Citations

Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

AbstractRecently, we showed that increased miR-181a expression was associated with improved outcomes in cytogenetically normal acute myeloid leukemia (CN-AML). Interestingly, miR-181a expression was increased in CN-AML patients harboring CEBPA mutations, which are usually biallelic and associate with better prognosis. CEBPA encodes the C/EBPα transcription factor. We demonstrate here that the presence of N-terminal CEBPA mutations and miR-181a expression are linked. Indeed, the truncated C/EBPα-p30 isoform, which is produced from the N-terminal mutant CEBPA gene or from the differential translation of wild-type CEBPA mRNA and is commonly believed to have no transactivation activity, binds to the miR-181a-1 promoter and up-regulates the microRNA expression. Furthermore, we show that lenalidomide, a drug approved for myelodysplastic syndromes and multiple myeloma, enhances translation of the C/EBPα-p30 isoform, resulting in higher miR-181a levels. In xenograft mouse models, ectopic miR-181a expression inhibits tumor growth. Similarly, lenalidomide exhibits antitumorigenic activity paralleled by increased miR-181a expression. This regulatory pathway may explain an increased sensitivity to apoptosis-inducing chemotherapy in subsets of AML patients. Altogether, our data provide a potential explanation for the improved clinical outcomes observed in CEBPA-mutated CN-AML patients, and suggest that lenalidomide treatment enhancing the C/EBPα-p30 protein levels and in turn miR-181a may sensitize AML blasts to chemotherapy.

Objective Obstructive sleep apnoea (OSA) and obesity are both associated with endothelial dysfunction, which precedes the development of atherosclerosis. As obesity is highly prevalent in OSA, we wanted to test the hypothesis that OSA is associated with endothelial dysfunction independently of obesity. Design Cross-sectional, population-based study. Setting Norwegian university hospital. Patients Seventy-one subjects (median age 44 years, 35% female) were recruited from a population-based study in Norway. Participants were categorised as obese (body mass index (BMI) ≥30 kg/m2), non-obese (BMI<30 kg/m2) with OSA (apnoea–hypopnoea index (AHI)≥10), or non-obese without OSA (AHI<5). Interventions None. Main outcome measures Endothelial function measured by brachial artery ultrasound and expressed as percentage of flow-mediated dilation (FMD%). Results When non-obese subjects without OSA were used as the reference (FMD% (mean±SD) 10.1±6.3), endothelial function was found to be impaired in subjects with OSA (FMD% 6.4±3.2) (p=0.003). FMD% did not differ between obese (6.0±3.4) and non-obese (6.7±3.1) OSA subjects (p=0.3). By univariate linear regression analysis, AHI, BMI, gender and baseline brachial artery diameter were significantly associated with FMD%. When these variables were entered into a multivariate model, only AHI was significantly associated with FMD%. Conclusions OSA is associated with endothelial dysfunction independently of obesity and conventional risk factors.

AbstractMucinous ovarian carcinomas (MCs) typically do not respond to current conventional therapy. We have previously demonstrated amplification of HER2 in 6 of 33 (18.2%) mucinous ovarian carcinomas (MCs) and presented anecdotal evidence of response with HER2‐targeted treatment in a small series of women with recurrent HER2‐amplified (HER2+) MC. Here, we explore HER2 amplification and KRAS mutation status in an independent cohort of 189 MCs and 199 mucinous borderline ovarian tumours (MBOTs) and their association to clinicopathological features. HER2 status was assessed by immunohistochemistry (IHC), FISH, and CISH, and interpreted per ASCO/CAP guidelines, with intratumoural heterogeneity assessment on full sections, where available. KRAS mutation testing was performed with Sanger sequencing. Stage and grade were associated with recurrence on both univariate and multivariate analysis (p < 0.001). Assessment of HER2 status revealed overexpression/amplification of HER2 in 29/154 (18.8%) MCs and 11/176 (6.2%) MBOTs. There was excellent agreement between IHC, FISH, and CISH assessment of HER2 status (perfect concordance of HER2 0 or 1+ IHC with non‐amplified status, and 3+ IHC with amplified status). KRAS mutations were seen in 31/71 (43.6%) MCs and 26/33 (78.8%) MBOTs, and were near mutually exclusive of HER2 amplification. In the 189 MC cases, a total of 54 recurrences and 59 deaths (53 of progressive disease) were observed. Within MCs, either HER2 amplification/overexpression or KRAS mutation was associated with decreased likelihood of disease recurrence (p = 0.019) or death (p = 0.0041) when compared to cases with neither feature. Intratumoural heterogeneity was noted in 26% of HER2‐overexpressing cases. These data support the stratification of MCs for the testing of new treatments, with HER2‐targeted therapy as a viable option for HER2+ advanced or recurrent disease. Further research is required to delineate the molecular and clinical features of the ∼34% of MC cases with neither HER2 amplification nor KRAS mutations.

Abstract Little is known about the effects of many recognized breast cancer risk factors on the normal breast. We hypothesize that risk factors affect the number and morphometry of terminal ductal lobular units (TDLUs), the microanatomical structure from which most breast cancers arise. To assess this hypothesis, we evaluated relationships between breast cancer risk factors and TDLU number, TDLU diameter, and acini per TDLU in breast tissue donated by healthy volunteers. Subjects included 786 healthy women ages 18-84 years without a personal history of any cancer, who provided a risk factor questionnaire and donated a 10-guage needle core from the upper outer breast quadrant. A pathologist, masked to subject data, assessed TDLU number per section, TDLU diameter and acini per TDLU using digitized images of hematoxylin and eosin stained sections of tissue. Seventy-two randomly selected images were examined by two additional pathologists. We generated ordered categorical variables for the number of TDLUs per section (0-1, 2-8, 9+), median TDLU diameter (53-262, 263-377, 378-1375 microns) and median number of acini per TDLU (2-10, 11-20, 21+). We computed Spearman correlations between measures, and intraobserver and interobserver agreement. Associations between breast cancer risk factors and TDLU measures were assessed by estimating odds ratios (OR) and 95% confidence intervals (CI) using ordinal logistic regression models, adjusted for age. TDLU diameter and acini count were highly correlated (rho =0.71); TDLU number per section was less strongly related to the diameter (rho= 0.18) and acini measures (rho=0.20). Inter and intraobserver agreement for TDLU measures were highly correlated (rho range 0.68-0.98). All TDLU measurements were significantly lower among women age 50 years and older compared with younger women. Compared with Caucasians, African American women had more TDLUs per section (ORadj=2.03, 95% CI= 1.06-3.89). Greater numbers of TDLUs were also related to having a family history of two or more relatives with breast cancer compared with none (ORadj=2.01, 95% CI=0.91-4.46); and for parous compared with nulliparous women (ORadj=1.61, 95% CI=1.16-2.25). In contrast, parity was associated with reduced median number of acini per TDLU (ORadj=0.60, 95% CI = 0.40-0.90) and median diameter (ORadj=0.64, 95% CI = 0.42-0.96) compared with nulliparity. Our data suggest that TDLUs are more frequent among women with a positive family history of breast cancer or African Americans. Parity, an established protective factor for breast cancer risk, was related to increased numbers of TDLUs, but fewer acini per TDLU, suggesting that TDLUs may increase with pregnancy and then involute. Our data, along with published results linking TDLU involution with a reduction in breast cancer risk, suggest TDLU morphometry may reflect early biologic changes marking breast cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4465. doi:1538-7445.AM2012-4465

Abstract We performed a multi-stage genome-wide association study (GWAS) for drug response in ovarian cancer. We selected 313 chemotherapy treated patients from the Australian Ovarian Cancer Study (AOCS). Patients were treated with paclitaxel/carboplatin and the trait of interest was Progression Free Survival (PFS). We maximized power for a fixed genotyping budget by genotyping individuals from the tails of the distribution: 94 with good survival and 94 with poor survival, taking into account extent of residual disease following surgery. Patients were genotyped on Illumina HumanOmni1-Quad arrays (1140419 loci).Two further cohorts with measures of PFS and whole genome data available; 134 ovarian patients from the Mayo clinic (genotyped on Illumina HumanHap 610 arrays, 620901 loci) and 68 patients from The Cancer Genome Atlas ovarian cancer set (genotyped on Illumina Human1M arrays, 1199187 loci) were meta-analyzed with the AOCS set (stage 1). We have imputed all the stage 1 samples with reference of the 1000 Genome data to allow more direct comparison of SNPs not common to all of the arrays used (up to 6 million SNPs with good imputation quality). Based on the chemotherapy treatment received by each patient, we assigned the patients into primary and secondary analysis, with primary analysis using a more strictly defined treatment subgroup. We followed up the stage 1 findings by genotyping 26 SNPs in more than 3,000 samples collected from 8 study sites of Ovarian Cancer Association Consortium (OCAC). These 26 SNPs were mainly genotyped SNPs, chosen from 23 distinct regions showing the strongest association with chemotherapy response from either primary or secondary analysis. 2 SNPs showed nominal significance in the replication sample (chr 12: rs1861932, chr 22: rs708444). We are currently genotyping more regions to seek replication of the initial findings. In summary, we sought to identify genes that underlie individual differences in chemoresistance. In the future, typing variations in these genes will be important for personalizing drug regimes for patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4679. doi:10.1158/1538-7445.AM2011-4679

Abstract The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion and proliferation. Here, we report that neuropilin-1 (NRP-1) orchestrates communications between myofibroblasts and soluble fibronectin that promote α5β1 integrin–dependent fibronectin fibril assembly, matrix stiffness, and tumor growth. Tumor growth and fibronectin fibril assembly were reduced by genetic depletion or antibody neutralization of NRP-1 from stromal myofibroblasts in vivo. Mechanistically, the increase in fibronectin fibril assembly required glycosylation of serine 612 of the extracellular domain of NRP-1, an intact intracellular NRP-1 SEA domain, and intracellular associations between NRP-1, the scaffold protein GIPC, and the nonreceptor tyrosine kinase c-Abl that augmented α5β1 fibronectin fibril assembly activity. Analysis of human cancer specimens established an association between tumoral NRP-1 levels and clinical outcome. Our findings indicate that NRP-1 activates the tumor microenvironment, thereby promoting tumor growth. These results not only identify new molecular mechanisms of fibronectin fibril assembly but also have important implications for therapeutic targeting of the myofibroblast in the tumor microenvironment. Cancer Res; 72(16); 4047–59. ©2012 AACR.