Exploring MRI and Mammography Lesion Features for Breast Cancer Detection in PTEN Hamartoma Tumor Syndrome.

(1) Background/Objectives: Women with hamartoma tumor syndrome (PHTS) face a significantly increased risk of breast cancer (up to 66%) and a high prevalence of benign breast lesions (30-75%), which can complicate cancer detection and underscore the need for effective surveillance strategies. This study aimed to evaluate the imaging characteristics of breast cancers and benign breast lesions using magnetic resonance imaging (MRI) and mammography, with the goal of improving early cancer detection, reducing unnecessary biopsies, and guiding future surveillance protocols. (2) Methods: This retrospective single-institution study included 65 PHTS women aged ≥18 years (2001-2021), 39 of whom participated in a high-risk breast cancer surveillance program.

Exome-based cancer predisposition gene testing can provide a genetic diagnosis for individuals with heterogeneous tumor phenotypes.

The development of multiple primary tumors is one of the hallmarks of hereditary cancer. The phenotypic presentation of individuals with multiple primary tumors is often heterogeneous, which hampers the establishment of a genetic diagnosis. The absence of a genetic diagnosis may lead to inappropriate surveillance advices and treatment choices.

Cancer and Overgrowth Manifestations of PTEN Hamartoma Tumour Syndrome: Management Recommendations from the International PHTS Consensus Guidelines Working Group.

Purpose: PTEN hamartoma tumour syndrome (PHTS) is an autosomal dominant cancer-predisposition and overgrowth syndrome occurring due to pathogenic germline variants in the PTEN gene, with an increased risk of both benign and malignant tumours involving the breast, colon, endometrium, thyroid, skin, and kidney. The objective of these clinical guidelines was to use the latest knowledge to generate an international consensus resource for providers, researchers, and individuals with PHTS on the best practices in the surveillance and management of cancer and overgrowth in PHTS.

Experimental Design: The International PHTS Cancer and Overgrowth Guidelines Working Group was established, comprising a core group of six international experts in the diagnosis and management of PHTS.

Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses.

Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.

Salpingectomy With Delayed Oophorectomy Versus Salpingo-Oophorectomy in BRCA1/2 Carriers: Three-Year Outcomes of a Prospective Preference Trial.

Objective: To compare menopause-related quality of life (QoL) after risk-reducing salpingectomy (RRS) versus risk-reducing salpingo-oophorectomy (RRSO) until 3 years of post-surgery.

Design: A prospective study (TUBA study) with treatment allocation based on patients' preference. Data were collected pre-surgery and at 3 months, 1 and 3 years of post-surgery.

Experience in a PHTS Expertise Centre: Yield of Thyroid Ultrasound Surveillance in Children with PTEN Hamartoma Tumor Syndrome.

Objective: Children with PTEN hamartoma tumor syndrome (PHTS) are at increased risk for developing thyroid abnormalities, including differentiated thyroid carcinoma (DTC). The Dutch PHTS guideline recommends ultrasound surveillance starting from age 18. Since the literature describes PHTS patients who developed DTC before age 18, the Dutch PHTS expertise centre has initiated annual ultrasound surveillance starting from age 12.

Genomic instability in non-breast or ovarian malignancies of individuals with germline pathogenic variants in BRCA1/2.

Background: Individuals with germline pathogenic variants in BRCA1 or BRCA2 are at a high risk of breast and ovarian carcinomas with BRCA1/2 deficiency and homologous recombination deficiency that can be detected by analysis of genome-wide genomic instability features such as large-scale state transitions, telomeric allelic imbalances, and genomic loss of heterozygosity. Malignancies with homologous recombination deficiency are more sensitive to platinum-based therapies and poly(ADP-ribose) polymerase inhibitors. We investigated the fraction of non-breast or ovarian malignancies that have BRCA1/2 deficiency and genomic instability features.

Histopathological phenotyping of cancers in PTEN Hamartoma Tumor Syndrome for improved recognition: A single-center study.

PTEN hamartoma tumor syndrome (PHTS) has a broad clinical spectrum including various benign and malignant tumors at varying age of diagnosis. Many patients remain unrecognized, unaware of their increased cancer risk. We aimed to describe the cancer spectrum, age of onset and histopathological cancer characteristics to assess whether specific cancer characteristics could improve PHTS recognition.

Optimizing the detection of hereditary predisposition in women with epithelial ovarian cancer: nationwide implementation of the Tumor-First workflow.

Genetic testing in patients with ovarian carcinoma (OC) is crucial, as around 10-15% of these women have a genetic predisposition to OC. Although guidelines have recommended universal germline testing for all patients with OC for a decade, implementation has proved challenging, thus resulting in low germline-testing rates (around 30-50%). Many new initiatives to improve genetic-testing rates have emerged, but most have been carried out at the local level, leading to differences in workflows within and between countries.

Lifestyle Factors and Breast Cancer in Females with PTEN Hamartoma Tumor Syndrome (PHTS).

Females with PTEN Hamartoma Tumor Syndrome (PHTS) have breast cancer risks up to 76%. This study assessed associations between breast cancer and lifestyle in European female adult PHTS patients. Data were collected via patient questionnaires (July 2020-March 2023) and genetic diagnoses from medical files.

The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2.

Purpose: Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies.

Methods: Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the CHEK2 (NM_007194.

Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer.

Background: Germline CDH1 pathogenic or likely pathogenic variants cause hereditary diffuse gastric cancer (HDGC). Once a genetic cause is identified, stomachs' and breasts' surveillance and/or prophylactic surgery is offered to asymptomatic CDH1 carriers, which is life-saving. Herein, we characterized an inherited mechanism responsible for extremely early-onset gastric cancer and atypical HDGC high penetrance.

The most efficient and effective BRCA1/2 testing strategy in epithelial ovarian cancer: Tumor-First or Germline-First?

Objective: Genetic testing in epithelial ovarian cancer (OC) is essential to identify a hereditary cause like a germline BRCA1/2 pathogenic variant (PV). An efficient strategy for genetic testing in OC is highly desired. We evaluated costs and effects of two strategies; (i) Tumor-First strategy, using a tumor DNA test as prescreen to germline testing, and (ii) Germline-First strategy, referring all patients to the clinical geneticist for germline testing.

Yield of annual endometrial cancer surveillance in women with PTEN Hamartoma Tumor Syndrome.

Objective: Expert-opinion based guidelines state that endometrial cancer surveillance (ECS) might be considered for patients with PTEN Hamartoma Tumor Syndrome (PHTS) based on an elevated lifetime risk of endometrial cancer. We aimed to evaluate the yield of ECS by annual transvaginal ultrasound (TVUS) and endometrial biopsy (EMB) in PHTS patients.

Methods: PHTS patients who visited our PHTS expert center between August 2012 and September 2020 and opted for annual ECS were included.

Microsatellite instability in noncolorectal and nonendometrial malignancies in patients with Lynch syndrome.

Background: Individuals with Lynch syndrome are at increased hereditary risk of colorectal and endometrial carcinomas with microsatellite instability (MSI-H) and mismatch repair-deficiency (dMMR), which make these tumors vulnerable to therapy with immune checkpoint inhibitors. Our aim is to assess how often other tumor types in these individuals share these characteristics.

Methods: We retrieved the full tumor history of a historical clinic-based cohort of 1745 individuals with Lynch syndrome and calculated the standardized incidence ratio for all tumor types.

[Genetic testing in epithelial ovarian cancer: implementation of the 'Tumor-First' workflow].

The new 'Tumor-First' workflow for genetic testing in epithelial ovarian cancer detects women with a genetic predisposition effectively and efficiently. 'Tumor-First' indicates that the tumor DNA of all patients diagnosed with epithelial ovarian cancer is examined for the presence of pathogenic variants in, amongst others, BRCA1 and BRCA2 genes. Women with an aberrant tumor DNA test result are eligible for genetic testing using a sample of blood to detect heredity.