Citations

Abstract Defective microRNA (miRNA) biogenesis contributes to the development and progression of epithelial ovarian cancer (EOC). In this study, we examined the hypothesis that single nucleotide polymorphisms (SNP) in miRNA biogenesis genes may influence EOC risk. In an initial investigation, 318 SNPs in 18 genes were evaluated among 1,815 EOC cases and 1,900 controls, followed up by a replicative joint meta-analysis of data from an additional 2,172 cases and 3,052 controls. Of 23 SNPs from 9 genes associated with risk (empirical P < 0.05) in the initial investigation, the meta-analysis replicated 6 SNPs from the DROSHA, FMR1, LIN28, and LIN28B genes, including rs12194974 (G>A), an SNP in a putative transcription factor binding site in the LIN28B promoter region (summary OR = 0.90, 95% CI: 0.82–0.98; P = 0.015) which has been recently implicated in age of menarche and other phenotypes. Consistent with reports that LIN28B overexpression in EOC contributes to tumorigenesis by repressing tumor suppressor let-7 expression, we provide data from luciferase reporter assays and quantitative RT-PCR to suggest that the inverse association among rs12194974 A allele carriers may be because of reduced LIN28B expression. Our findings suggest that variants in LIN28B and possibly other miRNA biogenesis genes may influence EOC susceptibility. Cancer Res; 71(11); 3896–903. ©2011 AACR.

Abstract Mitochondria have been implicated in carcinogenesis because of their central role in apoptosis, free radical production, and cellular energy metabolism. Although studies have identified somatic mitochondrial DNA mutations in ovarian cancers, little attention has been directed to the possible role of germline mitochondrial variants in mitochondrial dysfunction and subsequent ovarian cancer development. Through an ongoing epithelial ovarian cancer genome-wide association study of 1,856 invasive cases (59% with serous carcinomas) and 1,912 controls (frequency-matched on age, race, and study site), we genotyped 138 SNPs tagging variation in the maternally-inherited mitochondrial genome (mtDNA) to evaluate the hypothesis that single nucleotide polymorphisms (SNPs) in mtDNA are associated with ovarian cancer risk. All subjects were non-Hispanic, non-Jewish Caucasians, and were genotyped with the Illumina 610-quad Beadchip. Samples and SNPs with call rates less than 95% were excluded. Subjects with ambiguous gender, unresolved identical genotypes, and less than 80% European ancestry were excluded. For each SNP, logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) between carriers of the minor versus major maternally-inherited allele and case status. Subgroup analysis was conducted to estimate allele-specific risks between serous-only cases and controls. Haplotype analysis was performed for regions containing statistically significant SNPs (p<0.05). Two rare SNPs, C16329T in the displacement loop gene (MT-D-loop) (OR: 6.72, 95%CI: 1.5-29.8, p=0.004; minor allele frequency (MAF)=0.001) and C15905T in the tRNA threonine gene (MT-TT) (OR: 1.60, 95%CI: 1.1-2.3, p=0.009; MAF=0.027), were associated with increased ovarian cancer risk; whereas T6777C in the cytochrome c oxidase subunit 1 gene (MT-CO1) (OR: 0.68, 95%CI: 0.51-0.91, p=0.009; MAF=0.063) was associated with decreased risk. All three SNPs remained statistically significant after adjustment for multiple comparisons within the mitochondrial SNPs using permutation testing. C16329T and T6777C were also significantly associated among cases with serous histology, with ORs (95% CIs) of 6.13 (1.2-29.6) and 0.61 (0.43-0.87), respectively. Haplotype analysis for each of the three regions investigated revealed significant haplotype-disease associations; however, findings suggest that the respective associations were driven by the most significant SNP(s) listed above. This is the first large-scale epidemiologic study to provide evidence that SNPs in mitochondrial genes may be novel risk factors for ovarian cancer. Future investigation of additional mitochondrial variants (i.e. nuclear-encoded mitochondrial proteins) is necessary to more comprehensively investigate this association. Furthermore, replication of the most promising SNPs in a larger population is warranted to validate these findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2835.

Abstract Recent GWAS have identified and confirmed associations between several SNPs in the gene desert located on chromosome 8q24 with risk of cancers of the breast, prostate, glioma, bladder and colorectum. Evidence supporting an association with ovarian cancer is limited and inconsistent. Here we evaluate preliminary results in the 8q24 region from stage I of an ongoing invasive epithelial ovarian cancer GWAS among 1864 cases (1096 serous cases) and 1912 controls. All subjects were self-reported non-Hispanic non-Jewish Caucasian, and were genotyped with the Illumina 610quad Chip. Samples and SNPs with call rates less than 95% were excluded (9.6% and 9.9%, respectively) as well as 128 subjects with ambiguous gender, unresolved identical genotypes and less than 80% European ancestry were also excluded. Our most significant hit in the region was rs6651252 located at 8q24.21 with p = 0.000125 for all ovarian cancer, and 1.02*10−5 for serous cases only. This region is located approximately 849 kb downstream of the previous 8q24.21 findings on other cancers, and was not in linkage disequilibrium with any of the haplotype blocks reported previously. We further examined the block structure of this region with eight genotyped SNPs located within 129.61 to 129.64 MB (rs10088218, rs1516973, rs1516975, rs16903097, rs10098821, rs6651252, rs1561928, and rs1561927) and performed haplotype analysis to evaluate the association with ovarian cancer risk. One haplotype (AAGCAGGG, estimated frequency=0.11) was significantly associated with decreased ovarian cancer risk with an odds ratio of 0.67 (all cases, 95% CI: 0.78-0.91, p=0.0026, empirical p= 0.0020). This region contains no known genes, but it is located upstream and overlaps with a known copy number variation (CNV) reported by Redon et al. (2006). Previous published literature on array CGH and CNV results from TCGA (The Cancer Genome Atlas) also indicate that the 8q24.21 region is associated with frequent gains/amplification in ovarian tumors. Combined analysis of SNPs and CNV identified in this region is underway to elucidate the joint effect of these two types of genetic variation on ovarian cancer risk. Our result indicates a novel locus on 8q24.21 is associated with epithelial ovarian cancer susceptibility. Haplotype analysis reveals one specific haplotype that is associated with decreased ovarian cancer risk compared to the most common haplotype. Given previous 8q24 findings from other cancers and evidence from publicly available resources, fine-mapping and resequencing of this region is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4724.

By the time Harvey Cushing entered medical school, nerve reconstruction techniques had been developed, but peripheral nerve surgery was still in its infancy. As an assistant surgical resident influenced by Dr. William Halsted, Cushing wrote a series of reports on the use of cocaine for nerve blocks. Following his residency training and a hiatus to further his clinical interests and intellectual curiosity, he traveled to Europe and met with a variety of surgeons, physiologists, and scientists, who likely laid the groundwork for Cushing's increased interest in peripheral nerve surgery. Returning to The Johns Hopkins Hospital in 1901, he began documenting these surgeries. Patient records preserved at Yale's Cushing Brain Tumor Registry describe Cushing's repair of ulnar and radial nerves, as well as his exploration of the brachial plexus for nerve repair or reconstruction. The authors reviewed Harvey Cushing's cases and provide 3 case illustrations not previously reported by Cushing involving neurolysis, nerve repair, and neurotization. Additionally, Cushing's experience with facial nerve neurotization is reviewed. The history, physical examination, and operative notes shed light on Cushing's diagnosis, strategy, technique, and hence, his surgery on peripheral nerve injury. These contributions complement others he made to surgery of the peripheral nervous system dealing with nerve pain, entrapment, and tumor.

A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.