Publications by authors named "Joseph H Rothstein"

Background: The relationship between vitamin D and prostate cancer has primarily been characterized among White men. However, Black men have higher prostate cancer incidence and mortality rates, chronically low circulating vitamin D levels, and ancestry-specific genetic variants in vitamin D-related genes. Here, we examine six critical genes in the vitamin D pathway and prostate cancer risk in Black men.

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  • The study examined risk factors for epithelial ovarian cancer (EOC) among women of different racial and ethnic backgrounds, including Asian, Hispanic, Native Hawaiian/Pacific Islander, and White participants.
  • Findings indicated that oral contraceptive (OC) use and childbirth (parity) were generally associated with lower EOC risk across all groups, especially in Native Hawaiian/Pacific Islander and Asian women.
  • Significant differences in EOC risk factors were detected among the ethnic groups, suggesting that including more diverse populations in research could improve prevention strategies for ovarian cancer.
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The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes.

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Background: Imaging with late gadolinium enhancement (LGE) magnetic resonance (MR) and F-fluorodeoxyglucose (F-FDG) PET allows complementary assessment of myocardial injury and disease activity and has shown promise for improved characterization of active cardiac sarcoidosis (CS) based on the combined positive imaging outcome, MR(+)PET(+).

Objectives: This study aims to evaluate qualitative and quantitative assessments of hybrid MR/PET imaging in CS and to evaluate its association with cardiac-related outcomes.

Methods: A total of 148 patients with suspected CS underwent hybrid MR/PET imaging.

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Observational studies suggest that mammographic density (MD) may have a role in the unexplained protective effect of childhood adiposity on breast cancer risk. Here, we investigated a complex and interlinked relationship between puberty onset, adiposity, MD, and their effects on breast cancer using Mendelian randomization (MR). We estimated the effects of childhood and adulthood adiposity, and age at menarche on MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)) using MR and multivariable MR (MVMR), allowing us to disentangle their total and direct effects.

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Background: Breast density is strongly associated with breast cancer risk. Fully automated quantitative density assessment methods have recently been developed that could facilitate large-scale studies, although data on associations with long-term breast cancer risk are limited. We examined LIBRA assessments and breast cancer risk and compared results to prior assessments using Cumulus, an established computer-assisted method requiring manual thresholding.

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Background: Women with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC.

Methods: We performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available.

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  • The study aimed to investigate the relationship between p53 protein expression and survival rates in women with different types of ovarian cancer, particularly high-grade serous carcinoma (HGSC), endometrioid carcinoma (EC), and clear cell carcinoma (CCC), using a large cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium.
  • It was found that abnormal p53 expression patterns were prevalent in 93.4% of HGSC cases, but in EC and CCC, these abnormal patterns were linked to a significantly higher risk of death, indicating a poor prognosis.
  • The research concluded that while abnormal p53 expression doesn't affect survival in HGSC, it serves as a strong independent prognostic marker for EC and CCC,
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  • Human bulk tissue samples are made up of various cell types that influence disease development, but traditional studies overlook this cell diversity when analyzing gene expression and its association with diseases.
  • The MiXcan method improves on this by focusing on cell-type-specific gene expression, allowing researchers to combine data from different cell types to find genes linked to diseases more accurately.
  • In a study of breast cancer involving nearly 59,000 women, MiXcan identified 12 significant genes compared to 8 from conventional methods, revealing new insights into how specific cell types, like mammary epithelial and stromal cells, contribute to cancer susceptibility.
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Background: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC.

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Background: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants.

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Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology.

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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.

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Mammographic density (MD) phenotypes are strongly associated with breast cancer risk and highly heritable. In this GWAS meta-analysis of 24,192 women, we identify 31 MD loci at P < 5 × 10, tripling the number known to 46. Seventeen identified MD loci also are associated with breast cancer risk in an independent meta-analysis (P < 0.

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Background: Parity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated.

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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.

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Importance: Mammography screening currently relies on subjective human interpretation. Artificial intelligence (AI) advances could be used to increase mammography screening accuracy by reducing missed cancers and false positives.

Objective: To evaluate whether AI can overcome human mammography interpretation limitations with a rigorous, unbiased evaluation of machine learning algorithms.

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  • Percent density (PD) is a significant risk factor for breast cancer, influenced by both alcohol and tobacco use; while alcohol increases PD, tobacco decreases it.
  • A study involving 23,456 women found that alcohol is linked to higher PD and lower nondense area (NDA), while tobacco shows the opposite effects.
  • The findings highlight that lifestyle choices like alcohol consumption may impact breast cancer risk through changes in breast tissue composition, particularly affecting NDA rather than dense area (DA).
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The rapid development of deep learning, a family of machine learning techniques, has spurred much interest in its application to medical imaging problems. Here, we develop a deep learning algorithm that can accurately detect breast cancer on screening mammograms using an "end-to-end" training approach that efficiently leverages training datasets with either complete clinical annotation or only the cancer status (label) of the whole image. In this approach, lesion annotations are required only in the initial training stage, and subsequent stages require only image-level labels, eliminating the reliance on rarely available lesion annotations.

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An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls.

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Breast density is a modifiable factor that is strongly associated with breast cancer risk. We sought to understand the influence of newer technologies of full-field digital mammography (FFDM) on breast density research and to determine whether results are comparable across studies using FFDM and previous studies using traditional film-screen mammography. We studied 24,840 screening-age (40-74 years) non-Hispanic white women who were participants in the Research Program on Genes, Environment and Health of Kaiser Permanente Northern California and underwent screening mammography with either Hologic (Hologic, Inc.

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  • Thymidylate synthase (TYMS) is important for DNA synthesis and is regulated by an antisense mRNA called ENOSF1, which affects tumor growth if disrupted.
  • A study investigated the genetic variant rs495139 for its potential link to mucinous ovarian carcinoma (MOC), using data from over 15,000 ovarian cancer patients, including 665 with MOC, but found no significant association in the independent sample.
  • Meta-analysis hinted at a weak connection between rs495139 and MOC risk, especially noting a positive correlation with ENOSF1 expression in normal gastrointestinal tissues, while its impact on tumors is uncertain.
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  • Epithelial ovarian cancer (EOC) is a major cause of cancer deaths in women, and the study explores how variations in small GTPase genes may impact EOC risk.* -
  • Researchers analyzed genetic data from over 44,000 participants to find that specific variants in genes ARHGEF10L and AKAP6 are linked to increased risk for certain types of EOC.* -
  • The findings suggest that these genetic variants might influence EOC susceptibility by affecting gene regulation, indicating a need for further studies to confirm these associations.*
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Background: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias.

Methods: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls).

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Objective: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival.

Patients And Methods: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time.

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