 to 18.03]). Overweight and obese patients with type-2 diabetes and underweight patients with type-1 diabetes were at greater risk for periprosthetic joint infection compared with the general population (all p < 0.05)., Conclusions: Our data showed an increased risk of periprosthetic joint infection in patients with type-1 diabetes compared with those with type-2 diabetes, along with an increasing risk associated with additional diabetic complications. These findings emphasize the need to better understand the medical history of patients with diabetes for more appropriate risk management., Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10 -115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants., (© 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.)

Background: We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1 *R1699Q carriers., Methods: Data were collected from 129 BRCA1 *R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions., Results: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83)., Conclusion: Our results confirm that BRCA1 *R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history., Competing Interests: Competing interests: EGG has received an honorarium in the past 3 years from AstraZeneca for giving a course and a lecture. HE (or rather, his department with him as primary contact) has received funding from Novartis Oncology (unrestricted grant) and AstraZeneca (invited speaker). KT has received an honorarium for chairing a mainstreaming genetic testing subcommittee and day seminar for AstraZeneca. AET declares to have received an honorarium from American Cancer Society for grant review, NIH NCI PDQ as editorial board, Italian Ministry of Health for grant review. DEE receives an honorarium from AstraZeneca via a contract with the university to provide consultancy advice from time to time (one or two advisory boards each year on average at the moment). DEG has received royalties from patents on the BRCA1 and BRCA2 genes from the University of Utah that are licensed to Myriad Genetics. All the other authors declare to have no conflicts of interest., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10 -8 Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of ≈70-80% truncating transcripts, and ≈20-30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers., Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided., Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed., Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)