Understanding the Clinical Implications of Low Penetrant Genes and Breast Cancer Risk.

OPINION STATEMENT: Since the 2013 Supreme Court declaration, panel testing for hereditary cancer syndromes has evolved into the gold standard for oncology germline genetic testing. With the advent of next-generation sequencing, competitive pricing, and developing therapeutic options, panel testing is now well integrated into breast cancer management and surveillance. Although many established syndromes have well-defined cancer risks and management strategies, several breast cancer genes are currently classified as limited-evidence genes by the National Comprehensive Cancer Network (NCCN). Follow-up for individuals with mutations in these genes is a point of contention due to conflicting information in the literature. The most recent NCCN guidelines have stratified management based on gene-specific cancer risks indicating that expanding data will allow for better recommendations as research progresses. The evolving management for these genes emphasizes the clinicians' need for evidence-based understanding of low penetrance breast cancer genes and their implications for patient care. This article reviews current literature for limited evidence genes, detailing cancer risks, association with triple-negative breast cancer, and recommendations for surveillance. A brief review of the challenges and future directions is outlined to discuss the evolving nature of cancer genetics and the exciting opportunities that can impact management.

Genotype-Phenotype Features of Germline Variants of the TMEM127 Pheochromocytoma Susceptibility Gene: A 10-Year Update.

PURPOSE: This work aimed to evaluate genotype-phenotype associations in individuals carrying germline variants of transmembrane protein 127 gene (TMEM127), a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL). DESIGN: Data were collected from a registry of probands with TMEM127 variants, published reports, and public databases. MAIN OUTCOME ANALYSIS: Clinical, genetic, and functional associations were determined. RESULTS: The cohort comprised 110 index patients (111 variants) with a mean age of 45 years (range, 21-84 years). Females were predominant (76 vs 34, P < .001). Most patients had PHEO (n = 94; 85.5%), although PGL (n = 10; 9%) and renal cell carcinoma (RCC, n = 6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors, and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n = 63) occurred only once and 13 were recurrent (2-12 times). Although nontruncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEO-only vs 69% other, P < .001) and clustered disproportionately within transmembrane regions (P < .01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into 4 groups based on mutation type, localization, and predicted disruption. CONCLUSIONS: Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance.

Implementation of Universal Tumor Screening of Colorectal Cancer for Detection of Lynch Syndrome at a Hispanic-Rich County Hospital.

INTRODUCTION: In 2014, a reflexive screening protocol for Lynch syndrome (LS) via an immunohistochemistry (IHC) assay was shown to be cost-effective; however, the screening rates at a predominant Hispanic-rich institution are unclear. We hypothesized that implementation of a universal tumor screening (UTS) protocol requiring screening for LS via IHC in patients with newly diagnosed colorectal cancer (CRC) at our Hispanic-rich institution would improve detection of LS by increasing screening rates. METHODS AND MATERIALS: This is a retrospective analysis of screening rates of 3 sequential cohorts of newly diagnosed patients with CRC between January 2012 and April 2016 at the University Health System and with follow-up at National Cancer Institute-designated Mays Cancer Center at University of Texas Health San Antonio. Cohort 1 consisted of patients screened using old screening guidelines (PRE). Cohort 2 consisted of patients screened when treating clinicians were receiving education on the new protocol (PERI). Cohort 3 consisted of patients screened after implementation of the UTS protocol (POST). RESULTS: The majority of 312 patients were Hispanic (62.5%), 18.1% were < 50 years, and 81.9% were ≥ 50 years of age (median age, 57 years). Of patients with CRC screened for LS via IHC, the PRE, PERI, and POST cohorts had screening rates of 31%, 64%, and 58%, respectively. We found significant differences when comparing the PRE with POST sequential cohorts (P < .01). CONCLUSION: The quality of Lynch syndrome-related family histories and screening rates were significantly improved after implementation in our Hispanic-rich population. Future studies are warranted to provide insight into clinical effects of increased screening, provider and patient surveillance, and screening-related systemic barriers.