Frequency of actionable germline pathogenic variants identified through tumor next-generation sequencing in a gynecologic cancer cohort.

BACKGROUND: Tumor next-generation sequencing can identify potential germline pathogenic variants associated with cancer susceptibility. OBJECTIVE: To describe the frequency of tumor sequencing results that met European Society of Medical Oncology (ESMO) recommendations for further germline genetic testing, and the frequency of germline variants among a cohort with gynecologic cancer. METHODS: Patients with gynecologic cancer who underwent tumor sequencing between September 2019 and February 2022 in a large healthcare system in New York City were retrospectively identified. Eligible patients with suspected germline pathogenic variants on tumor sequencing were identified based on ESMO guidelines. Logistic regression was used to explore variables associated with referral and completion of germline testing. RESULTS: Of 358 patients with gynecologic cancers who underwent tumor sequencing, 81 (22.6%) had ≥1 suspected germline variant according to ESMO guidelines. Of the 81 patients with qualifying tumor sequencing results, 56 (69.1%) received germline testing: 41/46 (89.1%) eligible patients with ovarian cancer and 15/33 (45.5%) with endometrial cancer. In the endometrial cancer cohort, 11/33 (33.3%) eligible patients were not referred for germline testing and the majority of these patients had tumor variants in genes commonly known to cause hereditary cancer. Of the 56 patients who underwent germline testing, 40 (71.4%) had pathogenic germline variants. In multivariable analysis, race/ethnicity other than non-Hispanic white was associated with lower odds of germline testing referral and completion (OR=0.1, 95% CI 0.01 to 0.5 and OR=0.2, 95% CI 0.04 to 0.6, respectively). CONCLUSION: Given the high rate of pathogenic germline variant detection and the importance of identifying such variants for both patients and their family, it is imperative that eligible patients undergo germline testing. Additional education for providers on multidisciplinary guidelines and development of clinical pathways to ensure germline testing of suspected pathogenic variants identified on tumor sequencing is warranted, especially in light of the racial/ethnic inequity observed.

Lessons learned from testing cardiac channelopathy and cardiomyopathy genes in individuals who died suddenly: A two-year prospective study in a large medical examiner's office with an in-house molecular genetics laboratory and genetic counseling services.

This is a comprehensive review and analysis of 254 cases tested consecutively in the in-house College of American Pathologist-accredited molecular genetics laboratory within the New York City Office of Chief Medical Examiner between October 2015 and February 2018, using a multigene cardiac panel composed of 95 genes associated with cardiac channelopathy and cardiomyopathy. Demographics, autopsy findings, medical history, and postmortem genetic testing results were collected for each case. The majority of decedents were adults (>25 years old, 52.7%), followed by infants (<12 months, 25.6%), young adults (19-25 years old, 11.4%), and children (1-18 years old, 10.2%). There were more males (64.2%) than females (35.8%). The racial/ethnic composition of decedents was 40.2% Black, 29.9% Hispanic, 22.4% White, 5.1% Asian/Pacific Islander, and 2.8% mixed/unspecified. Overall, 45.7% of decedents had a negative autopsy, and the remaining had one to four cardiac findings (cardiac hypertrophy, dilation, atherosclerosis, and fatty change). Twenty-seven pathogenic/likely pathogenic variants (P/LP) and 99 variants of uncertain significance (VUS) were identified in 10.6% and 39% of decedents respectively. P/LP and VUS were found in 51 cardiac genes of the total 95 genes, where MYBPC3, TTN (predicted truncating variants), KCNH2, RYR2 and DSP genes had more than two P/LP variants identified. Among the 73 decedents who were suspected of having cardiac arrhythmia or cardiomyopathy, 20.3% had P/LP variants and 47.9% had VUS; among 23 decedents who had hypertensive cardiovascular diseases and 20 decedents with a history of substance use, 13% and 30% had P/LP variants, respectively. There were 26 referrals from medical examiners for genetic counseling and the outcomes are discussed. The study demonstrates characteristics of the diverse population typically seen by medical examiners in an urban center and our results support a broader implementation of molecular testing in sudden death.

Quantitative in vivo proton MR spectroscopic assessment of lipid metabolism: Value for breast cancer diagnosis and prognosis.

BACKGROUND: Breast magnetic resonance spectroscopy (1 H-MRS) has been largely based on choline metabolites; however, other relevant metabolites can be detected and monitored. PURPOSE: To investigate whether lipid metabolite concentrations detected with 1 H-MRS can be used for the noninvasive differentiation of benign and malignant breast tumors, differentiation among molecular breast cancer subtypes, and prediction of long-term survival outcomes. STUDY TYPE: Retrospective. SUBJECTS: In all, 168 women, aged ≥18 years. FIELD STRENGTH/SEQUENCE: Dynamic contrast-enhanced MRI at 1.5 T: sagittal 3D spoiled gradient recalled sequence with fat saturation, flip angle = 10°, repetition time / echo time (TR/TE) = 7.4/4.2 msec, slice thickness = 3.0 mm, field of view (FOV) = 20 cm, and matrix size = 256 × 192. 1 H-MRS: PRESS with TR/TE = 2000/135 msec, water suppression, and 128 scan averages, in addition to 16 reference scans without water suppression. ASSESSMENT: MRS quantitative analysis of lipid resonances using the LCModel was performed. Histopathology was the reference standard. STATISTICAL TESTS: Categorical data were described using absolute numbers and percentages. For metric data, means (plus 95% confidence interval [CI]) and standard deviations as well as median, minimum, and maximum were calculated. Due to skewed data, the latter were more adequate; unpaired Mann-Whitney U-tests were performed to compare groups without and with Bonferroni correction. ROC analyses were also performed. RESULTS: There were 111 malignant and 57 benign lesions. Mean voxel size was 4.4 ± 4.6 cm3 . Six lipid metabolite peaks were quantified: L09, L13 + L16, L21 + L23, L28, L41 + L43, and L52 + L53. Malignant lesions showed lower L09, L21 + L23, and L52 + L53 than benign lesions (P = 0.022, 0.027, and 0.0006). Similar results were observed for Luminal A or Luminal A/B vs. other molecular subtypes. At follow-up, patients were split into two groups based on median values for the six peaks; recurrence-free survival was significantly different between groups for L09, L21 + L23, and L28 (P = 0.0173, 0.0024, and 0.0045). DATA CONCLUSION: Quantitative in vivo 1 H-MRS assessment of lipid metabolism may provide an additional noninvasive imaging biomarker to guide therapeutic decisions in breast cancer. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:239-249.