Citations

AbstractBackground and AimPrimary sclerosing cholangitis (PSC) typically develops in middle‐age adults. Little is known about phenotypic differences when PSC is diagnosed at various ages. Therefore, we sought to compare the clinical characteristics of a large PSC cohort based on the age when PSC was diagnosed.MethodsWe performed a multicenter retrospective review to compare the features of PSC among those diagnosed between 1–19 (n = 95), 20–59 (n = 662), and 60–79 years (n = 102).ResultsThose with an early diagnosis (ED) of PSC were more likely to have small‐duct PSC (13%) than those with a middle‐age diagnosis (MD) (5%) and late diagnosis (LD) groups (2%), P < 0.01, and appeared to have a decrease risk of hepatobiliary malignancies: ED versus MD: hazard ratio (HR), 0.25; 95% confidence interval (CI) 0.06–1.03, and ED versus LD: HR, 0.07; 95% CI 0.01–0.62. Cholangiocarcinoma was diagnosed in 78 subjects (ED n = 0, MD n = 66, and LD n = 12) and was more likely to be diagnosed within a year after the PSC diagnosis among those found to have PSC late in life: ED 0% (0/95), MD 2% (14/662), and LD 6% (6/102), P = 0.02. Similarly, hepatic decompensation was more common among those with LD‐PSC versus younger individuals: LD versus MD: HR, 1.64; 95% CI 0.98–2.70, and LD versus ED: HR, 2.26; 95% CI 1.02–5.05.ConclusionsThose diagnosed with PSC early in life are more likely to have small‐duct PSC and less likely to have disease‐related complications. Clinicians should be vigilant for underlying cholangiocarcinoma among those with PSC diagnosed late in life.

54 Background: After diagnosis and treatment, lung cancer survivors do not return to a health-related quality of life (QOL) and function comparable to pre-diagnosis levels as observed in other adult cancer survivors. We hypothesize that inadequate attention has been paid to addressing and improving QOL and function among lung cancer survivors. Our primary goal is to evaluate existing symptoms and QOL deficits among lung cancer survivors. Methods: We are evaluating patterns of QOL deficits (scored 5 or less on the scale from 0 [worst] to 10 [best]) in relation to time of lung cancer diagnosis, treatments, progression and/or recurrence, and health-related conditions. We are collecting and analyzing relevant health care utilization for selected QOL deficits, and identifying availability, accessibility, and effectiveness of evidence-based interventions. The expected outcomes will be new knowledge on patterns of QOL deficits, quality-adjusted life years in relation to the availability, accessibility, and adequacy of needed care and the effectiveness of interventions targeting improvement in QOL and symptoms. Results: In our initial analysis, among 3,707 lung cancer survivors who were diagnosed in 1999 to 2010, post-cancer treatment, and followed through 2011, 39% (1,442) reported deficits in overall QOL, 71% fatigue, 60% dyspnea, 41% being sedentary, 17% low spiritual well-being (SWB), and 10% currently smoking cigarettes. Among the 1,442 lung cancer survivors with a deficit in overall QOL, 97.5% reported severe fatigue or dyspnea, being sedentary or smoking, or having low SWB. In the remaining 36 of the 1,442, 24 had pain, cough, poor appetite, or other symptoms; only 12 (<1%) did not report deficit in any of the measured QOL domains. Analyses are ongoing. Conclusions: Based on evidence gained to date, we are developing and testing interventions targeting symptoms and QOL deficits. We expect to gain strong evidence for recommendations in redefining and delivering care and support that are necessary for improving the health and QOL of lung cancer survivors.

Lung cancer is the deadliest cancer in the United States, killing roughly one of four cancer patients in 2016. While it is well-established that lung cancer is caused primarily by environmental effects (particularly tobacco smoking), there is evidence for genetic susceptibility. Lung cancer has been shown to aggregate in families, and segregation analyses have hypothesized a major susceptibility locus for the disease. Genetic association studies have provided strong evidence for common risk variants of small-to-moderate effect. Rare and highly penetrant alleles have been identified by linkage studies, including on 6q23–25. Though not common, some germline mutations have also been identified via sequencing studies. Ongoing genomics studies aim to identify additional high penetrance germline susceptibility alleles for this deadly disease.

Abstract Several papers have implicated mutations in the AT-rich interactive domain containing protein 1B (ARID1B) in carcinoma formation in multiple tissue types, including the lung. The ARID1B protein functions as part of SWI/SNF, a multi-subunit chromatin remodeling complex that repositions nucleosomes and may act as a tumor suppressor in cancer. ARID1B is located in a region in 6q that was previously shown to have strong evidence of linkage with lung cancer risk. As it is one of the more promising candidates within the target region, this study presents the viability of ARID1B as a candidate gene for familial lung cancer. Here, we chose individuals from families in our previous linkage study that showed the strongest linkage signal on 6q. 75 individuals from 9 families were sequenced for 37Mb of chromosome 6 from 130Mb to 167Mb using Illumina technology and a custom Agilent kit. Genotypes were imported into GoldenHelix SVS 7 for quality control and dropped if read depth &lt; 10, quality score &lt; 10 or a quality score to read depth ratio &lt; 0.5. Variants with more than 1 Mendelian error were dropped. Variants with a single Mendelian inconsistency were dropped only for that family. Two-point parametric linkage analysis at theta = 0 was performed using R and an implementation of the Elston-Stewart algorithm in the paramlink package using a penetrance model of 0.01/0.1/0.1 (dd/Dd/DD) and a disease allele (D) frequency of 0.01. Family 102 showed strong evidence for linkage near ARID1B. The highest LOD score (1.34) out of all sequenced variants was located near this gene in a known conserved intergenic region between ARID1B and NOX3. Four other LOD scores &gt; 0.7 were found in the intergenic region between these two genes. Two are transcription factor binding sites; two are conserved genomic elements. We also observed two linked intronic variants of ARID1B in this family; an enhancer (LOD = 0.89) and a transcribed region (LOD = 0.73). Two other families (47 and 59) displayed evidence of linkage in ARID1B. Here, the interest is not the value of the LOD scores (top scores were 0.64 and 0.54), but the centering of the linked haplotype around the gene. Family 47 has 60 variants with LODs between 0.64 and 0.61; 45 located within ARID1B or known regulatory regions. Family 59 has 61 variants with LODs between 0.54 and 0.51; 29 located within ARID1B or known regulatory regions The variants appear to be spread evenly throughout ARID1B, suggesting the presence of linked haplotypes. Analyses are currently underway to reconstruct possible haplotypes in these families. The results of this study show that variants in the ARID1B gene at least partially account for the linkage signal on 6q in three of the nine most strongly linked families in our cohort and thus we believe that ARID1B is a plausible candidate gene for further studies involving familial lung cancer. Replication studies using 27 new extended families are currently underway to confirm this initial result. Citation Format: Anthony M. Musolf, Claire L. Simpson, Mariza de Andrade, Diptasri Mandal, Colette Gaba, Ping Yang, Ming You, Elena Y. Kupert, Marshall W. Anderson, Ann G. Schwartz, Susan M. Pinney, Christopher I. Amos, Joan E. Bailey-Wilson. Chromatin remodeling gene ARID1B is linked to familial lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2542.

Inflammation plays a pivotal role in peripheral artery disease (PAD). Cellular adhesion proteins mediate the interaction of leukocytes with endothelial cells during inflammation. To determine the association of cellular adhesion molecules with ankle–brachial index (ABI) and ABI category (≤1.0 vs >1.0) in a diverse population, 15 adhesion proteins were measured in the Multi-Ethnic Study of Atherosclerosis (MESA). To assess multivariable associations of each protein with ABI and ABI category, linear and logistic regression was used, respectively. Among 2364 participants, 23 presented with poorly compressible arteries (ABI > 1.4) and were excluded and 261 had ABI ≤ 1.0. Adjusting for traditional risk factors, elevated levels of soluble P-selectin, hepatocyte growth factor, and secretory leukocyte protease inhibitor were associated with lower ABI ( P = .0004, .001, and .002, respectively). Per each standard deviation of protein, we found 26%, 20%, and 19% greater odds of lower ABI category ( P = .001, .01, and .02, respectively). Further investigation into the adhesion pathway may shed new light on biological mechanisms implicated in PAD.

Background Intracranial aneurysms ( IAs ), abdominal aortic aneurysms ( AAAs ), and thoracic aortic aneurysms ( TAAs ) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs , AAAs, and TAAs . Methods and Results We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study ( GWAS ) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA , AAA , and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA ‐, AAA ‐, and TAA ‐associated SNP s and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls ( IA ) and 4391 cases and 37 904 controls ( AAA ), and found nominally significant associations for IA risk locus 18q11 near RBBP 8 to AAA (odds ratio [ OR ]=1.11; P =4.1×10 −5 ) and for TAA risk locus 15q21 near FBN 1 to AAA ( OR =1.07; P =1.1×10 −3 ). Conclusions Although there was no evidence for polygenic overlap between IAs , AAAs , and TAAs , we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs . These two loci will require further replication.

Abstract Objective: Onset and symptoms of menopause, and response to hormone therapy (HT) show large interindividual variability. SULT1A1 encodes for a highly expressed enzyme that metabolizes estrogens. We evaluated the relationship between genetic variation in SULT1A1, menopause age, symptoms, and response to HT. Methods: Women enrolled in the Kronos Early Estrogen Prevention Study at Mayo Clinic were randomized to 48 months of treatment with oral conjugated equine estrogen (n = 34), transdermal 17β-estradiol (E2) (n = 33), or placebo (n = 35). Linear regression models and ANOVA were used to test for association of SULT1A1 copy number, rs3760091, rs750155, and rs9282861 (SULT1A1 ∗ 2), with age at menopause and symptoms, levels of estrogens (estrone [E1], estrone sulfate [E1S], E2, and estradiol sulfate [E2S]), before and after HT. Results: SULT1A1 gene copy number affected the minor allele frequency for each single nucleotide polymorphisms tested. Before administration of exogenous hormones, increasing number of G alleles at rs9282861 was associated with earlier age at menopause (P = 0.014), lower frequency of night sweats (P = 0.009), and less severe insomnia (P = 0.046). After 48 months of treatment, SULT1A1 genotype was not associated with the presence of menopausal symptoms. In women randomized to oral conjugated equine estrogen, increasing number of the A allele at rs750155 was associated with lower E1S and E2S (P = 0.004 and 0.017), whereas increasing number of the C allele at rs3760091 was associated with lower E2S/E2 (P = 0.044). Conclusions: Interindividual variability in onset of menopause and symptoms before initiation of HT is explained in part by genetic variation in SULT1A1 and may represent a step toward individualizing HT treatment decisions.