Optic nerve compression: a rare ocular manifestation of Proteus syndrome.

Proteus syndrome is characterized by progressive, asymmetric, and distorting overgrowth that involves the skeletal, cutaneous, subcutaneous, and nervous systems. We report the case of a 10-year-old girl with Proteus syndrome and a constellation of ocular signs, including congenital glaucoma, myopia, amblyopia, strabismus, megaloglobus, epibulbar tumors, and right retinal detachment. A decrease in left eye visual acuity coupled with significant deterioration in visual evoked potential response over time prompted urgent neuroimaging, which revealed massive overgrowth of the sphenoid bone, with bilateral optic nerve compression due to optic canal stenosis. Successful removal of the roof of the optic canal along its entire course resulted in optic nerve decompression.

Tobacco use increases the risk of chronic rhinosinusitis among patients undergoing endoscopic sinus surgery.

BACKGROUND: Although it has been postulated that tobacco use, as well as other environmental exposures, may contribute to chronic rhinosinusitis (CRS), the data remain limited. Here, we utilised a large state population database to assess the association between tobacco use and CRS prevalence among patients undergoing endoscopic sinus surgery (ESS). METHODS: Employing a case-control study design, the Utah Population Database was queried for patients age >18 with a diagnosis of CRS and tobacco use who underwent ESS between 1996 and 2018. Smoking status was compared between patients with CRS (n = 34 350) and random population controls matched 5:1 on sex, birth year, birthplace, time residing in Utah, and pedigree (i.e., familial) information (n = 166 020). Conditional logistic regression models were used for comparisons between CRS patients and their matched controls. All analyses were repeated, additionally adjusting for race, ethnicity, tobacco use, asthma history, and interaction between tobacco use and asthma history. RESULTS: A total of 200 370 patients were included in the final analysis. Patients with CRS were significantly more likely to demonstrate a history of tobacco use than controls (19.6% vs. 15.0%; p < .001), with an adjusted odds ratio (aOR) of 1.42, 95% confidence interval 1.37-1.47; p < .001. More patients with CRS and comorbid asthma used tobacco (19.5%) than controls with asthma (15.0%; p < .001). CONCLUSION: History of tobacco use may portend increased risk for the development of CRS among patients undergoing ESS compared to healthy controls.

Abdominal aortic aneurysm and exfoliation syndrome: A literature review comparing single site findings.

Several studies have suggested a possible relationship between exfoliation syndrome (XFS) and abdominal aortic aneurysm (AAA). A systematic literature review was undertaken to investigate this potential association. The systematic literature review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Clear definitions of XFS and AAA were used to identify eligible studies via an unrestricted search of the PubMed interface from 1979 to October 31st, 2021. After review, 876 citations were gathered and evaluated for inclusion, from which 22 articles were included. Of these 22, 16 were excluded because they did not assess the relationship between AAA and XFS or provide primary data. Ultimately, six studies were included in this literature review. Half of the studies explored AAA prevalence in a population with or without XFS, and the other half explored the opposite. Three studies supported XFS as a risk factor for the development of AAA, and the other three found this relationship to be inconclusive. This systematic review revealed inconsistent results regarding an association between AAA and XFS. A large database study including XFS and AAA patients would be useful in further determining if an association does in fact exist.

Abdominal aortic aneurysm and exfoliation syndrome in Utah.

PURPOSE: A pilot study of electronic medical records (EMR) in Utah was undertaken to investigate exfoliation syndrome and exfoliation glaucoma (XFS/XFG) in abdominal aortic aneurysm (AAA) patients. In a subsequent retrospective cohort study of Utah XFS/XFG patients and population controls, the risk of AAA was examined. METHODS: EMR of a statewide healthcare population were obtained from the Utah Population Database (UPDB) which links decades of medical records with Utah demographic and vital records data. In a pilot study, 7167 patients ages ≥40 years identified with AAA diagnosed from 1996 to 2015, based on International Classification of Diseases (ICD) version 9/10 codes, were included. A univariable hazards model was used to determine the risk of XFS/XFG in AAA patients. An XFS/XFG outcome based on ICD 9/10 codes in AAA patients and in 5:1 sex- and age-matched non-AAA controls was determined. A retrospective cohort of 3412 XFS/XFG patients ages ≥50 years diagnosed from 1996 to 2020 and 10 227 3:1 sex- and age-matched controls who underwent ≥1 dilated eye examination(s) were recently identified and updated diagnoses of AAA were obtained. Multivariable logistic regression was used to estimate AAA risk in XFS/XFG patients compared with controls. In a subset of XFS/XFG patients, chart reviews were conducted to confirm clinically diagnosed AAA. RESULTS: In the AAA pilot, 20 patients (0.3%) and 118 controls (0.3%) developed XFS/XFG, respectively. We observed no increased risk of XFS/XFG in AAA patients compared with non-AAA-matched controls (HR = 0.99, 95% CI 0.6-1.6). Among XFS/XFG study patients and controls, 122 patients (3.6%) and 376 controls (3.7%) had an AAA diagnosis. We likewise observed no increased risk of AAA in XFS/XFG patients (OR = 0.97, 95% CI 0.8-1.2). In 14 XFS/XFG patients with an ICD 9/10 diagnosis of AAA who underwent chart review, a clinical diagnosis of AAA was confirmed in 9 patients (64.3%). CONCLUSION: Our findings do not support an association between AAA and XFS/XFG.

Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes.

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10-8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10-9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10-8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.

Tobacco Use Increases the Adjusted Risk of Revision Endoscopic Sinus Surgery in Patients With Chronic Rhinosinusitis.

BACKGROUND: Large epidemiologic studies have suggested that a history of tobacco use may be associated with an increased risk of developing chronic rhinosinusitis (CRS). The impact of tobacco use on revision rates of endoscopic sinus surgery (ESS), however, remains limited. OBJECTIVE: This study seeks to define the independent risk of tobacco use (active or prior) on revision rates of ESS among a large cohort of patients with CRS. METHODS: A state population database was queried for patients age ≥18 years with CRS who underwent at least one ESS between 1996 and 2018. Demographic characteristics, history of ESS, and tobacco use status were compared across patients with CRS, using t tests for continuous variables and χ2 tests for categorical variables. Unadjusted and adjusted logistic regression models were used to understand the impact of tobacco status on revision surgery. RESULTS: The final analysis included 34 350 patients (29 916 CRS with no revision surgery and 4434 CRS with revision surgery). Unadjusted regression analysis demonstrated an increased odds of undergoing revision ESS (OR 1.12, 95% CI: 1.00-1.25, P = .05) among males with a history of tobacco use and CRS. Adjusted regression analysis demonstrated that the risk of revision ESS among CRS patients with a history of asthma and tobacco use was 1.72-fold, while the risk among CRS patients who were tobacco users without asthma was 1.11-fold. CONCLUSION: History of tobacco use is an independent risk factor for revision ESS among patients with CRS.

Early-Onset Colorectal Cancer Survival Differences and Potential Geographic Determinants Among Men and Women in Utah.

By 2030, early-onset colorectal cancer (EOCRC) is expected to become the leading cancer-related cause of death for people age 20 to 49. To improve understanding of this phenomenon, we analyzed the geographic determinants of EOCRC in Utah by examining county-level incidence and mortality. We linked data from the Utah Population Database to the Utah Cancer Registry to identify residents (age 18-49) diagnosed with EOCRC between 2000 and 2020, and we used spatial empirical Bayes smoothing to determine county-level hotspots. We identified 1,867 EOCRC diagnoses (52.7% in male patients, 69.2% in non-Hispanic White patients). Ten counties (34%) were classified as hotspots, with high EOCRC incidence or mortality. Hotspot status was unrelated to incidence rates, but non-Hispanic ethnic-minority men (incidence rate ratio, 1.49; 95% CI, 1.15-1.91), Hispanic White men and women (incidence rate ratio, 2.24; 95% CI, 2.00-2.51), and Hispanic ethnic-minority men and women (incidence rate ratio, 4.59; 95% CI, 3.50-5.91) were more likely to be diagnosed with EOCRC. After adjustment for income and obesity, adults living in hotspots had a 31% higher hazard for death (HR, 1.31; 95% CI, 1.02-1.69). Survival was poorest for adults with a late-stage diagnosis living in hotspots (chi square (1) = 4.0; p = .045). Adults who were married or who had a life partner had a lower hazard for death than single adults (HR, 0.73; 95% CI, 0.58-0.92). The risk for EOCRC is elevated in 34% of Utah counties, warranting future research and interventions aimed at increasing screening and survival in the population age 18 to 49.

Body Mass Index and Mammographic Density in a Multiracial and Multiethnic Population-Based Study.

BACKGROUND: Mammographic density (MD) is strongly associated with breast cancer risk. We examined whether body mass index (BMI) partially explains racial and ethnic variation in MD. METHODS: We used multivariable Poisson regression to estimate associations between BMI and binary MD [Breast Imaging Reporting and Database System (BI-RADS) A&B versus BI-RADS C&D] among 160,804 women in the Utah mammography cohort. We estimated associations overall and within racial and ethnic subgroups and calculated population attributable risk percents (PAR%). RESULTS: We observed the lowest BMI and highest MD among Asian women, the highest BMI among Native Hawaiian and Pacific Islander women, and the lowest MD among American Indian and Alaska Native (AIAN) and Black women. BMI was inversely associated with MD [RRBMI≥30 vs. BMI<25 = 0.43; 95% confidence interval (CI), 0.42-0.44] in the full cohort, and estimates in all racial and ethnic subgroups were consistent with this strong inverse association. For women less than 45 years of age, although there was statistical evidence of heterogeneity in associations between BMI and MD by race and ethnicity (P = 0.009), magnitudes of association were similar across groups. PAR%s for BMI and MD among women less than 45 years were considerably higher in White women (PAR% = 29.2, 95% CI = 28.4-29.9) compared with all other groups with estimates ranging from PAR%Asain = 17.2%; 95% CI, 8.5 to 25.8 to PAR%Hispanic = 21.5%; 95% CI, 19.4 to 23.6. For women ≥55 years, PAR%s for BMI and MD were highest among AIAN women (PAR% = 37.5; 95% CI, 28.1-46.9). CONCLUSIONS: While we observed substantial differences in the distributions of BMI and MD by race and ethnicity, associations between BMI and MD were generally similar across groups. IMPACT: Distributions of BMI and MD may be important contributors to breast cancer disparities.

Exfoliation Syndrome in Baja Verapaz Guatemala: A Cross-Sectional Study and Review of the Literature.

There are little epidemiologic data on exfoliation syndrome (XFS) or exfoliation glaucoma (XFG) in Guatemala, especially in the underserved Baja Verapaz region. This observational study assessing XFS/XFG and demographic factors of this region aims to better understand unique exogenous and endogenous risk factors associated with XFS/XFG in Guatemala. During Moran Eye Center's global outreach medical eye camps from 2016-2017, 181 patients age 15 years and older presented for complete eye exams. These individuals were screened for eye disease and evaluated for possible surgical interventions that could occur during the camps to improve eyesight. During the dilated exams, XFS was noted as missing or present. Of those 181, 10 had insufficient data and 18 lacked a definitive diagnosis of XFS or XFG, resulting in 153 evaluable patients; 46 XFS and 9 XFG were identified. Age, gender, hometown, ancestry (languages spoken by parents and grandparents), past medical history, family medical history, and occupational data (only 2017 trip) were obtained for each patient. The most common occupations of these individuals were farming and housekeeping. Higher rates of XFS/XFG were noted in individuals of rural compared to urban settings and Mayan speaking people compared with Spanish speakers. Based on this subset of patients, with various ocular pathologies being evaluated during medical eye outreach camps, the prevalence of XFS/XFG appeared to be 36%, a high prevalence compared to other world populations. Location and higher altitude, along with a farming occupation, may contribute to XFS development and subsequent progression to XFG. To our knowledge, this is the largest study looking at the epidemiology of XFS/XFG in the Baja Verapaz region of Guatemala for those over the age of 15 years seeking eye exams and interventions.

Audit of outcomes following attendance at the City West drive-through IOP glaucoma clinic during the COVID-19 pandemic.

BACKGROUND: Glaucoma is the leading cause of irreversible blindness globally. During the COVID-19 pandemic, an enforced reduction in capacity resulted in the deferral of routine outpatient appointments for glaucoma patients. AIM: This study analyses patient outcomes following the establishment of a drive-through intra-ocular pressure (IOP) clinic during the COVID-19 pandemic to alleviate increased pressure on the tertiary glaucoma services at Royal Victoria Eye and Ear Hospital (RVEEH) and Mater Misericordiae University Hospital (MMUH) between August 2020 and June 2021. METHODS: A 1-lane driveway system was established in a marquee on the grounds of City West hotel. IOPs were measured in patients' cars using a hand held iCare100 tonometer. Results were reviewed by a consultant ophthalmologist. At hospital follow-up clinic visits, IOP was measured using the Goldmann applanation tonometer (GAT). RESULTS: Three hundred one patients of a total of 672 who attended the drive-through clinic have subsequently attended a designated hospital follow-up appointment. In this cohort, the mean drive-through iCare IOP of 19.4 mmHg ± 6.0 was significantly higher (< 0.005) than the mean GAT IOP at the pre-drive through clinic visit (16.3 mmHg ± 3.7) and the post drive-through hospital follow-up visit (17.2 mmHg ± 4.1). Two hundred twenty-six (75%) patients did not need any treatment change, 53 (18%) required eye drop medication changes, 10 (3%) underwent a laser procedure, 4(1%) required surgical intervention, and 8 (3%) were discharged. When patient outcomes were analysed according to IOP grade assigned at the drive-through clinic, those with an iCare IOP < 21 were significantly less likely to require a treatment change. The cohort with iCare IOP ≥ 30 were significantly more likely to have a laser or surgical intervention. CONCLUSION: The implementation of a drive-through IOP clinic was a safe and effective way to monitor glaucoma patients during COVID-19, and identify those at high risk of poor IOP control or requiring a change in treatment.

Cancer Risk in Patients With and Relatives of Serrated Polyposis Syndrome and Sporadic Sessile Serrated Lesions.

INTRODUCTION: Patients with serrated polyposis syndrome (SPS) and their first-degree relatives (FDRs) have increased colorectal cancer (CRC) risk. Patients with sporadic sessile serrated lesion (SSL) have risk for progression to CRC. Yet familial risks of common extracolonic cancers and even CRC in these cohorts are poorly understood. Our aim was to examine cancer risk for patients with SPS and sporadic SSL and their close and more distant relatives using a large population database. METHODS: Patients with SPS (n = 59) from hereditary patient registries were eligible for study. Sporadic SSL (n = 754) and sex- and age-matched normal colonoscopy controls (n = 1,624) were selected from clinical data linked to the Utah Population Database. Cox models adjusting for the number of relatives, degree of relatedness, and person-years at risk were used to estimate CRC, extracolonic, and any-site adenocarcinoma/carcinoma cancer risk in patients and their relatives. RESULTS: Compared with controls, CRC risk was elevated 10-fold in patients with SPS (P = 0.04) and 5-fold in their FDRs (P = 0.001). Any-site adenoma/carcinoma risk was increased 2.6-fold in FDRs of patients with SPS. No elevated risks of other common extracolonic cancers were observed in SPS and family members. The FDRs, second-degree relatives, and third-degree relatives of patients with both SSL and adenomatous polyps exhibited a 50% increased CRC risk. DISCUSSION: Patients with SPS and their FDRs have an increased CRC risk, confirming other reports. Interestingly, patients with SSL were noted to have an increased risk of prostate cancer. Relatives of individuals with both sporadic SSL and adenomas, irrespective of size or dysplasia on examination, may have an elevated CRC risk, suggesting closer colonoscopy surveillance in this population.

Cystic Fibrosis Increases Long-Term Revision Rates of Endoscopic Sinus Surgery in Patients With Comorbid Chronic Rhinosinusitis.

Background: Comorbid chronic rhinosinusitis (CRS) of adulthood is increasing among patients with cystic fibrosis (CF) due to improved median survival. However, little is known about the natural history of endoscopic sinus surgery (ESS) in this cohort. The objective of this study was to evaluate the revision rate of ESS and associated risk factors among adults with CRS and CF (CRSwCF). Methods: The Utah Population Database was queried for patients age >18 with CRS who underwent at least one ESS between 1996 and 2018. Demographic information and ESS history were collected and compared for CRSwCF versus CRS without CF (CRSsCF) using chi-square and t-tests. Risk factors for revision were analyzed using Cox proportional hazard models and logistic regression analysis. Results: A total of 34 050 patients (33 639 CRSsCF and 411 CRSwCF) were included in the final analysis. The mean duration of follow-up was 9.3 and 9.3 years, respectively (P = .98). Adult patients with CF were significantly more likely to undergo revision ESS (18.7%) than those without CF (13.4%; P < .01). Logistic regression analysis indicated that a diagnosis of CF independently elevated the risk for revision ESS in the absence of nasal polyps (odds ratio [OR] 2.18, confidence interval [CI] 1.34-3.54), asthma (OR 1.36, CI 0.94-1.98), and allergies (OR 1.29, CI 0.90-1.73). Conclusion: In the era before highly effective modulator therapies, the mean revision rate of ESS among adults with CRSwCF was 18.7%, significantly greater than that of adults with CRSsCF. CF was an independent risk factor for revision ESS in the absence of nasal polyps, asthma, and allergies.

Risk of atrial fibrillation is increased in patients with exfoliation syndrome: the Utah project on exfoliation syndrome (UPEXS).

PURPOSE: Exfoliation syndrome, a systemic disorder with ocular manifestations, is associated with lysyl oxidase-like gene variants. Along with transforming growth factor beta-1, lysyl oxidase-like 1 is a key enzyme in stabilizing extracellular matrix and remodelling collagen/elastin. Given the role that transforming growth factor beta-1, lysyl oxidase-like gene variants and fibrosis play in atrial fibrillation, an association with exfoliation syndrome was investigated. METHODS: An exfoliation syndrome cohort of 2803 patients and an atrial fibrillation cohort of 43 694 patients aged 60-90 years at disease onset were identified using the Utah Population Database (1996-2015). Conditional logistic regression was used to estimate risk of atrial fibrillation in exfoliation syndrome patients and risk of exfoliation syndrome in atrial fibrillation patients compared with respective 5:1 sex- and age-matched control cohorts. Kaplan-Meier curves were examined to assess survival in atrial fibrillation patients by exfoliation syndrome status. RESULTS: Exfoliation syndrome patients had a 21% greater risk (95% CI 1.06-1.37; p < 0.0001) of atrial fibrillation. This was more pronounced in exfoliation syndrome patients with no hypertension history, who exhibited a 52% increased atrial fibrillation risk (95% CI 1.27-1.82; p < 0.0001). Atrial fibrillation patients exhibited a 20% increased risk of exfoliation syndrome (95% CI 1.07-1.35; p = 0.003), while atrial fibrillation patients with no hypertension had a 72% higher exfoliation risk (95% CI 1.45-2.03; p < 0.0001). Atrial fibrillation patients with exfoliation syndrome had a higher estimated probability of survival (alive at study end or at last follow-up) compared with patients with no exfoliation history (p < 0.0001, log-rank test). CONCLUSIONS: Exfoliation syndrome patients were at a statistically significant increased risk of atrial fibrillation. Similarly, atrial fibrillation patients were at a statistically significant higher risk of exfoliation, particularly when hypertension history was absent.

Protocol for #iBeatCRC: a community-based intervention to increase early-onset colorectal cancer awareness using a sequential explanatory mixed-methods approach.

INTRODUCTION: Th last two decades have seen a twofold increase in colorectal cancer (CRC) incidence among individuals under the recommended screening age of 50 years. Although the origin of this early-onset CRC (EOCRC) spike remains unknown, prior studies have reported that EOCRC harbours a distinct molecular and clinical phenotype in younger individuals. The sharp increase in EOCRC incidence rates may be attributable to a complex interplay of factors, including race; lifestyle; and ecological, sociodemographic and geographical factors. However, more research that address psychosocial experiences and accounts for lifestyle-related behaviours before, during and after an EOCRC diagnosis are warranted. This study aims to develop and pilot test a theory-driven, community-based intervention to increase awareness of EOCRC, reduce its associated risk factors and improve early detection among adults aged 18-49 years. METHODS AND ANALYSIS: Guided by the Behaviour Change Wheel, we will use a multistage mixed-methods study design. We will pilot a sequential mixed-methods intervention study as follows: (1) First, we will analyse linked quantitative data from the Utah Cancer Registry and National Cancer Institute Surveillance, Epidemiology and End Results registry, linked to state-wide demographic and vital records in the Utah Population Database to identify EOCRC hotspots in Utah by examining the EOCRC incidence and survival variance explained by personal and county-level factors. (2) Next, we will conduct one-on-one interviews with 20 EOCRC survivors residing in EOCRC hotspots to ascertain psychosocial and lifestyle challenges that accompany an EOCRC diagnosis. (3) Finally, we will consider existing evidence-based approaches, our integrated results (quantitative +qualitative) and community action board input to design a community-based intervention to increase EOCRC awareness that can feasibly be delivered by means of outdoor mass media, and via social media. We will pilot the multicomponent media campaign with a quasiexperimental design among 17 EOCRC hotspot residents and 17 EOCRC 'coldspot' residents. ETHICS AND DISSEMINATION: Ethics approval was obtained from the University of Utah Institutional Review Board (IRB_00138357). Signed informed consent will be obtained from all participants prior to any data collection. Study results will be disseminated through CRC community blogs, targeted infographics, conference presentations at national and international professional conferences and publications in peer-reviewed journals. Final intervention-specific data will be available on reasonable request from the corresponding author. TRIAL REGISTRATION NUMBER: NCT04715074.

Summary of Utah Project on Exfoliation Syndrome (UPEXS): using a large database to identify systemic comorbidities.

The purpose of the Utah Project on Exfoliation Syndrome (UPEXS) is to identify associations between exfoliation syndrome (XFS) and other diseases that share the commonality of abnormalities in elastin and Lysyl Oxidase-Like 1 gene regulation. The UPEXS is unique because it uses the Utah Population Database, which is linked to the Utah genealogy, that contains a compilation of large pedigrees of most families in the state of Utah that go back multiple generations (3 to ≥11). The health and medical records of these family members are linked to vital records and can be used effectively in studies focused on genetic disorders like XFS, where familial clustering of a disorder is a trend. There is increasing evidence that patients with XFS have a higher risk of certain systemic disorders that reflect the systemic tissue abnormalities of XFS. Epidemiological studies focused on patients with XFS have shown that there is an increased risk of these individuals developing other pathologies that have abnormalities in extracellular matrix metabolism and repair. UPEXS has focused on suspected comorbidities that involve abnormalities in elastin maintenance, a protein that plays a role in the makeup of the extracellular matrix. In this paper, the results from the analysis of chronic obstructive pulmonary disease, inguinal hernias, pelvic organ prolapse, obstructive sleep apnoea and atrial fibrillation are summarised along with the utility of using such a large dataset.

Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes.

AIM: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk. METHODS: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis. RESULTS: We discovered positive associations between FROH and CLL (ß = 21.1, SE = 4.41, P = 1.6 × 10-6) and FL (ß = 11.4, SE = 5.82, P = 0.02) but not DLBCL (P = 1.0) or MZL (P = 0.91). For F3, we observed an association with CLL (ß = 27.5, SE = 6.51, P = 2.4 × 10-5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. CONCLUSION: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.

Differential methylation of G-protein coupled receptor signaling genes in gastrointestinal neuroendocrine tumors.

Neuroendocrine tumors (NETs) of the small intestine undergo large chromosomal and methylation changes. The objective of this study was to identify methylation differences in NETs and consider how the differentially methylated genes may impact patient survival. Genome-wide methylation and chromosomal copy number variation (CNV) of NETs from the small intestine and appendix were measured. Tumors were divided into three molecular subtypes according to CNV results: chromosome 18 loss (18LOH), Multiple CNV, and No CNV. Comparison of 18LOH tumors with MultiCNV and NoCNV tumors identified 901 differentially methylated genes. Genes from the G-protein coupled receptor (GPCR) pathways are statistically overrepresented in the differentially methylated genes. One of the highlighted genes from the GPCR pathway is somatostatin (SST), a clinical target for NETs. Patient survival based on low versus high methylation in all samples identified four significant genes (p < 0.05) OR2S2, SMILR, RNU6-653P, and AC010543.1. Within the 18LOH molecular subtype tumors, survival differences were identified in high versus low methylation of 24 genes. The most significant is TRHR (p < 0.01), a GPCR with multiple FDA-approved drugs. By separating NETs into different molecular subtypes based on chromosomal changes, we find that multiple GPCRs and their ligands appear to be regulated through methylation and correlated with survival. These results suggest opportunities for better treatment strategies for NETs based on molecular features.

Sequencing at lymphoid neoplasm susceptibility loci maps six myeloma risk genes.

Inherited genetic risk factors play a role in multiple myeloma (MM), yet considerable missing heritability exists. Rare risk variants at genome-wide association study (GWAS) loci are a new avenue to explore. Pleiotropy between lymphoid neoplasms (LNs) has been suggested in family history and genetic studies, but no studies have interrogated sequencing for pleiotropic genes or rare risk variants. Sequencing genetically enriched cases can help discover rarer variants. We analyzed exome sequencing in familial or early-onset MM cases to identify rare, functionally relevant variants near GWAS loci for a range of LNs. A total of 149 distinct and significant LN GWAS loci have been published. We identified six recurrent, rare, potentially deleterious variants within 5 kb of significant GWAS single nucleotide polymorphisms in 75 MM cases. Mutations were observed in BTNL2, EOMES, TNFRSF13B, IRF8, ACOXL and TSPAN32. All six genes replicated in an independent set of 255 early-onset MM or familial MM or precursor cases. Expansion of our analyses to the full length of these six genes resulted in a list of 39 rare and deleterious variants, seven of which segregated in MM families. Three genes also had significant rare variant burden in 733 sporadic MM cases compared with 935 control individuals: IRF8 (P = 1.0 × 10-6), EOMES (P = 6.0 × 10-6) and BTNL2 (P = 2.1 × 10-3). Together, our results implicate six genes in MM risk, provide support for genetic pleiotropy between LN subtypes and demonstrate the utility of sequencing genetically enriched cases to identify functionally relevant variants near GWAS loci.