Whole-genome sequencing-based characterization of endometrial serous carcinoma.

Objective: To define the structural variants, mutational signatures, and DNA repair defects in serous endometrial carcinoma (EC) using whole-genome sequencing (WGS).

Methods: Ten primary untreated classic serous ECs diagnosed between 2012 and 2018 were selected. Tumor and matched normal DNAs were subjected to WGS, and sequencing data were analyzed using state-of-the-art bioinformatics methods.

Evolution and co-occurrence of PI3K pathway gene mutations in endometrial carcinoma molecular subtypes at the single-cell level.

Purpose: The PI3K pathway is altered in >85% of endometrioid endometrial carcinomas (EECs), with multiple mutations commonly co-occurring. Yet, the therapeutic effects of single-agent PI3K pathway inhibitors have been limited. We used single-cell sequencing to determine whether co-occurring PTEN, PIK3CA, and/or PIK3R1 somatic mutations in EECs stratified by molecular subtype originated through convergent or linear evolution.

Peritoneal washings analysis in endometrial cancer: Comparison of somatic mutation detection with panel sequencing and traditional cytology.

Objectives: The prognostic significance of positive pelvic washings in endometrial cancer (EC) remains unknown, and little data exist regarding washings as a source of genetic information in relation to a patient's tumor. We sought to assess the feasibility of identifying EC mutations in peritoneal washings.

Methods: Peritoneal washings from 21 biopsy-confirmed newly diagnosed patients with EC across disease stages between 09/2018 and 07/2019 were collected.

TROP2 expression and therapeutic targeting in uterine carcinosarcoma.

Objective: Uterine carcinosarcoma (UCS) is a rare and aggressive type of endometrial carcinoma (EC), and novel therapeutic strategies are needed. We sought to assess TROP2 expression in archival UCSs and TROP2 antibody-drug conjugate (ADC) targeting in patient-derived UCS organoid (PDO) and xenograft (PDX) models.

Methods: TROP2 protein (immunohistochemistry) and mRNA (qRT-PCR) expression were assessed in 72 archival UCS tissues.

Clinicopathologic Features, Molecular Landscape, and Prognostic Implications of Ovarian Low-grade Serous Tumors with Histologic Transformation.

Purpose: The purpose of this study was to characterize the clinicopathologic features, molecular genetic landscape, and clinical behavior of ovarian low-grade serous tumors with histologic transformation (LGS-HT) to indeterminate/high-grade carcinoma.

Experimental Design: LGS-HT were retrospectively identified from an institutional cohort of patients with ovarian cancer and underwent central pathology re-review. Data on clinicopathologic characteristics, including age, stage, surgical outcomes, systemic treatments, and overall survival (OS), were collected.

Clinicopathologic and Genomic Analysis of Uterine Serous Carcinomas Arising From Endometrial Hyperplasia.

Uterine serous carcinoma (USC) typically arises from atrophic endometrium but may be associated with hyperplasia in 5% to 10% of cases. We sought to identify USC with concurrent hyperplasia and (i) define if these are clonally related, and (ii) determine if USC associated with hyperplasia is genetically distinct from USC without hyperplasia. Patients diagnosed with USC and hyperplasia from their hysterectomy specimen between January 1, 2014 and February 29, 2022 were identified.

Oncocytic Tumors in the Salivary Gland: Cytopathological, Pathological, and Molecular Features.

Background: Primary oncocytic salivary gland tumors and oncocytic subtypes of traditionally non-oncocytic salivary gland neoplasms are occasionally encountered in fine needle aspiration specimens, biopsies, and resections. Oncocytes are cells, either non-neoplastic or neoplastic, containing increased numbers of mitochondria resulting in cells with abundant eosinophilic cytoplasm and a low N/C ratio.

Summary: A broad range of salivary gland tumors can be oncocytic including oncocytoma, Warthin tumor, mucoepidermoid carcinoma, salivary duct carcinoma, and others, especially those tumors where the oncocytic pattern represents a subtype of neoplasm; the oncocytic pattern can create a diagnostic challenge due to marked similarities in the oncocytic pattern of cells.

The genomic landscape of distant metastatic endometrial cancer.

Objective: The molecular underpinnings of primary treatment-naïve endometrial carcinoma (EC) are well described. Here we sought to characterize the genomic landscape of distant metastatic EC.

Methods: Distant metastatic ECs from a total of 1888 cases subjected to a clinical panel sequencing between 4/2015 and 6/2020 were identified, and their genomic profiles, affected pathways and actionable alterations were compared to those of 711 primary ECs.

Molecular and microenvironmental landscapes of human papillomavirus-independent invasive squamous cell carcinoma of the vulva.

Objective: Human papillomavirus (HPV)-independent vulvar squamous cell carcinoma has a worse prognosis compared to its HPV-associated counterpart. We sought to characterize the mutational landscape and the tumor microenvironment of HPV-independent vulvar cancer.

Methods: Primary, untreated vulvar cancers with known HPV-independent vulvar cancer or without definitive HPV association between 2006 and 2016 were identified.

Genomic profiling of lymph node and distant metastases from papillary and poorly differentiated thyroid carcinomas.

Purpose: To perform a molecular profiling of the metastases from papillary thyroid carcinomas (PTCs) and poorly differentiated thyroid carcinomas (PDTCs).

Methods: We retrieved and analyzed the molecular and clinical features of 136 metastases from PTCs and 35 metastases from PDTCs subjected to targeted DNA sequencing, from cBioPortal. The clinicopathological data included the number and location of the metastases, and genomic data included mutations, translocations, copy number alterations and fraction of the genome altered (FGA).

Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers: a phase 2 trial with biomarker analyses.

Programmed death-1 (PD-1) inhibitors are approved for therapy of gynecologic cancers with DNA mismatch repair deficiency (dMMR), although predictors of response remain elusive. We conducted a single-arm phase 2 study of nivolumab in 35 patients with dMMR uterine or ovarian cancers. Co-primary endpoints included objective response rate (ORR) and progression-free survival at 24 weeks (PFS24).

Molecular profiling of primary endometrioid endometrial cancer and matched lung metastases: mutation as a potential driver.

•Both primary endometrial cancers (ECs) and matched lung metastases shared a common ancestor with independent evolution at each site.•The two endometrioid ECs studied acquired additional mutations during the distant metastatic process.•Subclonal hotspot mutations in the two primary ECs studied became clonal in the distant metastases.

Unraveling the Significance of DGCR8 and miRNAs in Thyroid Carcinoma.

MicroRNAs (miRNAs) act as negative regulators for protein-coding gene expression impacting cell proliferation, differentiation, and survival. These miRNAs are frequently dysregulated in cancer and constitute classes of blood-based biomarkers useful for cancer detection and prognosis definition. In thyroid cancer (TC), the miRNA biogenesis pathway plays a pivotal role in thyroid gland formation, ensuring proper follicle development and hormone production.

Adenoid cystic carcinoma of the Bartholin's gland is underpinned by MYB- and MYBL1- rearrangements.

Objective: Adenoid cystic carcinoma (AdCC) of the Bartholin's gland (AdCC-BG) is a very rare gynecologic vulvar malignancy. AdCC-BGs are slow-growing but locally aggressive and are associated with high recurrence rates. Here we sought to characterize the molecular underpinning of AdCC-BGs.

Uterine washings as a novel method for early detection of ovarian cancer: Trials and tribulations.

Given the tubal origin of high-grade serous ovarian cancer (HGSC), we sought to investigate intrauterine lavage (IUL) as a novel method of biomarker detection. IUL and serum samples were collected from patients with HGSC or benign pathology. Although CA-125 and HE4 concentrations were significantly higher in IUL samples compared to serum, they were similar between IUL samples from patients with HGSC vs benign conditions.

Investigating Mutation as Underlying Cause of Familial Non-Medullary Thyroid Carcinoma.

In a family with Familial Non-Medullary Thyroid Carcinoma (FNMTC), our investigation using Whole-Exome Sequencing (WES) uncovered a novel germline mutation []. USP42 is known for regulating p53, cell cycle arrest, and apoptosis, and for being reported as overexpressed in breast and gastric cancer patients. Recently, a missense mutation was described in FNMTC, suggesting a potential involvement in thyroid cancer.

Decreased HER2 expression in endometrial cancer following anti-HER2 therapy.

Trastuzumab has demonstrated clinical efficacy in the treatment of HER2-positive serous endometrial cancer (EC), which led to its incorporation into standard-of-care management of this aggressive disease. Acquired resistance remains an important challenge, however, and its underlying mechanisms in EC are unknown. To define the molecular changes that occur in response to anti-HER2 therapy in EC, targeted next-generation sequencing (NGS), HER2 immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) were performed on pre- and post-treatment tumour samples from 14 patients with EC treated with trastuzumab or trastuzumab emtansine.

Most large structural variants in cancer genomes can be detected without long reads.

Short-read sequencing is the workhorse of cancer genomics yet is thought to miss many structural variants (SVs), particularly large chromosomal alterations. To characterize missing SVs in short-read whole genomes, we analyzed 'loose ends'-local violations of mass balance between adjacent DNA segments. In the landscape of loose ends across 1,330 high-purity cancer whole genomes, most large (>10-kb) clonal SVs were fully resolved by short reads in the 87% of the human genome where copy number could be reliably measured.

Molecular Characterization of Endometrial Carcinomas in Black and White Patients Reveals Disparate Drivers with Therapeutic Implications.

Unlabelled: Although the incidence of endometrial carcinoma (EC) is similar in Black and White women, racial disparities are stark, with the highest mortality rates observed among Black patients. Here, analysis of 1,882 prospectively sequenced ECs using a clinical FDA-authorized tumor-normal panel revealed a significantly higher prevalence of high-risk histologic and molecular EC subtypes in self-identified Black (n = 259) compared with White (n = 1,623) patients. Clinically actionable alterations, including high tumor mutational burden/microsatellite instability, which confer benefit from immunotherapy, were less frequent in ECs from Black than from White patients.

Long-molecule scars of backup DNA repair in BRCA1- and BRCA2-deficient cancers.

Homologous recombination (HR) deficiency is associated with DNA rearrangements and cytogenetic aberrations. Paradoxically, the types of DNA rearrangements that are specifically associated with HR-deficient cancers only minimally affect chromosomal structure. Here, to address this apparent contradiction, we combined genome-graph analysis of short-read whole-genome sequencing (WGS) profiles across thousands of tumours with deep linked-read WGS of 46 BRCA1- or BRCA2-mutant breast cancers.

Endometrial/Endometrioid Stromal Tumors With Extensive Whorling and CTNNB1 Translocation : A Report of 3 Cases.

Endometrial/endometrioid stromal tumors are rare and morphologically heterogenous, and their diagnosis may be challenging. We identified 3 endometrial/endometrioid stromal tumors with identical and previously undescribed histologic features and herein report their morphologic, immunohistochemical, and molecular profiles. Patients were 53, 62, and 79 years.