bims-lifras 2023-09-17 papers

J Natl Cancer Inst. 2023 Sep 09. pii: djad183. [Epub ahead of print]

Germline pathogenic variants in neuroblastoma patients are enriched in BARD1 and predict worse survival.

BACKGROUND: Neuroblastoma is an embryonal cancer of the developing sympathetic nervous system. The genetic contribution of rare pathogenic or likely pathogenic (P-LP) germline variants in patients without a family history remains unclear.
METHODS: Germline DNA sequencing was performed on 786 neuroblastoma patients. The frequency of rare cancer predisposition gene (CPG) P-LP variants in cases was compared to two cancer-free control cohorts. Matched tumor DNA sequencing was evaluated for "second hits" and germline DNA array data from 5,585 neuroblastoma cases and 23,505 cancer-free control children was analyzed to identify rare germline copy number variants (CNVs). Patients with germline P-LP variants were compared to those without to test for association with clinical characteristics, tumor features, and survival.
RESULTS: We observed 116 P-LP variants involving 13.9% (109/786) of patients, representing a significant excess burden compared to controls (odds ratio: 1.60, 95% confidence interval: 1.27-2.00). BARD1 harbored the most significant enrichment of P-LP variants (odds ratio: 32.30, 95% confidence interval: 6.44-310.35). Rare germline CNVs disrupting BARD1 were identified in patients but absent in controls (odds ratio: 29.47, 95% confidence interval: 1.52-570.70). Patients harboring a germline P-LP variant had a worse overall survival compared to those without (P = 8.6x10-3).
CONCLUSIONS: BARD1 is an important neuroblastoma predisposition gene harboring both common and rare germline P-LP variation. The presence of any germline P-LP variant in a CPG was independently predictive of worse overall survival. As centers move toward paired tumor-normal sequencing at diagnosis, efforts should be made to centralize data and provide an infrastructure to support cooperative longitudinal prospective studies of germline pathogenic variation.

DOI: https://doi.org/10.1093/jnci/djad183

Am J Hematol. 2023 Sep 13.

Germline DDX41 mutant predisposition syndromes: Slow driver states to hematological malignancies.

Timothy M Chlon, Mrinal M Patnaik.

DOI: https://doi.org/10.1002/ajh.27091

J Natl Cancer Inst. 2023 Sep 09. pii: djad182. [Epub ahead of print]

BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.

Michael P Randall, Laura E Egolf, Zalman Vaksman, Minu Samanta, Matthew Tsang, David Groff, J Perry Evans, Jo Lynne Rokita, Mehdi Layeghifard, Adam Shlien, John M Maris, Sharon J Diskin, Kristopher R Bosse.

BACKGROUND: High-risk neuroblastoma is a complex genetic disease that is lethal in over 50% of patients despite intense multimodal therapy. Through genome-wide association studies (GWAS) and next-generation sequencing (NGS), we have identified common single nucleotide polymorphisms (SNPs) and rare, pathogenic (P) or likely pathogenic (LP) germline loss-of-function (LOF) variants in BARD1 enriched in neuroblastoma patients. The functional implications of these findings remain poorly understood.
METHODS: We correlated BARD1 genotype with expression in normal tissues and neuroblastomas, along with the burden of DNA damage in tumors. To validate the functional consequences of germline P-LP BARD1 variants, we used CRISPR/Cas9 to generate isogenic neuroblastoma (IMR-5) and control (RPE1) cellular models harboring heterozygous BARD1 LOF variants (R112*, R150*, E287fs, and Q564*) and quantified genomic instability in these cells via NGS and with functional assays measuring the efficiency of DNA repair.
RESULTS: Both common and rare neuroblastoma associated BARD1 germline variants were significantly associated with lower levels of BARD1 mRNA and an increased burden of DNA damage. Using isogenic heterozygous BARD1 LOF variant cellular models, we functionally validated this association with inefficient DNA repair. BARD1 LOF variant isogenic cells exhibited reduced efficiency in repairing Cas9-induced DNA damage, ineffective RAD51 focus formation at DNA double-strand break sites, and enhanced sensitivity to cisplatin and poly-ADP ribose polymerase (PARP) inhibition both in vitro and in vivo.
CONCLUSIONS: Taken together, we demonstrate that germline BARD1 variants disrupt DNA repair fidelity. This is a fundamental molecular mechanism contributing to neuroblastoma initiation that may have important therapeutic implications.

DOI: https://doi.org/10.1093/jnci/djad182

Tumori. 2023 Sep 11. 3008916231197113

De novo germline pathogenic variant in Lynch Syndrome: A rare event or the tip of the iceberg?

Clorinda Brignola, Sara Volorio, Giovanna De Vecchi, Daniela Zaffaroni, Valentina Dall'Olio, Frederique Mariette, Domenico Sardella, Fabio Capra, Stefano Signoroni, Emanuele Rausa, Marco Vitellaro, Valeria Pensotti, Maria Teresa Ricci.

Lynch Syndrome is an autosomal dominant cancer predisposition syndrome caused by germline pathogenic variants or epimutation in one of the DNA mismatch repair genes. De novo pathogenic variants in mismatch repair genes have been described as a rare event in Lynch Syndrome (1-5%), although the prevalence of de novo pathogenic variants in Lynch Syndrome is probably underestimated. The de novo pathogenic variant was identified in a 26-year-old woman diagnosed with an adenocarcinoma of the caecum with mismatch repair protein deficiency at immunohistochemistry and a synchronous neuroendocrine tumor of the appendix with normal expression of mismatch repair proteins. DNA testing revealed deletion of exon 6 of the MLH1 gene. It appeared to be a de novo event, as the deletion was not detected in the patient's parents. The presence of a mosaicism in the patient was excluded and haplotype analysis demonstrated the paternal origin of the chromosome harboring the deletion. The de novo deletion probably originated either from a very early postzygotic or a single prezygotic mutational event, or from a gonadal mosaicism. In conclusion, the identification of de novo pathogenic variants is crucial to allow proper genetic counseling and appropriate management of the patient's family.

Keywords: Lynch syndrome; de novo pathogenic variant; germline mutations; mismatch repair genes

DOI: https://doi.org/10.1177/03008916231197113

Pharmacogenomics. 2023 Sep 13.

Integrating pharmacogenomic testing into paired germline and somatic genomic testing in patients with cancer.

Nathan D Seligson, Jill M Kolesar, Benish Alam, Laura Baker, Jatinder K Lamba, Brooke L Fridley, Ameen A Salahudeen, Daniel L Hertz, J Kevin Hicks.

Precision medicine has revolutionized clinical care for patients with cancer through the development of targeted therapy, identification of inherited cancer predisposition syndromes and the use of pharmacogenetics to optimize pharmacotherapy for anticancer drugs and supportive care medications. While germline (patient) and somatic (tumor) genomic testing have evolved separately, recent interest in paired germline/somatic testing has led to an increase in integrated genomic testing workflows. However, paired germline/somatic testing has generally lacked the incorporation of germline pharmacogenomics. Integrating pharmacogenomics into paired germline/somatic genomic testing would be an efficient method for increasing access to pharmacogenomic testing. In this perspective, the authors argue for the benefits of implementing a comprehensive approach integrating somatic and germline testing that is inclusive of pharmacogenomics in clinical practice.

Keywords: PGx; adverse events; cancer; malignancy; precision medicine

DOI: https://doi.org/10.2217/pgs-2023-0125

Cancer Med. 2023 Sep 11.

Advancing precision oncology through systematic germline and tumor genetic analysis: The oncogenetic point of view on findings from a prospective multicenter clinical trial of 666 patients.

Benoit Mazel, Geoffrey Bertolone, Amandine Baurand, Elodie Cosset, Caroline Sawka, Marion Robert, Elodie Gautier, Allan Lançon, Manon Réda, Laure Favier, Valentin Dérangère, Corentin Richard, Christine Binquet, Romain Boidot, Vincent Goussot, Juliette Albuisson, François Ghiringhelli, Laurence Faivre, Sophie Nambot.

INTRODUCTION: With the emergence of targeted therapies, there is a need to accurately identify more tumor biomarkers. The EXOMA trial was designed to offer tumor and germline exome sequencing (ES) to patients with solid malignant tumors and facing therapeutic failure. As hereditary cancer predispositions could be identified, with genetic counseling and health management implications, a genetic consultation was systematically established. This design needs to be discussed as genetic human resources are limited and indication of theranostic tests will increase.
METHODS: Genetic counseling was conducted within 15 days following inclusion in the study for patients recruited between December 2015 and July 2019. In silico analyses from theranostic ES were limited to 317 genes involved in oncogenesis, from both tumor and blood DNA.
RESULTS: Six hundred and sixty six patients had a genetic consultation before ES. In 65/666 patients, 66 germline pathogenic or likely pathogenic (P/LP) variants were identified in 16 actionable genes and seven non-actionable genes according to French guidelines. 24/65 patients had previously received genetic analysis for diagnostic purposes, and for 17 of them, a P/LP variant had already been identified. Among the 48/65 remaining cases for which the EXOMA protocol revealed a previously unknown P/LP variant, only 19 met the criteria for genetic testing for inherited cancer risk after familial survey. These criteria had not been identified by the oncologist in 10 cases. In 21/65 cases, the variant was considered incidental.
DISCUSSION: In 7.4% of patients, an undiagnosed hereditary genetic predisposition was identified, whether or not related to the clinical presentation, and germline analysis impacted oncological management for only 6.3% of the cohort. This low percentage should be weighed against the burden of systematic genetic consultation and urgent circuits. Information or training tools to form oncologists to the prescription of germline genetic analyses should be explored, as well as information supports and patient preferences.

Keywords: genetic counseling; incidental findings; information; oncogenetic; theranostic exome sequencing

DOI: https://doi.org/10.1002/cam4.6498

Clin Gastroenterol Hepatol. 2023 Sep 13. pii: S1542-3565(23)00698-5. [Epub ahead of print]

Spectrum and excess risk of gastrointestinal tumors in Li-Fraumeni syndrome.

Jessica N Hatton, Kelvin C de Andrade, Megan N Frone, Sharon A Savage, Payal P Khincha.

DOI: https://doi.org/10.1016/j.cgh.2023.08.028