Browsing by Author "Berchuck, Andrew"
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Item Restricted Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer.(PLoS One, 2010-04-08) Schildkraut, Joellen M; Iversen, Edwin S; Wilson, Melanie A; Clyde, Merlise A; Moorman, Patricia G; Palmieri, Rachel T; Whitaker, Regina; Bentley, Rex C; Marks, Jeffrey R; Berchuck, AndrewBACKGROUND: We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study. METHODS/PRINCIPAL FINDINGS: The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)(per allele) = 0.66; 95% credible interval (CI) = 0.44-1.00) and rs6005835 (median OR(per allele) = 0.69; 95% CI = 0.53-0.91) in CHEK2, rs2078486 (median OR(per allele) = 1.65; 95% CI = 1.21-2.25) and rs12951053 (median OR(per allele) = 1.65; 95% CI = 1.20-2.26) in TP53, rs411697 (median OR (rare homozygote) = 0.53; 95% CI = 0.35 - 0.79) in BACH1 and rs10131 (median OR( rare homozygote) = not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study. CONCLUSIONS/SIGNIFICANCE: Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results.Item Open Access Concordance Between Genomic Alterations Detected by Tumor and Germline Sequencing: Results from a Tertiary Care Academic Center Molecular Tumor Board.(The oncologist, 2023-01) Green, Michelle F; Watson, Catherine H; Tait, Sarah; He, Jie; Pavlick, Dean C; Frampton, Garrett; Riedel, Jinny; Plichta, Jennifer K; Armstrong, Andrew J; Previs, Rebecca A; Kauff, Noah; Strickler, John H; Datto, Michael B; Berchuck, Andrew; Menendez, Carolyn SObjective
The majority of tumor sequencing currently performed on cancer patients does not include a matched normal control, and in cases where germline testing is performed, it is usually run independently of tumor testing. The rates of concordance between variants identified via germline and tumor testing in this context are poorly understood. We compared tumor and germline sequencing results in patients with breast, ovarian, pancreatic, and prostate cancer who were found to harbor alterations in genes associated with homologous recombination deficiency (HRD) and increased hereditary cancer risk. We then evaluated the potential for a computational somatic-germline-zygosity (SGZ) modeling algorithm to predict germline status based on tumor-only comprehensive genomic profiling (CGP) results.Methods
A retrospective chart review was performed using an academic cancer center's databases of somatic and germline sequencing tests, and concordance between tumor and germline results was assessed. SGZ modeling from tumor-only CGP was compared to germline results to assess this method's accuracy in determining germline mutation status.Results
A total of 115 patients with 146 total alterations were identified. Concordance rates between somatic and germline alterations ranged from 0% to 85.7% depending on the gene and variant classification. After correcting for differences in variant classification and filtering practices, SGZ modeling was found to have 97.2% sensitivity and 90.3% specificity for the prediction of somatic versus germline origin.Conclusions
Mutations in HRD genes identified by tumor-only sequencing are frequently germline. Providers should be aware that technical differences related to assay design, variant filtering, and variant classification can contribute to discordance between tumor-only and germline sequencing test results. In addition, SGZ modeling had high predictive power to distinguish between mutations of somatic and germline origin without the need for a matched normal control, and could potentially be considered to inform clinical decision-making.Item Open Access Epigenetic Regulation of Claudin-1 in the Development of Ovarian Cancer Recurrence and Drug Resistance.(Frontiers in oncology, 2021-01) Visco, Zachary R; Sfakianos, Gregory; Grenier, Carole; Boudreau, Marie-Helene; Simpson, Sabrina; Rodriguez, Isabel; Whitaker, Regina; Yao, Derek Y; Berchuck, Andrew; Murphy, Susan K; Huang, ZhiqingOver 21,000 women are diagnosed with ovarian cancer (OC) in the United States each year and over half that number succumb to this disease annually, often due to recurrent disease. A deeper understanding of the molecular events associated with recurrent disease is needed to identify potential targets. Using genome-scale DNA methylation and gene expression data for 16 matched primary-recurrent advanced stage serous epithelial OCs, we discovered that Claudin-1 (CLDN1), a tight junction protein, shows a stronger correlation between expression and methylation in recurrent versus primary OC at multiple CpG sites (R= -0.47 to -0.64 versus R= -0.32 to -0.57, respectively). An independent dataset showed that this correlation is stronger in tumors from short-term (<3y) survivors than in tumors from long-term (>7y) survivors (R= -0.41 to -0.46 versus R= 0.06 to -0.19, respectively). The presence of this inverse correlation in short-term survivors and recurrent tumors suggests an important role for this relationship and potential predictive value for disease prognosis. CLDN1 expression increased following pharmacologic inhibition of DNA methyltransferase activity (p< 0.001), thus validating the role of methylation in CLDN1 gene inhibition. CLDN1 knockdown enhanced chemosensitivity and suppressed cell proliferation, migration, and wound healing (p< 0.05). Stable CLDN1 knockdown in vivo resulted in reduced xenograft tumor growth but did not reach significance. Our results indicate that the relationship between CLDN1 methylation and expression plays an important role in OC aggressiveness and recurrence.Item Open Access Expression signatures of TP53 mutations in serous ovarian cancers.(BMC Cancer, 2010-05-26) Bernardini, Marcus Q; Baba, Tsukasa; Lee, Paula S; Barnett, Jason C; Sfakianos, Gregory P; Secord, Angeles Alvarez; Murphy, Susan K; Iversen, Edwin; Marks, Jeffrey R; Berchuck, AndrewBACKGROUND: Mutations in the TP53 gene are extremely common and occur very early in the progression of serous ovarian cancers. Gene expression patterns that relate to mutational status may provide insight into the etiology and biology of the disease. METHODS: The TP53 coding region was sequenced in 89 frozen serous ovarian cancers, 40 early stage (I/II) and 49 advanced stage (III/IV). Affymetrix U133A expression data was used to define gene expression patterns by mutation, type of mutation, and cancer stage. RESULTS: Missense or chain terminating (null) mutations in TP53 were found in 59/89 (66%) ovarian cancers. Early stage cancers had a significantly higher rate of null mutations than late stage disease (38% vs. 8%, p < 0.03). In advanced stage cases, mutations were more prevalent in short term survivors than long term survivors (81% vs. 30%, p = 0.0004). Gene expression patterns had a robust ability to predict TP53 status within training data. By using early versus late stage disease for out of sample predictions, the signature derived from early stage cancers could accurately (86%) predict mutation status of late stage cancers. CONCLUSIONS: This represents the first attempt to define a genomic signature of TP53 mutation in ovarian cancer. Patterns of gene expression characteristic of TP53 mutation could be discerned and included several genes that are known p53 targets or have been described in the context of expression signatures of TP53 mutation in breast cancer.Item Open Access Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women.(Gynecologic oncology, 2019-03-19) Lawrenson, Kate; Song, Fengju; Hazelett, Dennis J; Kar, Siddhartha P; Tyrer, Jonathan; Phelan, Catherine M; Corona, Rosario I; Rodríguez-Malavé, Norma I; Seo, Ji-Hei; Adler, Emily; Coetzee, Simon G; Segato, Felipe; Fonseca, Marcos AS; Amos, Christopher I; Carney, Michael E; Chenevix-Trench, Georgia; Choi, Jiyeob; Doherty, Jennifer A; Jia, Weihua; Jin, Gang J; Kim, Byoung-Gie; Le, Nhu D; Lee, Juyeon; Li, Lian; Lim, Boon K; Adenan, Noor A; Mizuno, Mika; Park, Boyoung; Pearce, Celeste L; Shan, Kang; Shi, Yongyong; Shu, Xiao-Ou; Sieh, Weiva; Australian Ovarian Cancer Study Group; Thompson, Pamela J; Wilkens, Lynne R; Wei, Qingyi; Woo, Yin L; Yan, Li; Karlan, Beth Y; Freedman, Matthew L; Noushmehr, Houtan; Goode, Ellen L; Berchuck, Andrew; Sellers, Thomas A; Teo, Soo-Hwang; Zheng, Wei; Matsuo, Keitaro; Park, Sue; Chen, Kexin; Pharoah, Paul DP; Gayther, Simon A; Goodman, Marc TOBJECTIVE:Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. METHODS:Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. RESULTS:At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10-8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10-7) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10-7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10-7). CONCLUSION:While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.Item Open Access Periostin facilitates ovarian cancer recurrence by enhancing cancer stemness.(Scientific reports, 2023-12) Huang, Zhiqing; Byrd, Olivia; Tan, Sarah; Hu, Katrina; Knight, Bailey; Lo, Gaomong; Taylor, Lila; Wu, Yuan; Berchuck, Andrew; Murphy, Susan KThe lethality of epithelial ovarian cancer (OC) is largely due to a high rate of recurrence and development of chemoresistance, which requires synergy between cancer cells and the tumor microenvironment (TME) and is thought to involve cancer stem cells. Our analysis of gene expression microarray data from paired primary and recurrent OC tissues revealed significantly elevated expression of the gene encoding periostin (POSTN) in recurrent OC compared to matched primary tumors (p = 0.015). Secreted POSTN plays a role in the extracellular matrix, facilitating epithelial cell migration and tissue regeneration. We therefore examined how elevated extracellular POSTN, as we found is present in recurrent OC, impacts OC cell functions and phenotypes, including stemness. OC cells cultured with conditioned media with high levels of periostin (CMPOSTNhigh) exhibited faster migration (p = 0.0044), enhanced invasiveness (p = 0.006), increased chemoresistance (p < 0.05), and decreased apoptosis as compared to the same cells cultured with control medium (CMCTL). Further, CMPOSTNhigh-cultured OC cells exhibited an elevated stem cell side population (p = 0.027) along with increased expression of cancer stem cell marker CD133 relative to CMCTL-cultured cells. POSTN-transfected 3T3-L1 cells that were used to generate CMPOSTNhigh had visibly enhanced intracellular and extracellular lipids, which was also linked to increased OC cell expression of fatty acid synthetase (FASN) that functions as a central regulator of lipid metabolism and plays a critical role in the growth and survival of tumors. Additionally, POSTN functions in the TME were linked to AKT pathway activities. The mean tumor volume in mice injected with CMPOSTNhigh-cultured OC cells was larger than that in mice injected with CMCTL-cultured OC cells (p = 0.0023). Taken together, these results show that elevated POSTN in the extracellular environment leads to more aggressive OC cell behavior and an increase in cancer stemness, suggesting that increased levels of stromal POSTN during OC recurrence contribute to more rapid disease progression and may be a novel therapeutic target. Furthermore, they also demonstrate the utility of having matched primary-recurrent OC tissues for analysis and support the need for better understanding of the molecular changes that occur with OC recurrence to develop ways to undermine those processes.Item Open Access Pleiotropic MLLT10 variation confers risk of meningioma and estrogen-mediated cancers.(Neuro-oncology advances, 2022-01) Walsh, Kyle M; Zhang, Chenan; Calvocoressi, Lisa; Hansen, Helen M; Berchuck, Andrew; Schildkraut, Joellen M; Bondy, Melissa L; Wrensch, Margaret; Wiemels, Joseph L; Claus, Elizabeth BBackground
Risk of tumors of the breast, ovary, and meninges has been associated with hormonal factors and with one another. Genome-wide association studies (GWAS) identified a meningioma risk locus on 10p12 near previous GWAS hits for breast and ovarian cancers, raising the possibility of genetic pleiotropy.Methods
We performed imputation-based fine-mapping in three case-control datasets of meningioma (927 cases, 790 controls), female breast cancer (28 108 cases, 22 209 controls), and ovarian cancer (25 509 cases, 40 941 controls). Analyses were stratified by sex (meningioma), estrogen receptor (ER) status (breast), and histotype (ovarian), then combined using subset-based meta-analysis in ASSET. Lead variants were assessed for association with additional traits in UK Biobank to identify potential effect-mediators.Results
Two-sided subset-based meta-analysis identified rs7084454, an expression quantitative trait locus (eQTL) near the MLLT10 promoter, as lead variant (5.7 × 10-14). The minor allele was associated with increased risk of meningioma in females (odds ratio (OR) = 1.42, 95% Confidence Interval (95%CI):1.20-1.69), but not males (OR = 1.19, 95%CI: 0.91-1.57). It was positively associated with ovarian (OR = 1.09, 95%CI:1.06-1.12) and ER+ breast (OR = 1.05, 95%CI: 1.02-1.08) cancers, and negatively associated with ER- breast cancer (OR = 0.91, 95%CI: 0.86-0.96). It was also associated with several adiposity traits (P < 5.0 × 10-8), but adjusting for body mass index did not attenuate its association with meningioma. MLLT10 and ESR1 expression were positively correlated in normal meninges (P = .058) and meningioma tumors (P = .0065).Conclusions
We identify a MLLT10 eQTL positively associated with risk of female meningioma, ER+ breast cancer, ovarian cancer, and obesity, and implicate a potential estrogenic mechanism underlying this pleiotropy.Item Restricted Risk of ovarian cancer and inherited variants in relapse-associated genes.(PLoS One, 2010-01-27) Peedicayil, Abraham; Vierkant, Robert A; Hartmann, Lynn C; Fridley, Brooke L; Fredericksen, Zachary S; White, Kristin L; Elliott, Elaine A; Phelan, Catherine M; Tsai, Ya-Yu; Berchuck, Andrew; Iversen, Edwin S; Couch, Fergus J; Peethamabaran, Prema; Larson, Melissa C; Kalli, Kimberly R; Kosel, Matthew L; Shridhar, Vijayalakshmi; Rider, David N; Liebow, Mark; Cunningham, Julie M; Schildkraut, Joellen M; Sellers, Thomas A; Goode, Ellen LBACKGROUND: We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk. METHODS AND FINDINGS: Women with and without invasive ovarian cancer (749 cases, 1,041 controls) were genotyped at 136 single nucleotide polymorphisms (SNPs) within 13 candidate genes. Risk was estimated for each SNP and for overall variation within each gene. At the gene-level, variation within MSL1 (male-specific lethal-1 homolog) was associated with risk of serous cancer (p = 0.03); haplotypes within PRPF31 (PRP31 pre-mRNA processing factor 31 homolog) were associated with risk of invasive disease (p = 0.03). MSL1 rs7211770 was associated with decreased risk of serous disease (OR 0.81, 95% CI 0.66-0.98; p = 0.03). SNPs in MFSD7, BTN3A3, ZNF200, PTPRS, and CCND1A were inversely associated with risk (p<0.05), and there was increased risk at HEXIM1 rs1053578 (p = 0.04, OR 1.40, 95% CI 1.02-1.91). CONCLUSIONS: Tumor studies can reveal novel genes worthy of follow-up for cancer susceptibility. Here, we found that inherited markers in the gene encoding MSL1, part of a complex that modifies the histone H4, may decrease risk of invasive serous ovarian cancer.Item Open Access Risk Prediction for Epithelial Ovarian Cancer in 11 United States-Based Case-Control Studies: Incorporation of Epidemiologic Risk Factors and 17 Confirmed Genetic Loci.(Am J Epidemiol, 2016-10-15) Clyde, Merlise A; Palmieri Weber, Rachel; Iversen, Edwin S; Poole, Elizabeth M; Doherty, Jennifer A; Goodman, Marc T; Ness, Roberta B; Risch, Harvey A; Rossing, Mary Anne; Terry, Kathryn L; Wentzensen, Nicolas; Whittemore, Alice S; Anton-Culver, Hoda; Bandera, Elisa V; Berchuck, Andrew; Carney, Michael E; Cramer, Daniel W; Cunningham, Julie M; Cushing-Haugen, Kara L; Edwards, Robert P; Fridley, Brooke L; Goode, Ellen L; Lurie, Galina; McGuire, Valerie; Modugno, Francesmary; Moysich, Kirsten B; Olson, Sara H; Pearce, Celeste Leigh; Pike, Malcolm C; Rothstein, Joseph H; Sellers, Thomas A; Sieh, Weiva; Stram, Daniel; Thompson, Pamela J; Vierkant, Robert A; Wicklund, Kristine G; Wu, Anna H; Ziogas, Argyrios; Tworoger, Shelley S; Schildkraut, Joellen MPreviously developed models for predicting absolute risk of invasive epithelial ovarian cancer have included a limited number of risk factors and have had low discriminatory power (area under the receiver operating characteristic curve (AUC) < 0.60). Because of this, we developed and internally validated a relative risk prediction model that incorporates 17 established epidemiologic risk factors and 17 genome-wide significant single nucleotide polymorphisms (SNPs) using data from 11 case-control studies in the United States (5,793 cases; 9,512 controls) from the Ovarian Cancer Association Consortium (data accrued from 1992 to 2010). We developed a hierarchical logistic regression model for predicting case-control status that included imputation of missing data. We randomly divided the data into an 80% training sample and used the remaining 20% for model evaluation. The AUC for the full model was 0.664. A reduced model without SNPs performed similarly (AUC = 0.649). Both models performed better than a baseline model that included age and study site only (AUC = 0.563). The best predictive power was obtained in the full model among women younger than 50 years of age (AUC = 0.714); however, the addition of SNPs increased the AUC the most for women older than 50 years of age (AUC = 0.638 vs. 0.616). Adapting this improved model to estimate absolute risk and evaluating it in prospective data sets is warranted.