Hereditary breast cancer: syndromes, tumour pathology and molecular testing.

Hereditary factors account for a significant proportion of breast cancer risk. Approximately 20% of hereditary breast cancers are attributable to pathogenic variants in the highly penetrant BRCA1 and BRCA2 genes. A proportion of the genetic risk is also explained by pathogenic variants in other breast cancer susceptibility genes, including ATM, CHEK2, PALB2, RAD51C, RAD51D and BARD1, as well as genes associated with breast cancer predisposition syndromes - TP53 (Li-Fraumeni syndrome), PTEN (Cowden syndrome), CDH1 (hereditary diffuse gastric cancer), STK11 (Peutz-Jeghers syndrome) and NF1 (neurofibromatosis type 1). Polygenic risk, the cumulative risk from carrying multiple low-penetrance breast cancer susceptibility alleles, is also a well-recognised contributor to risk. This review provides an overview of the established breast cancer susceptibility genes as well as breast cancer predisposition syndromes, highlights distinct genotype-phenotype correlations associated with germline mutation status and discusses molecular testing and therapeutic implications in the context of hereditary breast cancer.

Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.

BACKGROUND: Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer. PATIENTS AND METHODS: We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30). RESULTS: Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2. CONCLUSIONS: Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases.

Adolescent version of the questionnaire of eating and weight patterns: reliability and gender differences.

OBJECTIVE: The present study determined the test-retest reliability of the adolescent version of the Questionnaire of Eating and Weight Patterns (QEWP-A) and examined gender differences in QEWP-A responses. METHOD: The QEWP-A was administered to 106 male and female adolescents between the ages of 12 and 18 in a classroom setting and readministered 3 weeks later under the same conditions. Adolescent responses were classified into no diagnosis (ND), nonclinical binge (NCB), and binge eating disorder (BED) diagnostic categories. RESULTS: BED diagnoses were rare, but nonclinical levels were observed. Significant levels of stability for males and females were observed over a 3-week time period (phi = 0.42). Male and female differences were examined. Female responses changed significantly at the second testing. DISCUSSION: The implications for these results regarding the utility for the QEWP-A are reviewed.

Pharmacokinetics of the acyl coenzyme A:cholesterol acyl transferase inhibitor CP-105,191 in dogs--the effect of food and sesame oil on systemic exposure following oral dosing.

Inhibition of acyl coenzyme A:cholesterol acyl transferase (ACAT) decreases total plasma cholesterol in animals and may be an effective therapy for atherosclerosis in man. The pharmacokinetics of CP-105,191, a potent inhibitor of ACAT, were explored in fed and fasted dogs. Following oral administration of drug, mean apparent plasma half-life ranged from 9 to 16 h. Systemic availability of CP-105,191, as determined by AUC(0-infinity), was approximately 3-4-fold higher in fed dogs than in fasted dogs when 50 mg doses were administered as aqueous suspensions. Tmax was achieved more rapidly and Cmax was lower in fasted dogs. When 50 mg doses, partially dissolved in 20 mL sesame oil, were administered to fed dogs, the availability of CP-105,191 increased by another factor of 2. A 12.5 mg dose of CP-105,191, completely dissolved in sesame oil, was administered to fed and fasted dogs. Plasma AUC's were similar for fed and fasted dogs following the 12.5 mg dose, indicating that the increased availability of drug when administered with food is related to the presence of lipid.

Pharmacokinetics of zopolrestat, a carboxylic acid aldose reductase inhibitor, in normal and diabetic rats.

The pharmacokinetics of zopolrestat, a carboxylic acid aldose reductase inhibitor, were examined in normal male rats dosed intravenously at 2 mg/kg and in normal and streptozotocin-diabetic male rats after oral administration at 50 mg/kg. After oral dosing, Cmax was 127 micrograms/ml for normal rats and 144 micrograms/ml for diabetic rats. AUC(0-infinity), however, was lower for diabetic rats than for normal rats and plasma half-life was longer in normal rats (8.0 vs 6.6 hr). Half-lives of zopolrestat in nerve, kidney, and lens were longer than plasma half-life and were similar for both diabetic and normal rats. Less than 2% of the dose was excreted in the urine as unchanged zopolrestat during the 48-hr period following dosing by diabetic or normal rats. Protein binding of zopolrestat was less extensive in plasma from diabetic rats than in plasma from normal rats. Similar kinetics were observed in diabetic animals receiving five daily doses of zopolrestat at 50 mg/kg/day. There was no plasma or liver accumulation of zopolrestat at steady state, consistent with the observed half-lives. However, zopolrestat did accumulate in nerve, kidney, and lens to varying degrees during multiple dosing, reflecting the longer half-lives of zopolrestat in these tissues.

Cunninghamella bertholletiae and Pneumocystis carinii pneumonia as a fatal complication of chronic lymphocytic leukemia.

A unique patient with chronic lymphocytic leukemia died with pneumonia caused by both Cunninghamella bertholletiae and Pneumocystis carinii. In tissue sections, the hyphae of C bertholletiae were twisted and ribbon-like, but were smaller than those typical for zygomycetes, displayed more than occasional septa, and exhibited Y branching, making histologic distinction from Aspergillus sp difficult.

Interference by endogenous glycerol in an enzymatic assay of phosphatidylglycerol in amniotic fluid.

We investigated the possibility of interference by endogenous glycerol with the enzymatic measurement of phosphatidylglycerol in amniotic fluid. Phosphatidylglycerol is an important indicator of fetal lung maturity. The concentrations of glycerol and phosphatidylglycerol in amniotic fluid were measured by using a coupled enzymatic assay with and without phospholipase D (EC 3.1.4.4). The precision of the assay was acceptable (within-run CV = 1.2%, between-run CV = 4.8%). Endogenous glycerol content was demonstrated to be approximately 10-20 times that of phosphatidylglycerol. This high proportion of endogenous glycerol in amniotic fluid would preclude the accurate enzymatic determination of amniotic fluid phosphatidylglycerol unless the glycerol is first removed. Nor can the actual phosphatidylglycerol concentration be determined by subtracting the endogenous glycerol concentration from the total glycerol, which includes that glycerol derived from phosphatidylglycerol. With a usual range of 9 +/- 7 mumol/L, the error for a given phosphatidylglycerol measurement of +/- 6.6 mumol/L (+/- 2 SD) clearly is too high for this assay to be clinically useful. There was no correlation between concentration of endogenous glycerol or apparent phosphatidylglycerol in amniotic fluid and the lecithin/sphingomyelin ratio of the sample.