Expedited evaluation of hereditary hematopoietic malignancies in the setting of stem cell transplantation.

Not available.

Stagnation in quality of next-generation sequencing assays for the diagnosis of hereditary hematopoietic malignancies.

Hereditary hematopoietic malignancies (HHMs) are inherited syndromes that confer the risk of blood cancer development. With the rapid acceleration of next-generation sequencing (NGS) into commercial biotechnology markets, HHMs are increasingly recognized by genetic counselors and clinicians. In 2020, it was demonstrated that most diagnostic test offerings for HHMs were insufficient for accurate diagnosis, failing to sequence the full spectrum of genetic events known to cause HHMs. We hypothesized the number of genes on commercially available HHM assay increased from 2020 to 2022, consistent with a more comprehensive sequencing approach. Here, we analyzed assays from eight commercial laboratories to determine the HHM-related genes sequenced by these assays. We compared these assays with panels from 2020 to determine trends in sequencing quality. Most HHM diagnostic assays did not change and remain insensitive for the detection of all HHM-related variants. Most (75%) HHM assays do not sequence CHEK2, the gene most frequently mutated in HHMs, and 25% of HHM assays does not sequence DDX41, the second most frequent HHM driver. The quality of HHM diagnostic assays stagnated despite the discovery of novel HHM-related genes and prior work demonstrating heterogeneity in the quality of HHM testing. Most commercially available HHM tests remain insufficient.

Addressing gaps in healthcare provider knowledge regarding germline testing for prostate cancer through development and testing of a virtual genetics board.

BACKGROUND: Germline testing is important in prostate cancer and evaluation can be complex. METHODS: We instituted a monthly multi-disciplinary virtual genetics tumor board (7/2021-3/2022). Participants and panelists were surveyed on usefulness and acceptability. RESULTS: 101 participants attended a session, and 77 follow-up surveys were completed. Over 90% participants and 100% panelists endorsed usefulness of the case discussions and usability of the technology. The majority felt it provided new information they will use. CONCLUSIONS: A multidisciplinary genetics board was successfully developed to address complexity in prostate cancer genetics. The virtual platform may enhance dissemination of expertise where there are regional gaps.

Family Matters: Germline Testing in Thoracic Cancers.

Most thoracic cancers arise via a series of stepwise somatic alterations driven by a well-defined carcinogen (ie, tobacco or asbestos for lung cancer and mesothelioma, respectively). A small proportion can emerge on a background of pathogenic germline variants (PGVs), which have the property of heritability. In general, PGVs may be initially suspected on the basis of the presence of specific clinical features. Such gene × environment interactions significantly increase the risk of developing lung cancer (1.5- to 3.2-fold). PGVs have been discovered involving the actionable driver oncogene, epidermal growth factor receptor (EGFR), with an EGFR T790M PGV rate of 0.3%-0.9% in the nonsquamous non-small-cell lung cancer subtype. Its appearance during routine somatic DNA sequencing in those patients who have not had a previous tyrosine kinase inhibitor should raise suspicion. In patients with sporadic mesothelioma, BAP1 is the most frequently mutated tumor driver, with a PGV rate between 2.8% and 8%, associated with a favorable prognosis. BAP1 PGVs accelerate mesothelioma tumorigenesis after asbestos exposure in preclinical models and may be partly predicted by clinical criteria. At present, routine germline genetic testing for thoracic cancers is not a standard practice. Expert genetic counseling is, therefore, required for patients who carry a PGV. Ongoing studies aim to better understand the natural history of patients harboring PGVs to underpin future cancer prevention, precise counseling, and cancer management with the goal of improving the quality and length of life.

Investigating Fumarate Hydratase-Deficient Uterine Fibroids: A Case Series.

Uterine leiomyomas or uterine fibroids are the most common benign soft tissue tumor in reproductive-aged women. Fumarate hydratase deficient (FH-d) uterine fibroids are a rare subtype that is diagnosed only on pathologic evaluation. FH-d uterine fibroids may be the first indicator of hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Therefore, identifying and understanding the clinical implication and diagnosis of FH-d uterine fibroids is critical for early diagnosis of HLRCC. This case series investigates the uncommon yet significant condition of FH-d uterine fibroids. We examined the clinical manifestation, diagnostic imaging, and histopathological characteristics of FH-d uterine fibroids in five cases identified at our institution over the last ten years. All diagnoses were confirmed by pathologic evaluation after surgical treatment. Gynecologists and pathologists play a critical role in the early diagnosis of FH-d uterine fibroids and must recognize the relevant clinical and pathologic findings that raise suspicion about this diagnosis. The detection of these cases is largely dependent on the pathologist's ability to recognize unique histopathologic features. Once these characteristics are identified, it should prompt a referral to a gynecologist to consider conducting germline genetic testing. The management of FH-d uterine fibroids necessitates a multidisciplinary approach, including proper genetic screening and regular surveillance, especially for renal tumors.

Germline Variants Incidentally Detected via Tumor-Only Genomic Profiling of Patients With Mesothelioma.

Importance: Patients with mesothelioma often have next-generation sequencing (NGS) of their tumor performed; tumor-only NGS may incidentally identify germline pathogenic or likely pathogenic (P/LP) variants despite not being designed for this purpose. It is unknown how frequently patients with mesothelioma have germline P/LP variants incidentally detected via tumor-only NGS. Objective: To determine the prevalence of incidental germline P/LP variants detected via tumor-only NGS of mesothelioma. Design, Setting, and Participants: A series of 161 unrelated patients with mesothelioma from a high-volume mesothelioma program had tumor-only and germline NGS performed during April 2016 to October 2021. Follow-up ranged from 18 months to 7 years. Tumor and germline assays were compared to determine which P/LP variants identified via tumor-only NGS were of germline origin. Data were analyzed from January to March 2023. Main Outcomes and Measures: The proportion of patients with mesothelioma who had P/LP germline variants incidentally detected via tumor-only NGS. Results: Of 161 patients with mesothelioma, 105 were male (65%), the mean (SD) age was 64.7 (11.2) years, and 156 patients (97%) self-identified as non-Hispanic White. Most (126 patients [78%]) had at least 1 potentially incidental P/LP germline variant. The positive predictive value of a potentially incidental germline P/LP variant on tumor-only NGS was 20%. Overall, 26 patients (16%) carried a P/LP germline variant. Germline P/LP variants were identified in ATM, ATR, BAP1, CHEK2, DDX41, FANCM, HAX1, MRE11A, MSH6, MUTYH, NF1, SAMD9L, and TMEM127. Conclusions and Relevance: In this case series of 161 patients with mesothelioma, 16% had confirmed germline P/LP variants. Given the implications of a hereditary cancer syndrome diagnosis for preventive care and familial counseling, clinical approaches for addressing incidental P/LP germline variants in tumor-only NGS are needed. Tumor-only sequencing should not replace dedicated germline testing. Universal germline testing is likely needed for patients with mesothelioma.

Consumers' desire towards current and prospective reproductive genetic testing.

As our knowledge and abilities in molecular genetics continues to expand, so does our ability to detect certain conditions/traits prenatally; however, it is unknown if this increase in scientific ability will be utilized by the consumers of genetic services. Our study gauges the consumers' opinion towards reproductive testing for diseases and enhancements. Prior to their initial visit with a genetic counselor, patients were asked to participate in a survey. These consumers were asked to indicate traits and conditions for which they would choose reproductive genetic testing. The majority of respondents would elect to have prenatal genetic testing for mental retardation (75%), deafness (54%), blindness (56%), heart disease (52%), and cancer (51%). Our results indicated that 49.3% would choose testing for a condition that resulted in death by 5 years of age, whereas only 41.1%, 24.9%, and 19% would choose testing for conditions that results in death by 20, 40, and 50 years of age, respectively. Most respondents did not desire testing for enhancements (e.g. 13% would choose testing for superior intelligence). Our study suggests that consumers desire more reproductive genetic testing than what is currently offered; however, their selection of tests suggests self-imposed limits on testing.