The anti-HER2 antibody trastuzumab acts by different mechanisms, one of which is antibody-dependent cellular cytotoxicity of immune effector cells via Fcγ receptors (FCGRs). Lower affinity to trastuzumab has been described for the minor alleles in FCGR2A (H131R, rs1801274) and in FCGR3A (V158F, rs396991). These genotypes were previously associated with poorer response to trastuzumab in metastatic breast cancer. This study investigates the association of these genetic polymorphisms with disease-free survival (DFS) in HER2 positive breast cancer patients from the adjuvant SUCCESS A trial.

A novel missense variant in PRKCB segregates low-frequency hearing loss in an autosomal dominant family with Meniere's disease C. Martın-Sierra, T. Requena, L. Frejo, SD Price, A. Gallego-Martinez, A. Batuecas-Caletrio, S. Santos-Pe´rez, A. Soto-Varela, A. Lysakowski, and JA Lopez-Escamez . . . . . . . . . . . . . . . . . . . . . 3407 … Functional rescue of REP1 following treatment with PTC124 and novel derivative PTC-414 in human choroideremia fibroblasts and the nonsense-mediated zebrafish model M. Moosajee, D. Tracey-White, M. Smart, M. Weetall, S. Torriano, V. Kalatzis, L. da Cruz, P. Coffey, AR Webster, and E. Welch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3416 … Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease J. Magalhaes, ME Gegg, A. Migdalska-Richards, MK Doherty, PD Whitfield, and AHV Schapira . . . 3432

Abstract Background: Epithelial ovarian cancer (EOC) is composed of five major histologic types: 1) high-grade serous carcinoma (HGSC), accounting for most cases (∼70%); and the rarer 2) clear cell, 3) endometrioid, 4) mucinous, and 5) low- grade serous carcinoma (LGSC). As EOC risk factors are histology specific, as are the site of precursor lesions, accurate subtyping is critical to understanding EOC prognostic factors and etiology. Our aim was to compare two currently employed histology assignment strategies using gene expression, DNA methylation, and clinical outcome data Methods: Histology assignment based on: a) pathologist, and b) an integrated pathologist and IHC prediction algorithm (pathIHC) (using ARID1A, CDKN2A, DKK1, HNF1B, MDM2, PGR, TP53, TFF3, VIM, and WT1 staining patterns), was compared for tumors of all histologies at the Mayo Clinic, Rochester. The 500 most variable probes from Illumina Methylation450 BeadChips (N = 259) and Agilent 4×44K expression arrays (N = 245) were used to perform unsupervised hierarchical clustering. Fisher's Exact test was used to test the association of clusters with histology. Cox proportional hazards regression analysis was used to test the association of clusters and histology with time to progression (TTP) and time to death (TTD). Results: Eighty-two percent of tumors were concordant between histology assignment strategies. Clustering based on methylation data produced two distinct clusters. PathIHC produced more homogenous clusters (p-value = 2.8×10-16) than pathology alone (p = 1.3×10-9). Cluster M1, characterized by high levels of methylation across almost all probes, was enriched for the rarer EOC subtypes; cluster M2, characterized by moderate levels of methylation across 50%-75% of probes, was predominantly HGSC. These patterns were observed irrespective of histology assignment strategy; however, when using histology by pathologist, cluster M2 had more endometrioid and LGSC tumors interspersed with HGSC tumors. Clustering based on expression data also produced two clusters. PathIHC produced slightly more homogenous clusters (p = 9.0×10-11, pathology alone, p = 2.3×10-10). Cluster E1 was enriched for the rarer EOC subtypes; cluster E2 was primarily serous lineage tumours (HGSC and LGSC), particularly when using histology by pathIHC. Considering only clinical outcomes, histologies by pathology were more significantly different in terms of TTP (p = 1.1×10-6) and TTD (p = 1.7×10-3) than histologies by pathIHC (TTP, p = 5.4×10-6; TTD, p = 5.7×10-3). Conclusions: Histology by pathIHC produced more homogeneous clusters in both the methylation and expression data; thus, molecular data supports this strategy. Differences in clinical outcomes (TTP and TTD) between histology groups were more pronounced when using assignment by pathologist; thus, clinical data supports this strategy. Citation Format: M A. Earp, S J. Winham, S M. Armasu, B L. Fridley, M C. Larson, Z C. Fogarty, K R. Kalli, C Wang, G L. Keeney, J M. Cunningham, S Ramus, M Kobel, E L. Goode. Comparison of pathology versus IHC-based ovarian carcinoma histology assignment using gene expression, DNA methylation, and clinical outcome data. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4246. doi:10.1158/1538-7445.AM2015-4246

Large-scale genotyping studies have identified over 70 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. However, knowledge regarding genetic risk factors associated with the prognosis is limited. The aim of this study was therefore to investigate the prognostic effect of nine known breast cancer risk SNPs. BC patients (n = 1687) randomly sampled in an adjuvant, randomized phase III trial (SUCCESS A study) were genotyped for nine BC risk SNPs: rs17468277(CASP8), rs2981582(FGFR2), rs13281615(8q24), rs3817198(LSP1), rs889312(MAP3K1), rs3803662(TOX3), rs13387042(2q35), rs4973768(SLC4A7), rs6504950(COX11). Cox proportional hazards models were used to test the SNPs' association with overall survival (OS) and progression-free survival (PFS). Additional analyses were carried out for molecular subgroups. rs3817198 in LSP1 (lymphocyte-specific protein 1) was the only SNP that significantly influenced OS (p = 0.01) and PFS (p < 0.01) in the likelihood ratio test comparing the genetic survival model with the clinical survival model. In the molecular subgroups, triple-negative patients with two minor alleles in rs3817198 had a much better prognosis relative to OS (adjusted HR 0.03; 95% CI 0.002-0.279) and PFS (HR 0.09; 95% CI 0.02-0.36) than patients with the common alleles. The same effect on PFS was shown for patients with luminal A tumors (HR 0.19; 95% CI 0.05-0.84), whereas patients with luminal B tumors had a poorer PFS with two minor alleles (HR 2.13; 95% CI 1.02-4.40). The variant in rs3817198 has a prognostic effect particularly in the subgroup of patients with triple-negative BC, suggesting a possible link with immunomodulation and BC.

We evaluated homologous recombination deficient (HRD) phenotypes in epithelial ovarian cancer (EOC) considering BRCA1, BRCA2 and RAD51C in a large well-annotated patient set. We evaluated EOC patients for germline deleterious mutations (n = 899), somatic mutations (n = 279) and epigenetic alterations (n = 482) in these genes using NGS and genome-wide methylation arrays. Deleterious germline mutations were identified in 32 (3.6%) patients for BRCA1, in 28 (3.1%) for BRCA2 and in 26 (2.9%) for RAD51C. Ten somatically sequenced patients had deleterious alterations, six (2.1%) in BRCA1 and four (1.4%) in BRCA2. Fifty two patients (10.8%) had methylated BRCA1 or RAD51C. HRD patients with germline or somatic alterations in any gene were more likely to be high grade serous, have an earlier diagnosis age and have ovarian and/or breast cancer family history. The HRD phenotype was most common in high grade serous EOC. Identification of EOC patients with an HRD phenotype may help tailor specific therapies.

Summary.  Objectives:  To identify venous thromboembolism (VTE) disease‐susceptibility genes.

Background: Venous thromboembolism (VTE) is highly heritable (estimated heritability [h2] = 0.62) and likely to be a result of multigenic action. Objective: To systematically test variation within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways for an independent association with VTE. Methods: Non-Hispanic adults of European ancestry with objectively-diagnosed VTE, and age- and sex- matched controls, were genotyped for 13 031 single nucleotide polymorphisms (SNPs) within 764 genes. Analyses (n = 12 296 SNPs) were performed with plink using an additive genetic model and adjusted for age, sex, state of residence, and myocardial infarction or stroke. Results: Among 2927 individuals, one or more SNPs within ABO, F2, F5, F11, KLKB1, SELP and SCUBE1 were significantly associated with VTE, including factor (F) V Leiden, prothrombin G20210A, ABO non-O blood type, and a novel association with ABO rs2519093 (OR = 1.68, P-value = 8.08 x 10-16) that was independent of blood type. In stratified analyses, SNPs in the following genes were significantly associated with VTE: F5 and ABO among both genders and LY86 among women; F2, ABO and KLKB1 among FV Leiden non-carriers; F5, F11, KLKB1 and GFRA1 in those with ABO non-O blood type; and ABO, F5, F11, KLKB1, SCUBE1 and SELP among prothrombin G20210A non-carriers. The ABO rs2519093 population-attributable risk (PAR) exceeded that of FV Leiden and prothrombin G20210A, and the joint PAR of FV Leiden, prothrombin G20210A, ABO non-O and ABO rs2519093 was 0.40. Conclusions: Anticoagulant, procoagulant, fibrinolytic and innate immunity pathway genetic variation accounts for a large proportion of VTE among non-Hispanic adults of European ancestry.

BACKGROUNDSmall-cell lung cancer (SCLC) carries the worst prognosis among lung cancer diagnoses. Combined radiation and chemotherapy is the standard of care; however, treatment outcomes vary. Variability in the rate at which chemotherapy agents are metabolized and in the capacity of repairing DNA damage has been hypothesized to be partly responsible for the treatment response variation. Genes in the glutathione metabolism and DNA repair pathways were tested through tag single-nucleotide polymorphisms (SNPs) to assess their association with survival in SCLC.PATIENTS AND METHODSBlood DNA from 248 patients with primary SCLC was genotyped for 419 tag SNPs from 49 genes in the glutathione and DNA repair pathways. Association analyses with patient survival were carried out at single-SNP, whole-gene, and haplotype levels after adjusting for age, gender, tumor stage, treatment modalities, and smoking history.RESULTSAmong the 375 SNPs successfully genotyped, 21 SNPs, located on 11 genes, showed significant association with survival. Whole-gene analyses confirmed 3 of the 11 genes: GSS, ABCC2, and XRCC1. Haplotype analyses of these three genes identified haplotype combinations and genomic locations underlying the observed SNP associations.CONCLUSIONGenetic variations in genes involved in the glutathione and DNA repair pathways are associated with SCLC survival.

Correction to: British Journal of Cancer (2009) 100, 412–420. doi:10.1038/sj.bjc.6604820 www.bjcancer.com Upon publication of this paper in Volume 100, one of the co-author's names was incorrectly stated – Julie Cunningham's middle initial was stated as ‘C’ rather than ‘M’. The authors and publishers apologise for this mistake.

Background: Dysregulation of the cell cycle is a hallmark of many cancers including ovarian cancer, a leading cause of gynaecologic cancer mortality worldwide. Methods: We examined single nucleotide polymorphisms (SNPs) ( n =288) from 39 cell cycle regulation genes, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors, in a two-stage study. White, non-Hispanic cases ( n =829) and ovarian cancer-free controls ( n =941) were genotyped using an Illumina assay. Results: Eleven variants in nine genes ( ABL1, CCNB2, CDKN1A, CCND3, E2F2, CDK2, E2F3, CDC2 , and CDK7 ) were associated with risk of ovarian cancer in at least one genetic model. Seven SNPs were then assessed in four additional studies with 1689 cases and 3398 controls. Association between risk of ovarian cancer and ABL1 rs2855192 found in the original population [odds ratio, OR BB vs AA 2.81 (1.29–6.09), P =0.01] was also observed in a replication population, and the association remained suggestive in the combined analysis [OR BB vs AA 1.59 (1.08–2.34), P =0.02]. No other SNP associations remained suggestive in the replication populations. Conclusion: ABL1 has been implicated in multiple processes including cell division, cell adhesion and cellular stress response. These results suggest that characterization of the function of genetic variation in this gene in other ovarian cancer populations is warranted.

The influence of genetic variations in SLC6A4 (serotonin transporter gene) on citalopram treatment of depression using the Sequenced Treatment to Relieve Depression (STAR*D) sample was assessed. Of primary interest were three previously studied polymorphisms: 1) the VNTR variation of the second intron, 2) the indel promoter polymorphism (5HTTLPR or SERT), and 3) a single nucleotide polymorphism (SNP) rs25531. Additionally, SLC6A4 was resequenced to identify new SNPs for exploratory analyses. DNA from 1914 subjects in the STAR*D study were genotyped for the intron 2 VNTR region, the indel promoter polymorphism, and rs25531. Associations of these variants with remission of depressive symptoms were evaluated following citalopram treatment. In white non‐Hispanic subjects, variations in the intron 2 VNTR (point‐wise P = 0.041) and the indel promoter polymorphism (point‐wise P = 0.039) were associated with remission following treatment with citalopram. The haplotype composed of the three candidate loci was also associated with remission, with a global p‐value of 0.040 and a maximum statistic simulation p‐value of 0.0031 for the S‐a‐12 haplotype, under a dominant model. One SNP identified through re‐sequencing the SLC6A4 gene, Intron7‐83‐TC, showed point‐wise evidence of association, which did not remain significant after correction for the number of SNPs evaluated in this exploratory analysis. No associations between these SLC6A4 variations and remission were found in the white Hispanic or black subjects. These findings suggest that multiple variations in the SLC6A4 gene are associated with remission in white non‐Hispanic depressed adults treated with citalopram. The mechanism of action of these variants remains to be determined. © 2008 Wiley‐Liss, Inc.

BACKGROUND:Aggregation and fibrillization of the alpha-synuclein protein (encoded by the SNCA gene) may represent key events in the pathogenesis of Parkinson disease (PD). Variability in the length of a dinucleotide repeat sequence (REP1) within the SNCA promoter confers susceptibility to sporadic PD. Pesticide exposures may also confer susceptibility to PD. Our objective was to test possible joint effects of SNCA REP1 genotypes and pesticide exposures on the risk of PD. METHODS:This was a case-control study. Cases were recruited prospectively from the Department of Neurology of the Mayo Clinic, Rochester, MN, after June 1, 1996. The control subjects included unaffected siblings of cases and unrelated population control subjects. We assessed pesticide exposures by telephone interview and genotyped SNCA REP1. Odds ratios (ORs) and 95% CIs were determined using conditional logistic regression models. RESULTS:There were 833 case-control pairs. We observed an increased risk of PD with increasing SNCA REP1 bp length (OR, 1.18 for each score unit; 95% CI, 1.02-1.37; p = 0.03). Pesticide exposures were associated with PD in younger subjects only (lowest quartile of age at study, <or=59.8 years; OR, 1.80; 95% CI, 1.12-2.87; p = 0.01 for all pesticides; OR, 2.46; 95% CI, 1.34-4.52; p = 0.004 for herbicides). In multivariate analyses, both SNCA REP1 score and pesticide exposures were significantly associated with PD in younger subjects, but there were no pairwise interactions. CONCLUSIONS:Our findings suggest that SNCA REP1 genotype and herbicides have independent effects on risk of Parkinson disease, primarily in younger subjects.

Objectives. To investigate the associations between benign prostatic hyperplasia (BPH) and polymorphisms in genes that encode growth factors, cytokines, and vitamin D and their receptors.Methods. A total of 510 white men (median age 60 years) randomly selected from the Olmsted County, Minnesota community participated in a study of BPH from 1990 to 2000. Biennial measurements were made to assess the International Prostate Symptom Score, peak urinary flow rate, and prostate volume. Genotyping of genes that encode transforming growth factor, interleukin-10, tumor necrosis factor, and vitamin D receptor, among others, was performed.Results. The CC genotype of the transforming growth factor-beta 1 gene was inversely associated with treatment for BPH (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.15 to 0.98). The presence of at least one allele with 17 or more CA repeats of the epidermal growth factor receptor gene was positively associated with an International Prostate Symptom Score greater than 7 (HR 1.32, 95% CI 1.01 to 1.73). The AA genotype of tumor necrosis factor-alpha was inversely associated with peak urinary flow rate (HR 0.33, 95% CI 0.12 to 0.90). For the vitamin D receptor gene, positive associations were found between prostate volume and the CC genotype of the T_C (Taq 1) polymorphism (HR 1.39, 95% CI 1.0 to 1.92) and the AA genotype of the G_ A(Bm 1) polymorphism (HR 1.36, 95% CI 1.06 to 1.74).Conclusions. These findings suggest that transforming growth factor-beta 1, tumor necrosis factor-alpha, epidermal growth factor receptor, and vitamin D receptor polymorphisms may be involved in the pathogenesis of BPH.