Clonal Hematopoiesis and Mosaicism Revealed by a Multi-Tissue Analysis of Constitutional TP53 Status.

Background: Though germline TP53 pathogenic/likely pathogenic variants (PV) are associated with Li-Fraumeni syndrome, many detected by multigene panels represent aberrant clonal expansion (ACE), most due to clonal hematopoiesis (CH). Discerning ACE/CH from germline variants and postzygotic mosaicism (PZM) is critically needed for risk assessment and management.

Methods: Participants in the Li-Fraumeni & TP53 Understanding & Progress (LiFT UP) study with a TP53 PV were eligible.

Cross-sectional clinical cancer genomics community of practice survey analysis of provider attitudes and beliefs regarding the use of deceased family member tissue to guide living family member genetic cancer risk assessment.

Next-generation tumor tissue sequencing techniques may result in the detection of putative germline pathogenic variants (PVs), raising the possibility that germline cancer predisposition could be identified from archival medical tissue samples of deceased relatives. The approach, termed traceback, is designed to inform risk management recommendations for living family members. Provider perspectives regarding traceback testing have not yet been explored, so we conducted a cross-sectional survey of Clinical Cancer Genomics Community of Practice providers regarding their attitudes and beliefs toward traceback testing.

Genetic epidemiology of BRCA1- and BRCA2-associated cancer across Latin America.

The prevalence and contribution of BRCA1/2 (BRCA) pathogenic variants (PVs) to the cancer burden in Latin America are not well understood. This study aims to address this disparity. BRCA analyses were performed on prospectively enrolled Latin American Clinical Cancer Genomics Community Research Network participants via a combination of methods: a Hispanic Mutation Panel (HISPANEL) on MassARRAY; semiconductor sequencing; and copy number variant (CNV) detection.

Germline mutations and age at onset of lung adenocarcinoma.

Background: To identify additional at-risk groups for lung cancer screening, which targets persons with a long history of smoking and thereby misses younger or nonsmoking cases, the authors evaluated germline pathogenic variants (PVs) in patients with lung adenocarcinoma for an association with an accelerated onset.

Methods: The authors assembled a retrospective cohort (1999-2018) of oncogenetic clinic patients with lung adenocarcinoma. Eligibility required a family history of cancer, data on smoking, and a germline biospecimen to screen via a multigene panel.

Breast cancer associated pathogenic variants among women 61 years and older with triple negative breast cancer.

Unlabelled: Women with triple negative breast cancer (TNBC) have a high prevalence of BRCA1 mutations, and current clinical guidelines recommend genetic testing for patients with TNBC aged ≤60 years. However, studies supporting this recommendation have included few older women with TNBC.

Methods: Genetic testing results from women aged >60 years with TNBC enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) registry were included in this analysis.

Confirmation and refinement of the heterozygous deletion of the small leucine-rich proteoglycans associated with posterior amorphous corneal dystrophy.

Purpose: To present the clinical and cytogenetic features of a previously unreported family with posterior amorphous corneal dystrophy (PACD) associated with a heterozygous deletion of the small leucine-rich proteoglycan (SRLP) genes on chromosome 12.

Methods: Clinical characterization was performed using slit lamp biomicroscopic and optical coherence tomography (OCT) imaging. Genomic DNA was collected from affected and unaffected family members, and a cytogenomic array was used to identify copy number variations (CNV) present in the PACD locus.

Elucidating the molecular basis of PPCD: Effects of decreased ZEB1 expression on corneal endothelial cell function.

Purpose: To investigate the functional role that the () gene, which underlies the genetic basis of posterior polymorphous corneal dystrophy 3 (PPCD3), plays in corneal endothelial cell proliferation, apoptosis, migration, and barrier function.

Methods: A human corneal endothelial cell line (HCEnC-21T) was transfected with siRNA targeting mRNA. Cell proliferation, apoptosis, migration, and barrier assays were performed: Cell proliferation was assessed with cell counting using a hemocytometer; cell apoptosis, induced by either ultraviolet C (UVC) radiation or doxorubicin treatment, was quantified by measuring cleaved caspase 3 (cCASP3) protein levels; and cell migration and barrier function were monitored with electric cell-substrate impedance sensing (ECIS).

Vortex Pattern of Corneal Deposits in Granular Corneal Dystrophy Associated With the p.(Arg555Trp) Mutation in TGFBI.

Purpose: To describe 2 unrelated families with multiple members demonstrating a less commonly recognized vortex pattern of corneal deposits confirmed to be granular corneal dystrophy type 1 (GCD1) after identification of the p.(Arg555Trp) mutation in the transforming growth factor β-induced gene (TGFBI).

Methods: A slit-lamp examination was performed on individuals from 2 families, one of Mexican descent and a second of Italian descent.

Confirmation of the OVOL2 Promoter Mutation c.-307T>C in Posterior Polymorphous Corneal Dystrophy 1.

Purpose: To identify the genetic basis of posterior polymorphous corneal dystrophy (PPCD) in families mapped to the PPCD1 locus and in affected individuals without ZEB1 coding region mutations.

Methods: The promoter, 5' UTR, and coding regions of OVOL2 was screened in the PPCD family in which linkage analysis established the PPCD1 locus and in 26 PPCD probands who did not harbor a ZEB1 mutation. Copy number variation (CNV) analysis in the PPCD1 and PPCD3 intervals was performed on DNA samples from eight probands using aCGH.