bims-lifras 2024-05-12 papers

Issue of 2024–05–12
five papers selected by
Joanna Zawacka, Karolinska Institutet

Clin Genet. 2024 May 07.

Outcomes of a universal germline screening program in a community urology practice.

Neil Mendhiratta, Herman Hauver, Whitley Hatton, Andrew Ostrusky, Devika S Sathe, Sandeep Gurram, Patricia Rice, Heather Chalfin.

The role of germline genetic testing in urologic oncology has expanded in recent years. However, implementation of genetic testing in community practices remains a challenge, often due to limited access to qualified genetics trained providers. In this study, we report outcomes of a universal germline screening program in a community urology practice. Between November 2021 and September 2022, all patients referred for urology clinic visits at Frederick Health (Frederick, MD, USA) were provided an online genetics screening questionnaire prior to the visit. Responses were compared against National Comprehensive Cancer Network (NCCN) criteria for germline testing. Those who met criteria were provided educational materials at the end of the questionnaire, and then counseled by a trained urologic oncologist (HC) in the clinic or referred to a genetic counselor prior to testing. Testing was performed with a 36-gene pan-cancer panel (CancerNext) or a 14-gene targeted prostate cancer panel (ProstateNext), with or without additional RNA analysis (RNAinsight) (Ambry Genetics, CA, USA). Demographic and clinical parameters, as well as genetic testing results, were retrospectively collected under IRB approval. In the study period, 765 patients were seen over 1370 clinic visits. Of these, 505 patients (66.0%) completed the screening questionnaire. The majority were completed via email (54.5%) with the remainder (45.5%) via text message. Of the patients who completed screening, 125/505 (24.7%) met NCCN criteria for germline testing. 58/125 patients (46.4%) who met criteria underwent germline testing, of whom 5/58 (8.6%) had distinct pathogenic mutations identified. These included actionable mutations in BRCA1, BRCA2, and CHEK2, as well as an additional pathogenic mutation in NBN. Variants of unknown significance were identified in 8/58 patients (13.8%) in 11 total genes. Challenges to implementation of this program included meeting institutional requirements for genetic testing consent, facilitating specimen collection in clinic, and integration of results into the electronic health record. Genetic risk assessment for high-risk individuals is feasible as part of a universal screening program in a community urology practice. Approximately 8% of tested patients were found to have pathogenic germline mutations, which is consistent with contemporary tertiary referral cohorts.

Keywords: germline; screening; urology

DOI: https://doi.org/10.1111/cge.14541

J Clin Endocrinol Metab. 2024 May 06. pii: dgae310. [Epub ahead of print]

Pancreatic neuroendocrine tumors in French VHL mutation carriers: a multicentric retrospective study.

Marie Muller, Pascal Hammel, Anne Couvelard, Anne-Laure Védie, Jérôme Cros, Nelly Burnichon, Agathe Hercent, Alain Sauvanet, Stéphane Richard, Louis de Mestier.

BACKGROUND: Von Hippel-Lindau disease (VHL) is a rare autosomal dominant hereditary cancer-predisposition syndrome caused by germline pathogenic variants (PV) in VHL gene. It is associated with a high penetrance of benign and malignant vascular tumors in multiples organs, including pancreatic neuroendocrine tumors (PanNETs), whose long-term natural history is ill-known.
METHODS: Patients with both documented germline PV in VHL gene and PanNETs included in the French PREDIR database between 1995 and 2022 were included. Primary endpoint was the proportion of patients with PanNET-related metastases and secondary endpoint was overall survival (OS). Genotype/phenotype correlations were studied.
RESULTS: We included 121 patients with 259 PanNETs. Median age at diagnosis was 38 years. Median follow-up was 89.5 months. PanNET surgical resection was performed in 51 patients. Overall, 29 patients (24%) had metastases (5 synchronous, 10 metachronous), with a higher risk in case of larger PanNET size (p=0.0089; best threshold 28 mm) and grade 2 PanNET (p=0.048), and a pejorative prognostic impact (p=0.043). Patients with PV in VHL exon 1 had larger PanNETs (p=0.018), more often metastatic disease (48% vs 11.5%; p < 0.001) and a trend toward shorter OS (p=0.16).
CONCLUSION: The risk of metastases associated to VHL-related PanNETs remains low (24%) but increases with tumor size >28 mm, higher grade and in case of PV located VHL exon 1. These data might help improving the management of these patients, who should be referred to an expert center.

Keywords: VHL gene; hereditary neoplastic syndromes; pancreatic neuroendocrine tumors; von Hippel-Lindau disease

DOI: https://doi.org/10.1210/clinem/dgae310

Curr Treat Options Oncol. 2024 May 07.

Genetic Predisposition to Sarcoma: What Should Clinicians Know?

Jennie Vagher, Casey J Mehrhoff, Vaia Florou, Luke D Maese.

OPINION STATEMENT: Pathogenic germline variants in the setting of several associated cancer predisposition syndromes (CPS) may lead to the development of sarcoma. We would consider testing for a CPS in patients with a strong family history of cancer, multiple primary malignancies, and/or pediatric/adolescent/young adult patients diagnosed with other malignancies strongly associated with CPS. When a CPS is diagnosed in a patient with sarcoma, additional treatment considerations and imaging options for those patients are required. This applies particularly to the use of radiation therapy, ionizing radiation with diagnostic imaging, and the use of alkylating chemotherapy. As data and guidelines are currently lacking for many of these scenarios, we have adopted a shared decision-making process with patients and their families. If the best chance for cure in a patient with CPS requires utilization of radiation therapy or alkylating chemotherapy, we discuss the risks with the patient but do not omit these modalities. However, if there are treatment options that yield equivalent survival rates, yet avoid these modalities, we elect for those options. Considering staging imaging and post-therapy evaluation for sarcoma recurrence, we avoid surveillance techniques that utilize ionizing radiation when possible but do not completely omit them when their use is indicated.

Keywords: Alkylator; Cancer predisposition syndrome; Pediatric cancer; Radiation; Sarcoma

DOI: https://doi.org/10.1007/s11864-024-01192-6

JCO Oncol Pract. 2024 May 08. OP2400237

Bridging the Divide: From Universal Germline Testing Guidance to Real-World Implementation in Pancreatic Cancer Care.

Harshabad Singh, Ryan D Nipp.

In this editorial accompanying manuscript the by Klatte and colleagues, Drs Singh, and Nipp review the data behind universal germline testing in pancreatic adenocarcinoma, and review possible reasons for and solutions continued inadequate rates of germline testing in our community. Making germline testing for all patients with pancreatic adenocarcinoma is critical and will require cross-disciplinary collaboration and innovation.

DOI: https://doi.org/10.1200/OP.24.00237

Eur J Cancer. 2024 Apr 26. pii: S0959-8049(24)00744-5. [Epub ahead of print]205 114088

Germline NGS targeted analysis in adult patients with sporadic adrenocortical carcinoma.

Maria Scatolini, Salvatore Grisanti, Pasquale Tomaiuolo, Enrico Grosso, Vittoria Basile, Deborah Cosentini, Soraya Puglisi, Marta Laganà, Paola Perotti, Laura Saba, Elisa Rossini, Flavia Palermo, Sandra Sigala, Marco Volante, Alfredo Berruti, Massimo Terzolo.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare cancer that arises sporadically or due to hereditary syndromes. Data on germline variants (GVs) in sporadic ACC are limited. Our aim was to characterize GVs of genes potentially related to adrenal diseases in 150 adult patients with sporadic ACC.
METHODS: This was a retrospective analysis of stage I-IV ACC patients with sporadic ACC from two reference centers for ACC in Italy. Patients were included in the analysis if they had confirmed diagnosis of ACC, a frozen peripheral blood sample and complete clinical and follow-up data. Next generation sequencing technology was used to analyze the prevalence of GVs in a custom panel of 17 genes belonging to either cancer-predisposition genes or adrenocortical-differentiation genes categories.
RESULTS: We identified 18 GVs based on their frequency, enrichment and predicted functional characteristics. We found six pathogenic (P) or likely pathogenic (LP) variants in ARMC5, CTNNB1, MSH2, PDE11A and TP53 genes; and twelve variants lacking evidence of pathogenicity. New unique P/LP variants were identified in TP53 (p.G105D) and, for the first time, in ARMC5 (p.P731R). The presence of P/LP GVs was associated with reduced survival outcomes and had a significant and independent impact on both progression-free survival and overall survival.
CONCLUSIONS: GVs were present in 6.7 % of patients with sporadic ACC, and we identified novel variants of ARMC5 and TP53. These findings may improve understanding of ACC pathogenesis and enable genetic counseling of patients and their families.

Keywords: Adrenal cancer; Genetics; Mutation; Oncogenes; Outcome; Pathogenesis; Progression; Progression.; Survival; Tumor suppressors

DOI: https://doi.org/10.1016/j.ejca.2024.114088