Publications by authors named "Beth Y Karlan"

280 Publications

MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma.

Virchows Arch 2021 Nov 15. Epub 2021 Nov 15.

Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA.

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.
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http://dx.doi.org/10.1007/s00428-021-03232-0DOI Listing
November 2021

Attributions of survival and methods of coping of long-term ovarian cancer survivors: a qualitative study.

BMC Womens Health 2021 Oct 28;21(1):376. Epub 2021 Oct 28.

Division of OVP, Cancer Prevention and Population Sciences, Department of Behavioral Science, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.

Background: Only 8-23% of advanced epithelial ovarian cancer patients survive for 10 years or longer. Given the need for targeted interventions to improve survival, we interviewed this relatively rare survivor population to gain personalized insights into the reasons for their survival. The aim of this study was to characterize subjective attributions of survival and specific coping mechanisms long-term survivors of ovarian cancer.

Methods: Twenty-two semi-structured, qualitative interviews assessing survival attributions and coping strategies were conducted from April to November 2014. Data were analyzed in a multistep process using ATLAS.ti.8: codes were identified during review of the transcripts and refined with literature review; the frequency of codes and code co-occurrence was calculated, and codes were grouped into themes. Resulting themes were checked by a national leader of an ovarian cancer advocacy organization and compared against available literature.

Results: Thematic analysis found that participants credited their long-term survival to a variety of factors including medical, social, religious/spiritual, and lifestyle/personal characteristics. Some participants rejected these same attributions, concluding that the reason for survival was due to luck or unknowable. Several of Carver et al.'s theoretical dimensions of coping were evident in our sample: planning, positive reinterpretation, social support, religion and acceptance whereas three relatively new strategies were uncovered: conserving emotional energy, value-based activity coping, and self-care.

Conclusions: Long-term survivors' perspectives were largely consistent with those of newly diagnosed ovarian cancer patients and ovarian cancer survivors of shorter duration. However, the long-term survivors were also willing to reject conventional attributions for survival and recognized the importance of disciplined self-preservational coping strategies.
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http://dx.doi.org/10.1186/s12905-021-01476-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554947PMC
October 2021

DNA Methylation Profiles of Ovarian Clear Cell Carcinoma.

Cancer Epidemiol Biomarkers Prev 2021 Oct 25. Epub 2021 Oct 25.

Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota.

Background: Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC.

Methods: We interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways.

Results: Two approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 ( = 137), Cluster 1 cases ( = 134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery ( < 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and mutation ( < 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes ( = 369 genes) were differentially expressed across cluster in transcriptomic subset analysis ( < 10). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNγ responses ( < 10).

Conclusions: DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways.

Impact: This work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0677DOI Listing
October 2021

Weight Gain and the Risk of Ovarian Cancer in and Mutation Carriers.

Cancer Epidemiol Biomarkers Prev 2021 Nov 23;30(11):2038-2043. Epub 2021 Aug 23.

Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.

Background: Weight gain and other anthropometric measures on the risk of ovarian cancer for women with mutations are not known. We conducted a prospective analysis of weight change since age 18, height, body mass index (BMI) at age 18, and current BMI and the risk of developing ovarian cancer among and mutation carriers.

Methods: In this prospective cohort study, height, weight, and weight at age 18 were collected at study enrollment. Weight was updated biennially. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for ovarian cancer.

Results: This study followed 4,340 women prospectively. There were 121 incident cases of ovarian cancer. Weight gain of more than 20 kg since age 18 was associated with a 2-fold increased risk of ovarian cancer, compared with women who maintained a stable weight (HR, 2.00; 95% CI, 1.13-3.54; = 0.02). Current BMI of 26.5 kg/m or greater was associated with an increased risk of ovarian cancer in mutation carriers, compared with those with a BMI less than 20.8 kg/m (Q4 vs. Q1 HR, 2.13; 95% CI, 1.04-4.36; = 0.04). There were no significant associations between height or BMI at age 18 and risk of ovarian cancer.

Conclusions: Adult weight gain is a risk factor for ovarian cancer in women with a or mutation.

Impact: These findings emphasize the importance of maintaining a healthy body weight throughout adulthood in women at high risk for ovarian cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0296DOI Listing
November 2021

PARP inhibitor maintenance for primary ovarian cancer - A missed opportunity for precision medicine.

Gynecol Oncol 2021 Oct 12;163(1):11-13. Epub 2021 Aug 12.

Division of Gynecologic Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ygyno.2021.08.002DOI Listing
October 2021

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer.

HGG Adv 2021 Jul 16;2(3). Epub 2021 Jun 16.

Department of Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.
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http://dx.doi.org/10.1016/j.xhgg.2021.100042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312632PMC
July 2021

Identification of a Locus Near Associated With Progression-Free Survival in Ovarian Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Sep 23;30(9):1669-1680. Epub 2021 Jun 23.

Gynecologic Oncology Center, Kiel, Germany.

Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance.

Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy.

Results: We found seven SNPs at 12q24.33 associated with PFS ( < 5 × 10), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; = 1.47 × 10). High expression of a nearby gene, , is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin .

Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. is a plausible candidate for the target of this association.

Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options..
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419101PMC
September 2021

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

Genet Med 2021 09 10;23(9):1726-1737. Epub 2021 Jun 10.

Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Purpose: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS and CBC risk.

Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

Conclusion: The PRS can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
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http://dx.doi.org/10.1038/s41436-021-01198-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460445PMC
September 2021

Association of Germline BRCA Pathogenic Variants With Diminished Ovarian Reserve: A Meta-Analysis of Individual Patient-Level Data.

J Clin Oncol 2021 06 23;39(18):2016-2024. Epub 2021 Apr 23.

Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT.

Purpose: To determine whether germline (g) pathogenic variants are associated with decreased ovarian reserve.

Materials And Methods: An individual patient-level data meta-analysis was performed using five data sets on 828 evaluable women who were tested for g. Of those, 250 carried g, whereas 578 had tested negative and served as controls. Of the women with g four centers studied those affected with breast cancer (n = 161) and one studied unaffected individuals (n = 89). The data were adjusted for the center, age, body mass index, smoking, and oral contraceptive pill use before the final analysis. Anti-Müllerian hormone (AMH) levels in affected women were drawn before presystemic therapy.

Results: The mean age of women with versus without g (34.1 ± 4.9 34.3 ± 4.8 years; = .48) and with g versus g (33.7 ± 4.9 34.6 ± 4.8 years; = .16) was similar. After the adjustments, women with g had significantly lower AMH levels compared with controls (23% lower; 95% CI, 4 to 38; = .02). When the adjusted analysis was limited to affected women (157 with g 524 without, after exclusions), the difference persisted (25% lower; 95% CI, 9 to 38; = .003). The serum AMH levels were lower in women with g (33% lower; 95% CI, 12 to 49; = .004) but not g compared with controls (7% lower; 95% CI, 31% lower to 26% higher; = .64).

Conclusion: Young women with g pathogenic variants, particularly those affected and with g, have lower serum AMH levels compared with controls. They may need to be preferentially counseled about the possibility of shortened reproductive lifespan because of diminished ovarian reserve.
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http://dx.doi.org/10.1200/JCO.20.02880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260903PMC
June 2021

Single-cell transcriptomics identifies gene expression networks driving differentiation and tumorigenesis in the human fallopian tube.

Cell Rep 2021 04;35(2):108978

Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address:

The human fallopian tube harbors the cell of origin for the majority of high-grade serous "ovarian" cancers (HGSCs), but its cellular composition, particularly the epithelial component, is poorly characterized. We perform single-cell transcriptomic profiling of around 53,000 individual cells from 12 primary fallopian specimens to map their major cell types. We identify 10 epithelial subpopulations with diverse transcriptional programs. Based on transcriptional signatures, we reconstruct a trajectory whereby secretory cells differentiate into ciliated cells via a RUNX3 intermediate. Computational deconvolution of advanced HGSCs identifies the "early secretory" population as a likely precursor state for the majority of HGSCs. Its signature comprises both epithelial and mesenchymal features and is enriched in mesenchymal-type HGSCs (p = 6.7 × 10), a group known to have particularly poor prognoses. This cellular and molecular compendium of the human fallopian tube in cancer-free women is expected to advance our understanding of the earliest stages of fallopian epithelial neoplasia.
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http://dx.doi.org/10.1016/j.celrep.2021.108978DOI Listing
April 2021

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Nat Commun 2021 02 17;12(1):1078. Epub 2021 Feb 17.

Copenhagen General Population Study, Herlev and Gentofte Hospital Copenhagen University Hospital, Herlev, Denmark.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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http://dx.doi.org/10.1038/s41467-020-20496-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890067PMC
February 2021

Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2021 01 6;19(1):77-102. Epub 2021 Jan 6.

The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.
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http://dx.doi.org/10.6004/jnccn.2021.0001DOI Listing
January 2021

Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Cancer Epidemiol Biomarkers Prev 2021 01 3;30(1):217-228. Epub 2020 Nov 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( = 0.43, = 2.66 × 10). We found seven loci associated with risk for both cancers ( < 2.4 × 10). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( < 5 × 10). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0739DOI Listing
January 2021

Breast Cancer Surveillance Following Ovarian Cancer in BRCA Mutation Carriers.

Am Surg 2020 Oct 26;86(10):1243-1247. Epub 2020 Oct 26.

Cedars-Sinai Medical Center, Los Angeles, CA, USA.

1 or 2 mutations result in higher cancer risk for breast cancer (BC) and epithelial ovarian cancer (EOC) for carriers than exists in the general population. Optimal breast imaging surveillance in these patients has not been well defined. An Institutional Review Board-approved, multi-institutional retrospective chart review was performed. Patients diagnosed with BRCA-associated EOC between 1990-2015 were identified; demographic and clinical data were collected and analyzed. 192 BRCA mutation-positive patients with EOC were identified. 16/192 (8.3%) women were diagnosed with BC following EOC, at a median of 50 (range 5-327) months following EOC diagnosis and median age 59.5 (45-84) years. Breast cancer was most commonly detected on mammogram 7/16 (44%) or clinical exam 7/16 (44%). 2/16 (12.5%) had occult BC found during risk-reducing mastectomy. 14 (88%) had early-stage (0-2) disease. At mean follow-up of 8.1 years, 6 (37.5%) patients with BC following EOC had died due to EOC. The risk of BC diagnosis following EOC in BRCA mutation carriers is low; most of these BCs are early stage and diagnosed with mammography or physical exam. Overall, survival in BRCA mutation carriers is dominated by EOC-related mortality. Breast cancer surveillance in BRCA mutation carriers following EOC should prioritize nonsurgical strategies.
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http://dx.doi.org/10.1177/0003134820964208DOI Listing
October 2020

Breastfeeding and the risk of epithelial ovarian cancer among women with a BRCA1 or BRCA2 mutation.

Gynecol Oncol 2020 12 30;159(3):820-826. Epub 2020 Sep 30.

Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. Electronic address:

Objective: BRCA mutation carriers face a high lifetime risk of developing ovarian cancer. The strong inverse association between breastfeeding and the risk of ovarian cancer is established in the general population but is less well studied among women with a germline BRCA1 or BRCA2 mutation.

Method: Thus, we conducted a matched case-control analysis to evaluate the association between breastfeeding history and the risk of developing ovarian cancer. After matching for year of birth, country of residence, BRCA gene and personal history of breast cancer, a total of 1650 cases and 2702 controls were included in the analysis. Conditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CI) associated with various breastfeeding exposures.

Results: A history of ever-breastfeeding was associated with a 23% reduction in risk (OR = 0.77; 95%CI 0.66-0.90; P = 0.001). The protective effect increased with breastfeeding from one month to seven months after which the association was relatively stable. Compared to women who never breastfed, breastfeeding for seven or more months was associated with a 32% reduction in risk (OR = 0.68; 95%CI 0.57-0.81; P < 0.0001) and did not vary by BRCA gene or age at diagnosis. The combination of breastfeeding and oral contraceptive use was strongly protective (0.47; 95%CI 0.37-0.58; P < 0.0001).

Conclusions: These findings support a protective effect of breastfeeding for at least seven months among women with a BRCA1 or BRCA2 mutation, that is independent of oral contraceptive use.
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http://dx.doi.org/10.1016/j.ygyno.2020.09.037DOI Listing
December 2020

Planning for post-pandemic cancer care delivery: Recovery or opportunity for redesign?

CA Cancer J Clin 2021 01 30;71(1):34-46. Epub 2020 Sep 30.

Division of Medical Oncology, Department of Medicine, University of California San Francisco, San Francisco, California.

The delivery of cancer care has never changed as rapidly and dramatically as we have seen with the coronavirus disease 2019 (COVID-19) pandemic. During the early phase of the pandemic, recommendations for the management of oncology patients issued by various professional societies and government agencies did not recognize the significant regional differences in the impact of the pandemic. California initially experienced lower than expected numbers of cases, and the health care system did not experience the same degree of the burden that had been the case in other parts of the country. In light of promising trends in COVID-19 infections and mortality in California, by late April 2020, discussions were initiated for a phased recovery of full-scale cancer services. However, by July 2020, a surge of cases was reported across the nation, including in California. In this review, the authors share the response and recovery planning experience of the University of California (UC) Cancer Consortium in an effort to provide guidance to oncology practices. The UC Cancer Consortium was established in 2017 to bring together 5 UC Comprehensive Cancer Centers: UC Davis Comprehensive Cancer Center, UC Los Angeles Jonsson Comprehensive Cancer Center, UC Irvine Chao Family Comprehensive Cancer Center, UC San Diego Moores Cancer Center, and the UC San Francisco Helen Diller Family Comprehensive Cancer Center. The interventions implemented in each of these cancer centers are highlighted, with a focus on opportunities for a redesign in care delivery models. The authors propose that their experiences gained during this pandemic will enhance pre-pandemic cancer care delivery.
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http://dx.doi.org/10.3322/caac.21644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537198PMC
January 2021

21 Code of Federal Regulations Part 11-Compliant Digital Signature Solution for Cancer Clinical Trials: A Single-Institution Feasibility Study.

JCO Clin Cancer Inform 2020 09;4:854-864

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA.

Purpose: Inefficiencies in the clinical trial infrastructure result in protracted trial completion timelines, physician-investigator turnover, and a shrinking skilled labor force and present obstacles to research participation. Taken together, these barriers hinder scientific progress. Technological solutions to improve clinical trial efficiency have emerged, yet adoption remains slow because of concerns with cost, regulatory compliance, and implementation.

Methods: A prospective pilot study that compared regulatory-compliant digital and traditional wet ink paper signatures was conducted over a 6.5-month period in a hospital-based health system. Staff time and effort, error rate, costs, and time to completion were measured. Wilcoxon rank sum tests were used to compare staff time and time to completion. A value analysis was conducted. A survey was administered to measure user satisfaction.

Results: There where 96 participants (47 digital, 49 paper), 132 studies included (31 digital, 101 paper), and 265 documents processed (156 digital, 109 paper). A moderate reduction in staff time required to prepare documents for signature was observed ( < .0001). Error rates were reported in 5.1% of digital and 2.8% of paper documents, but this difference was not significant. Discrepancies requiring revisions included incomplete mandatory fields, inaccurate information submitted, and technical issues. A value analysis demonstrated a 19% labor savings with the use of digital signatures. Survey response rate was 57.4% (n = 27). Most participants (85.2%) preferred digital signatures. The time to complete documents was faster with digital signatures compared with paper ( = .0241).

Conclusion: The use of digital signatures resulted in a decrease in document completion time and regulatory burden as represented by staff hours. Additional cost and time savings and information liquidity could be realized by integrating digital signatures and electronic document management systems.
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http://dx.doi.org/10.1200/CCI.20.00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529516PMC
September 2020

Comparison of up-front cash cards and checks as incentives for participation in a clinician survey: a study within a trial.

BMC Med Res Methodol 2020 08 17;20(1):210. Epub 2020 Aug 17.

Brigham and Women's Hospital, 75 Francis St, Boston, MA, 02115, USA.

Background: Evidence is needed regarding effective incentive strategies to increase clinician survey response rates. Cash cards are increasingly used as survey incentives; they are appealing because of their convenience and because in some cases their value can be reclaimed by investigators if not used. However, their effectiveness in clinician surveys is not known. In this study within the BRCA Founder OutReach (BFOR) study, a clinical trial of population-based BRCA1/2 mutation screening, we compared the use of upfront cash cards requiring email activation versus checks as clinician survey incentives.

Methods: Participants receiving BRCA1/2 testing in the BFOR study could elect to receive their results from their primary care provider (PCP, named by the patient) or from a geneticist associated with the study. In order to understand PCPs' knowledge, attitudes, experiences and willingness to disclose results we mailed paper surveys to the first 501 primary care providers (PCPs) in New York, Boston, Los Angeles and Philadelphia who were nominated by study participants to disclose their BRCA1/2 mutation results obtained through the study. We used alternating assignment stratified by city to assign the first 303 clinicians to receive a $50 up-front incentive as a cash card (N = 155) or check (N = 148). The cash card required PCPs to send an activation email in order to be used. We compared response rates by incentive type, adjusting for PCP characteristics and study site.

Results: In unadjusted analyses, PCPs who received checks were more likely to respond to the survey than those who received cash cards (54.1% versus 41.9%, p = 0.046); this remained true when we adjusted for provider characteristics (OR for checks 1.61, 95% CI 1.01, 2.59). No other clinician characteristics had a statistically significant association with response rates in adjusted analyses. When we included an interaction term for incentive type and city, the favorable impact of checks on response rates was evident only in Los Angeles and Philadelphia.

Conclusions: An up-front cash card incentive requiring email activation may be less effective in eliciting clinician responses than up-front checks. However, the benefit of checks for clinician response rates may depend on clinicians' geographic location.

Trial Registration: ClinicalTrials.gov ( NCT03351803 ), November 24, 2017.
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http://dx.doi.org/10.1186/s12874-020-01086-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430023PMC
August 2020

Factors associated with use of hormone therapy after preventive oophorectomy in BRCA mutation carriers.

Menopause 2020 12;27(12):1396-1402

Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada.

Objective: Bilateral salpingo-oophorectomy (oophorectomy) is recommended to women with a germline BRCA1 or BRCA2 mutation before natural menopause to prevent ovarian and fallopian tube cancer. The adverse effects of early surgical menopause are well established. Although many of the side effects can be ameliorated by the use of hormone therapy (HT); use of HT in this group of predominantly young patients remains suboptimal. The goal of this study was to identify the frequency of HT use, as well as predictors of HT uptake in BRCA mutation carriers who underwent preventive oophorectomy before natural menopause.

Methods: Eligible participants were identified from a longitudinal study of BRCA mutation carriers. We included premenopausal women with no personal history of cancer who underwent oophorectomy before age 50 and who had a minimum of 2 years of follow-up. Detailed information on HT use and other important variables was collected by a research questionnaire every 2 years. Descriptive statistics were used to evaluate the use of HT in various subgroups.

Results: A total of 793 women with a BRCA1 or BRCA2 mutation were included in this analysis. The mean age at oophorectomy was 42 years (range 28-49). Sixty-one percent of the women reported using HT after oophorectomy. Factors associated with HT use included young age at surgery, a high level of education and preventive mastectomy.

Conclusions: The uptake of HT after oophorectomy in women with a BRCA1 or BRCA2 mutation varies by age, education, and surgical history. Clinician and patient awareness may lead to better utilization of HT in women who undergo oophorectomy at an early age to help mitigate the adverse effects associated with surgical menopause.
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http://dx.doi.org/10.1097/GME.0000000000001629DOI Listing
December 2020

Are Epithelial Ovarian Cancers of the Mesenchymal Subtype Actually Intraperitoneal Metastases to the Ovary?

Front Cell Dev Biol 2020 17;8:647. Epub 2020 Jul 17.

Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

Primary ovarian high-grade serous carcinoma (HGSC) has been classified into 4 molecular subtypes: Immunoreactive, Proliferative, Differentiated, and Mesenchymal (Mes), of which the Mes subtype (Mes-HGSC) is associated with the worst clinical outcomes. We propose that Mes-HGSC comprise clusters of cancer and associated stromal cells that detached from tumors in the upper abdomen/omentum and disseminated in the peritoneal cavity, including to the ovary. Using comparative analyses of multiple transcriptomic data sets, we provide the following evidence that the phenotype of Mes-HGSC matches the phenotype of tumors in the upper abdomen/omentum: (1) irrespective of the primary ovarian HGSC molecular subtype, matched upper abdominal/omental metastases were typically of the Mes subtype, (2) the Mes subtype was present at the ovarian site only in patients with concurrent upper abdominal/omental metastases and not in those with HGSC confined to the ovary, and (3) ovarian Mes-HGSC had an expression profile characteristic of stromal cells in the upper abdominal/omental metastases. We suggest that ovarian Mes-HGSC signifies advanced intraperitoneal tumor dissemination to the ovary rather than a subtype of primary ovarian HGSC. This is consistent with the presence of upper abdominal/omental disease, suboptimal debulking, and worst survival previously reported in patients with ovarian Mes-HGSC compared to other molecular subtypes.
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http://dx.doi.org/10.3389/fcell.2020.00647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380132PMC
July 2020

Dual targeting of GSK3B and HDACs reduces tumor growth and improves survival in an ovarian cancer mouse model.

Gynecol Oncol 2020 10 19;159(1):277-284. Epub 2020 Jul 19.

Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. Electronic address:

Objective: To investigate the anti-tumor effect of a newly-developed dual inhibitor (APCS-540) of glycogen synthase kinase 3 beta (GSK3B) and histone deacetylases (HDACs) in ovarian cancer cells.

Methods: The effects of APCS-540 on cancer cell proliferation, migration, invasion and cancer stemness were investigated in vitro in human (KURAMOCHI, OVCA420, OVSAHO) and mouse (BR-Luc, ID8, MOSE-HRas-Myc) ovarian cancer cells. Cisplatin-sensitive (A2780) and cisplatin-resistant (A2780cis) cell lines were used to evaluate APCS-540's effect on chemoresistance. The immunocompetent syngeneic mouse model BR-Luc was used to test the effect of APCS-540 on ovarian cancer progression and survival.

Results: APCS-540 showed significant anti-tumor effects in vitro in both human and mouse ovarian cancer cells. Importantly, APCS-540 demonstrated marked cytotoxicity against cisplatin-resistant cancer cells and reversed cisplatin-resistance when used in combination with platinum. APCS-540 significantly decreased cancer cell invasion. A significant 66% increase in survival was observed in mice treated with APCS-540 compared to control mice.

Conclusion: Dual inhibition of GSK3B and HDACs via APCS-540 showed potent anti-tumor activity in vitro and in vivo, suggesting that APCS-540 may provide a novel treatment option for ovarian cancer, including the platinum-resistant disease.
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http://dx.doi.org/10.1016/j.ygyno.2020.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769125PMC
October 2020

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

Genet Med 2020 10 15;22(10):1653-1666. Epub 2020 Jul 15.

Royal Devon & Exeter Hospital, Department of Clinical Genetics, Exeter, UK.

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.

Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.

Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10) carriers. The associations in the prospective cohort were similar.

Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
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http://dx.doi.org/10.1038/s41436-020-0862-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521995PMC
October 2020

Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium.

Br J Cancer 2020 09 18;123(5):793-802. Epub 2020 Jun 18.

Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Cambridge, England.

Background: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study.

Methods: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests.

Results: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016).

Conclusions: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
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http://dx.doi.org/10.1038/s41416-020-0900-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463007PMC
September 2020

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

Clin Cancer Res 2020 10 17;26(20):5411-5423. Epub 2020 Jun 17.

Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.

Purpose: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.

Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting.

Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations.

Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572656PMC
October 2020

Population-based targeted sequencing of 54 candidate genes identifies as a susceptibility gene for high-grade serous ovarian cancer.

J Med Genet 2021 05 16;58(5):305-313. Epub 2020 Jun 16.

Hereditary Cancer Program, Catalan Institute of Oncology, Barcelona, Catalunya, Spain.

Purpose: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.

Methods: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.

Results: The ORs associated for high-grade serous ovarian cancer were 3.01 for (95% CI 1.59 to 5.68; p=0.00068), 1.99 for (95% CI 1.15 to 3.43; p=0.014) and 4.07 for (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for in high-grade serous ovarian cancer is likely to represent a true positive.

Conclusions: We have found strong evidence that carriers of deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.
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http://dx.doi.org/10.1136/jmedgenet-2019-106739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086250PMC
May 2021

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Nat Genet 2020 06 18;52(6):572-581. Epub 2020 May 18.

Molecular Medicine Unit, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
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http://dx.doi.org/10.1038/s41588-020-0609-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808397PMC
June 2020

HOXB13 controls cell state through super-enhancers.

Exp Cell Res 2020 08 4;393(1):112039. Epub 2020 May 4.

Women's Cancer Program, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, 90095, USA; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA. Electronic address:

Expression of the homeodomain transcription factor HOXB13 has been demonstrated in several malignancies but its role in tumorigenesis remains elusive. We observed high levels of HOXB13 in poorly differentiated pediatric tumors including a highly aggressive childhood neoplasm - malignant rhabdoid tumor. In a xenograft model of rhabdoid tumor, knockout of HOXB13 diminished tumor growth while partial knockdown of HOXB13 promoted differentiation of tumor cells into bone. These results suggest that HOXB13 enhances rhabdoid malignancy by interfering with mesenchymal stem cell differentiation. Consistent with this hypothesis, overexpression of HOXB13 in mesenchymal progenitor cells inhibited adipogenic, myogenic, and osteogenic differentiation. Mechanistically, we demonstrated that HOXB13 binds to super-enhancer regions regulating genes involved in differentiation and tumorigenesis.
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http://dx.doi.org/10.1016/j.yexcr.2020.112039DOI Listing
August 2020

Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer.

Nat Commun 2020 04 24;11(1):2020. Epub 2020 Apr 24.

Cedars-Sinai Women's Cancer Program at the Samuel Oschin Cancer Center, Los Angeles, CA, USA.

The functional consequences of somatic non-coding mutations in ovarian cancer (OC) are unknown. To identify regulatory elements (RE) and genes perturbed by acquired non-coding variants, here we establish epigenomic and transcriptomic landscapes of primary OCs using H3K27ac ChIP-seq and RNA-seq, and then integrate these with whole genome sequencing data from 232 OCs. We identify 25 frequently mutated regulatory elements, including an enhancer at 6p22.1 which associates with differential expression of ZSCAN16 (P = 6.6 × 10-4) and ZSCAN12 (P = 0.02). CRISPR/Cas9 knockout of this enhancer induces downregulation of both genes. Globally, there is an enrichment of single nucleotide variants in active binding sites for TEAD4 (P = 6 × 10-11) and its binding partner PAX8 (P = 2×10-10), a known lineage-specific transcription factor in OC. In addition, the collection of cis REs associated with PAX8 comprise the most frequently mutated set of enhancers in OC (P = 0.003). These data indicate that non-coding somatic mutations disrupt the PAX8 transcriptional network during OC development.
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http://dx.doi.org/10.1038/s41467-020-15951-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181647PMC
April 2020
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