Publications by authors named "David G Huntsman"

Study Question: Is there an association between the somatic loss of PTEN (phosphatase and tensin homolog) and ARID1A (AT-rich interaction domain 1A) and endometriosis disease severity and worse clinical outcomes?

Summary Answer: Somatic PTEN loss in endometriosis epithelium was associated with greater disease burden and subsequent surgical complexity.

What Is Known Already: Somatic cancer-driver mutations including those involving the PTEN and ARID1A genes exist in endometriosis without cancer; however, their clinical impact remains unclear.

Study Design, Size, Duration: This prospective longitudinal study involved endometriosis tissue and clinical data from 126 participants who underwent surgery at a tertiary center for endometriosis (2013-2017), with a follow-up period of 5-9 years.

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Objectives: We have previously shown that DNA based, single test molecular classification by next generation sequencing (NGS) (Proactive Molecular risk classifier for Endometrial cancer (ProMisE) NGS) is highly concordant with the original ProMisE classifier and maintains prognostic value in endometrial cancer. Our aim was to validate ProMisE NGS in an independent cohort and assess the performance of ProMisE NGS in real world clinical practice to address if there were any practical challenges or learning points for implementation.

Methods: We evaluated DNA extracted from an external research cohort of 211 endometrial cancer cases diagnosed in 2016 from Germany, Switzerland, and Austria, across seven European centers, comparing standard molecular classification (NGS for status, immunohistochemistry for mismatch repair and p53) with ProMisE NGS (NGS for and microsatellite instability assay) for concordance metrics and Kaplan-Meier survival statistics across molecular subtypes.

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Article Synopsis
  • ARID1A, a key part of the BAF chromatin remodeling complex and mutated in about 8% of cancers, shows highest mutation rates in clear cell ovarian carcinoma (CCOC), reaching over 50%.
  • Current treatments for ARID1A-deficient cancers are limited, prompting research into genetic dependencies using CRISPR screening.
  • The study identifies KEAP1 as a critical factor in ARID1A-deficient cells, where targeting KEAP1 leads to selective growth inhibition and worsens genome instability, highlighting a potential new therapeutic approach.
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Clear cell ovarian carcinoma (CCOC) is an aggressive malignancy affecting younger women. Despite ovarian cancer subtypes having diverse molecular and clinical characteristics, the mainstay of treatment for advanced stage disease remains cytotoxic chemotherapy. Late stage CCOC is resistant to conventional chemotherapy, which means a suboptimal outcome for patients affected.

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  • Low-grade serous ovarian carcinoma (LGSC) is a rare and dangerous type of ovarian cancer that is different from the more common high-grade version.
  • Researchers studied tissue samples from LGSC, high-grade serous ovarian carcinoma (HGSC), and serous borderline tumors (SBTs) to understand how they differ.
  • They found that the environment around the tumors was different in LGSC, including specific proteins and immune cells, which suggests that changing this environment could help develop new treatments.
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Investigation of histopathology slides by pathologists is an indispensable component of the routine diagnosis of cancer. Artificial intelligence (AI) has the potential to enhance diagnostic accuracy, improve efficiency, and patient outcomes in clinical pathology. However, variations in tissue preparation, staining protocols, and histopathology slide digitization could result in over-fitting of deep learning models when trained on the data from only one center, thereby underscoring the necessity to generalize deep learning networks for multi-center use.

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Endometrial cancer (EC) has four molecular subtypes with strong prognostic value and therapeutic implications. The most common subtype (NSMP; No Specific Molecular Profile) is assigned after exclusion of the defining features of the other three molecular subtypes and includes patients with heterogeneous clinical outcomes. In this study, we employ artificial intelligence (AI)-powered histopathology image analysis to differentiate between p53abn and NSMP EC subtypes and consequently identify a sub-group of NSMP EC patients that has markedly inferior progression-free and disease-specific survival (termed 'p53abn-like NSMP'), in a discovery cohort of 368 patients and two independent validation cohorts of 290 and 614 from other centers.

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Article Synopsis
  • The study examines the clinical significance of detecting cell-free circulating tumor DNA (ctDNA) mutations in patients with endometrial and ovarian cancers, identifying its potential as a real-time biomarker for therapy response and recurrence.
  • Out of 44 patients, somatic mutations were found in tumor tissue for 91%, with only 27% having detectable preoperative ctDNA mutations, which correlated with advanced cancer stages and potential for disease recurrence.
  • The findings suggest that ctDNA can indicate tumor volume and treatment effectiveness, and its clearance may indicate treatment success before traditional biomarkers, highlighting the need for targeted patient selection in future therapies.
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Purpose: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).

Experimental Design: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes.

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Purpose: Shallow whole-genome sequencing (sWGS) can detect copy-number (CN) aberrations. In high-grade serous ovarian cancer (HGSOC) sWGS identified CN signatures such as homologous recombination deficiency (HRD) to direct therapy. We applied sWGS with targeted sequencing to p53abn endometrial cancers to identify additional prognostic stratification and therapeutic opportunities.

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We performed a deep proteogenomic analysis of bulk tumor and laser microdissection enriched tumor cell populations from high-grade serous ovarian cancer (HGSOC) tissue specimens spanning a broad spectrum of purity. We identified patients with longer progression-free survival had increased immune-related signatures and validated proteins correlating with tumor-infiltrating lymphocytes in 65 tumors from an independent cohort of HGSOC patients, as well as with overall survival in an additional 126 HGSOC patient cohort. We identified that homologous recombination deficient (HRD) tumors are enriched in pathways associated with metabolism and oxidative phosphorylation that we validated in independent patient cohorts.

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Article Synopsis
  • Survival rates for ovarian cancer are influenced by the success of primary surgery in removing tumors.
  • Researchers conducted genome-wide studies on 7,705 ovarian cancer patients to find genetic variants linked to resection status, particularly focusing on high-grade serous carcinoma (HGSOC).
  • The study highlighted significant associations with the rs72845444 variant and the genes MGMT (involved in DNA repair) and PPP2R5C (a tumor suppressor), correlating with disease outcomes and patient survival.*
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Introduction: Targeted-immunotherapies such as antibody-drug conjugates (ADC), chimeric antigen receptor (CAR) T cells or bispecific T-cell engagers (eg, BiTE) all aim to improve cancer treatment by directly targeting cancer cells while sparing healthy tissues. Success of these therapies requires tumor antigens that are abundantly expressed and, ideally, tumor specific. The CD34-related stem cell sialomucin, podocalyxin (PODXL), is a promising target as it is overexpressed on a variety of tumor types and its expression is consistently linked to poor prognosis.

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Article Synopsis
  • Researchers studied a common genetic change that happens in a type of ovarian cancer called high-grade serous carcinoma (HGSC), looking at how it affects patient survival.
  • They found that losing the RB1 protein was linked to longer survival in patients with HGSC, but it was the opposite for a different type of ovarian cancer called endometrioid cancer.
  • Patients with both RB1 loss and certain inherited genetic changes had much better survival rates compared to those with just one of these problems or none at all.
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Objectives: Opportunistic salpingectomy (OS) is the removal of fallopian tubes during another pelvic surgery for the purpose of ovarian cancer prevention. Herein, we describe the rates of OS at the time of hysterectomy and tubal sterilization between 2017 and 2020.

Methods: This study uses the Canadian Institute of Health Information's Discharge Abstract Database and National Ambulatory Care Reporting System for all Canadian provinces and territories except for Quebec between the fiscal years 2017 and 2020.

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Unlabelled: Clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (ENOC) are ovarian carcinoma histotypes, which are both thought to arise from ectopic endometrial (or endometrial-like) cells through an endometriosis intermediate. How the same cell type of origin gives rise to two morphologically and biologically different histotypes has been perplexing, particularly given that recurrent genetic mutations are common to both and present in nonmalignant precursors. We used RNA transcription analysis to show that the expression profiles of CCOC and ENOC resemble those of normal endometrium at secretory and proliferative phases of the menstrual cycle, respectively.

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Unlabelled: DICER1 is an RNase III enzyme essential for miRNA biogenesis through cleaving precursor-miRNA hairpins. Germline loss-of-function DICER1 mutations underline the development of DICER1 syndrome, a rare genetic disorder that predisposes children to cancer development in organs such as lung, gynecologic tract, kidney, and brain. Unlike classical tumor suppressors, the somatic "second hit" in DICER1 syndrome-associated cancers does not fully inactivate DICER1 but impairs its RNase IIIb activity only, suggesting a noncanonical two-hit hypothesis.

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Objectives: Despite recommendations for integrating molecular classification of endometrial cancers (EC) into pathology reporting and clinical management, uptake is inconsistent. To assign ProMisE subtype, all molecular components must be available (POLE mutation status, mismatch repair (MMR) and p53 immunohistochemistry (IHC)) and often these are assessed at different stages of care and/or at different centres resulting in delays in treatment. We assessed a single-test DNA-based targeted next generation sequencing (NGS) molecular classifier (ProMisE NGS), comparing concordance and prognostic value to the original ProMisE classifier.

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SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodeling complexes frequently inactivated in cancers. Cells deficient in either ATPase have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss of SMARCA4/2 occurs in a subset of cancers associated with very poor outcomes.

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Article Synopsis
  • - DICER1 syndrome increases the risk of over 30 types of tumors, mainly in children and adolescents, with a focus on a specific group of mesenchymal tumors linked to this syndrome.
  • - These tumors are categorized into three main classes: "low-grade mesenchymal tumor with DICER1 alteration" (LGMT DICER1), "sarcoma with DICER1 alteration" (SARC DICER1), and primary intracranial sarcoma with DICER1 alteration (PIS DICER1).
  • - The study aims to improve classification and clinical management of these tumors, suggesting that global hypomethylation and other molecular changes play a role in tumor development, which can help
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Article Synopsis
  • 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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