Identification of a 6-cM Minimal Deletion at 11q23.1–23.2 and Exclusion of PPP2R1B Gene as a Deletion Target in Cervical Cancer

Previous functional and deletion mapping studies on cervical cancer (CC) have implicated one or more tumor suppressor genes (TSGs) on chromosome 11 at q13 and q22–24 regions. Of these, the 11q22–24 region exhibits frequent allelic deletions in a variety of solid tumor types, sug- gesting the presence of critical genes for tumor suppression in this region. However, the precise region of deletion on 11q is not clearly defined in CC. In an attempt to accurately map the deleted region, we performed an extensive loss of heterozygosity (LOH) mapping in 58 tumors using 25 polymorphic loci on both the short and long arms. The pattern of LOH identified three sites of deletions, two on 11p (p15.11–p15.3 and p12–13), and one on 11q (q23.1–q23.2). The 11q23.1–q23.2 exhibited highest fre- quency (60.6%) of deletions, suggesting that this could be the site of a candidate TSG in CC. The minimal deletion at 11q23.1–23.2 was re- stricted to a 6-cM region between 123.5 and 129.5 cM genetic distance on chromosome 11, identifying the site of a potential TSG important in the pathogenesis of CC. At least five known genes and 28 UniGene clusters were mapped to the present commonly deleted region. In addition, we have excluded a previously known TSG PPP2R1B at 11q23 as a deletion target in CC. The definition of the minimal deletion and the availability of expressed sequence resources should facilitate the identification of the candidate TSG

Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice.

It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes.To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes.This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals.Genetic test results.Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms.Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%).Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.VoRSUNY DownstateNeurologyN/

Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice

IMPORTANCE: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. OBJECTIVE: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. EXPOSURES: Genetic test results. MAIN OUTCOMES AND MEASURES: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. RESULTS: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). CONCLUSIONS AND RELEVANCE: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes

Characterization of the Role of the PP2A-AB Gene, a Putative Tumor Suppressor, in Cell Growth and Tumorigenesis

The PP2A-Aβ gene (PPP2R1B) encodes the β isoform of the A subunit of serine/threonine protein phosphatase 2A. Mutations in PP2A-Aβ have been identified in a wide variety of human cancers. The important role of protein phosphatase 2A in down regulating cell growth suggests these mutations may contribute to cancer susceptibility and tumorigenesis by compromising the function of PP2A-Aβ and that PP2A-Aβ may act as a tumor suppressor. Screening of cancer patient DNAs revealed an association between a germline alteration of the PP2A-Aβ and breast carcinoma and identified alterations of PP2A-Aβ in lung carcinoma and ALL patient genomic DNAs. The biochemical consequences of these PP2A-Aβ mutations on PP2A function were investigated by in vitro and in vivo coimmunoprecipitations between the PP2A-Aβ subunit and the B and C subunits of PP2A. These studies showed mutations in PP2A-Aβ confer a loss of function by reducing its ability to bind the B and C subunits, destabilizing the PP2A-Aβ containing PP2A complex. The affect of the PP2A-Aβ gene on cell growth was analyzed by transfecting the PP2A-Aβ gene into cancer cell line deficient for wild type PP2A-Aβ and deriving stable cell lines. The PP2A-Aβ gene appeared to confer a relative disadvantage to transfected cells, resulting in a lower fraction of derived stable lines compared to controls. These cell lines were tested for proliferation and colony formation in soft agar. No significant difference was observed in the growth rate of PP2A-Aβ cell lines compared to controls. One of the PP2A-Aβ stable cell lines demonstrated dramatic suppression of colony formation in soft agar, but this was not confirmed in any additional PP2A-Aβ stable cell lines, leaving this finding inconclusive. The stable cell lines were also analyzed by Western blotting for changes in the Wnt signaling cascade. Cell lines expressing exogenous PP2A-Aβ are found to have lower levels of β-catenin compared to control cell lines. This suggests that the PP2A-Aβ gene is involved in regulating the Wnt signaling pathway, which is shown to be involved in cell growth control and is similarly affected by known tumor suppressor genes

Comprehensive germline panel testing across cancer types: Diagnostic yield and clinical utility in 100,000 patient dataset.

e13013 Background: Over 608,000 patients with ovarian, breast, pancreatic, prostate and colorectal cancer are diagnosed each year. NCCN guidelines recommend offering germline genetic testing to all patients with ovarian and pancreatic cancer, and patients with prostate and breast cancer who meet specific criteria. We present data from ~113,000 patients who were tested on a comprehensive multigene panel and compare the diagnostic yield and clinical actionability with that of a limited gene panel strategy. Methods: We analyzed de-identified sequence data for 83 cancer-risk genes in patients with breast, ovarian, prostate and pancreatic cancer referred for germline genetic testing. Positive rates for a minimal gene panel for the respective indication were computed and compared to the positive rates when the comprehensive 83 gene panel was analyzed. Results: Four percent of 103,428 patients with breast, ovarian, pancreatic and prostate cancer harbored a BRCA1 or BRCA2 germline mutation including: breast 3.7%, ovarian 8.2%, prostate 5.2% and pancreatic 4.2%. When the comprehensive panel is applied, the overall diagnostic yield for all 113,107 patients increased to 16%. Excluding mono-allelic P/LP variants in recessive cancer-risk genes (e.g. MUTYH) reduces the diagnostic yield to 13%. Stratified by cancer type, and removing mono-allelic recessives, positive yield was: breast 11.8%, ovarian 18%, prostate 15%, and pancreatic 16%. Conclusions: These data show that comprehensive panel testing in patients with a broad range of cancers more than doubles the diagnostic yield, providing actionable results for an additional 9,737 per 113,107 patients tested. Potential germline-based clinical actionability for these patients includes: 1) pan-cancer eligibility for PARP inhibitor clinical trials, 2) FDA approved PD1 blockade for advanced cancer of ANY type and a molecular diagnosis of Lynch syndrome, 3) cascade family variant testing.This study suggests that genetic testing guidelines should be expanded to include recommendations supporting multigene panel testing in patients with cancer to improve the care of patients and their family members. </jats:p