bims-lifras 2024-03-24 papers

Issue of 2024–03–24
six papers selected by
Joanna Zawacka, Karolinska Institutet

Int J Hematol. 2024 Mar 16.

Evaluation of the pathogenic potential of germline DDX41 variants in hematopoietic neoplasms using the ACMG/AMP guidelines.

Hirotaka Matsui, Makoto Hirata.

Clinical use of gene panel testing for hematopoietic neoplasms in areas, such as diagnosis, prognosis prediction, and exploration of treatment options, has increased in recent years. The keys to interpreting gene variants detected in gene panel testing are to distinguish between germline and somatic variants and accurately determine whether the detected variants are pathogenic. If a variant is suspected to be a pathogenic germline variant, it is essential to confirm its consistency with the disease phenotype and gather a thorough family history. Donor eligibility must also be considered, especially if the patient's variant is also detected in the expected donor for hematopoietic stem cell transplantation. However, determining the pathogenicity of gene variants is often complicated, given the current limited availability of databases covering germline variants of hematopoietic neoplasms. This means that hematologists will frequently need to interpret gene variants themselves. Here, we outline how to assess the pathogenicity of germline variants according to criteria from the American College of Medical Genetics and Genomics/Association for Molecular Pathology standards and guidelines for the interpretation of variants using DDX41, a gene recently shown to be closely associated with myeloid neoplasms with a germline predisposition, as an example.

Keywords: ACMG/AMP guidelines; DDX41; Gene panel testing; Germline variant

DOI: https://doi.org/10.1007/s12185-024-03728-w

Clin Genet. 2024 Mar 20.

BRCA1-associated protein 1: Tumor predisposition syndrome and Kury-Isidor syndrome, from genotype-phenotype correlation to clinical management.

Elizabeth Casey West, Marco Chiappetta, Aubrey Anne Mattingly, Maria Teresa Congedo, Jessica Evangelista, Annalisa Campanella, Carolina Sassorossi, Sara Flamini, Teresa Rossi, Mariaelena Pistoni, Ludovico Abenavoli, Stefano Margaritora, Filippo Lococo, Luigi Boccuto.

The BAP1 tumor suppressor gene encodes a deubiquitinase enzyme involved in several cellular activities, including DNA repair and apoptosis. Germline pathogenic variants in BAP1 have been associated with heritable conditions including BAP1 tumor predisposition syndrome 1 (BAP1-TPDS1) and a neurodevelopmental disorder known as Kury-Isidor syndrome (KURIS). Both these conditions are caused by monoallelic, dominant alterations of BAP1 but have never been reported in the same subject or family, suggesting a mutually exclusive genotype-phenotype correlation. This distinction is extremely important considering the early onset and aggressive nature of the types of cancer reported in individuals with TPDS1. Genetic counseling in subjects with germline BAP1 variants is fundamental to predicting the effect of the variant and the expected phenotype, assessing the potential risk of developing cancer for the tested subject and the family members who may carry the same variant and providing the multidisciplinary clinical team with the proper information to establish precise surveillance and management protocols.

Keywords: BAP1; genotype-phenotype correlation; mesothelioma; neurodevelopmental disorders

DOI: https://doi.org/10.1111/cge.14507

Front Oncol. 2024 ;14 1338022

Looking beyond year 1 in the molecular era of pediatric brain tumor diagnosis: confirmatory testing of germline variants found on tumor sequencing.

Brittany L Greene, Shannon M Stasi, Michelle A Ting, Natalie Waligorski, Bonnie L Cole, Christina M Lockwood, Vera A Paulson, Jillian G Buchan, Amy Lee, Jeffrey G Ojemann, Richard G Ellenbogen, Jeffrey Stevens, Sarah E S Leary.

Purpose: Somatic molecular profiling of pediatric brain tumors aids with the diagnosis and treatment of patients with a variety of high- and low-grade central nervous system neoplasms. Here, we report follow-up targeted germline evaluation for patients with possible germline variants following tumor only testing in the initial year in which somatic molecular testing was implemented at a single institution.
Patients and Methods: Somatic testing was completed for all tumors of the central nervous system (CNS) undergoing diagnostic workup at Seattle Children's Hospital during the study period of November 2015 to November 2016. Sequencing was performed in a College of American Pathologists-accredited, Clinical Laboratory Improvements Amendments-certified laboratory using UW-OncoPlex™ assay (version 5), a DNA-based targeted next generation sequencing panel validated to detect genetic alterations in 262 cancer-related genes. We tracked subsequent clinical evaluation and testing on a subgroup of this cohort found to have potential germline variants of interest.
Results: Molecular sequencing of 88 patients' tumors identified 31 patients with variants that warranted consideration of germline testing. To date, 19 (61%) patients have been tested. Testing confirmed germline variants for ten patients (31% of those identified for testing), one with two germline variants (NF1 and mosaic TP53). Eight (26%) patients died before germline testing was sent. One patient (13%) has not yet had testing.
Conclusion: Clinically validated molecular profiling of pediatric brain tumors identifies patients who warrant further germline evaluation. Despite this, only a subset of these patients underwent the indicated confirmatory sequencing. Further work is needed to identify barriers and facilitators to this testing, including the role of genetic counseling and consideration of upfront paired somatic-germline testing.

Keywords: brain tumor; childhood cancer; germline; molecular testing; next-generation sequencing

DOI: https://doi.org/10.3389/fonc.2024.1338022

Fam Cancer. 2024 Mar 16.

Progress report: Peutz-Jeghers syndrome.

Anne Marie Jelsig, John Gásdal Karstensen, Thomas V Overeem Hansen.

Peutz-Jeghers syndrome is a rare, autosomal dominant polyposis syndrome. Presenting with a remarkable phenotype including development of characteristic gastrointestinal polyps, mucocutaneous pigmentations, and an increased risk of cancer, the syndrome has been subject to many studies concerning the natural course of disease. In most patients, pathogenic germline variants are detected in the STK11 gene including cases of mosaicism and structural variants. Yet, studies assessing the effect of surveillance, understanding of cancer development, as well as clinical studies evaluating chemoprevention are lacking. In addition, the impact of Peutz-Jeghers syndrome on mental health, education, and family planning are insufficiently addressed. In this progress report, we describe current knowledge, clinical phenotype, surveillance strategies, and future areas of research.

Keywords: Germline; Hamartomatous; Hereditary; Peutz–Jeghers syndrome; Polyposis; STK11

DOI: https://doi.org/10.1007/s10689-024-00362-7

Sci Rep. 2024 03 20. 14(1): 6702

Characteristics of germline DNA damage response gene mutations in ovarian cancer in Southwest China.

Kaiyu Fu, Qingli Li, Jie Wang, Mengpei Zhang, Xinyu Yan, Kemin Li, Liang Song, Lan Zhong, Yu Ma, Jinghong Chen, Jing Zeng, Danqing Wang, Di Shao, Shida Zhu, Rutie Yin.

DNA damage response (DDR) pathways are responsible for repairing endogenous or exogenous DNA damage to maintain the stability of the cellular genome, including homologous recombination repair (HRR) pathway, mismatch repair (MMR) pathway, etc. In ovarian cancer, current studies are focused on HRR genes, especially BRCA1/2, and the results show regional and population differences. To characterize germline mutations in DDR genes in ovarian cancer in Southwest China, 432 unselected ovarian cancer patients underwent multi-gene panel testing from October 2016 to October 2020. Overall, deleterious germline mutations in DDR genes were detected in 346 patients (80.1%), and in BRCA1/2 were detected in 126 patients (29.2%). The prevalence of deleterious germline mutations in BRCA2 is higher than in other studies (patients are mainly from Eastern China), and so is the mismatch repair genes. We identified three novel BRCA1/2 mutations, two of which probably deleterious (BRCA1 p.K1622* and BRCA2 p.L2987P). Furthermore, we pointed out that deleterious mutations of FNACD2 and RECQL4 are potential ovarian cancer susceptibility genes and may predispose carriers to ovarian cancer. In conclusion, our study highlights the necessity of comprehensive germline mutation detection of DNA damage response genes in ovarian cancer patients, which is conducive to patient management and genetic counseling.

DOI: https://doi.org/10.1038/s41598-024-52707-y