bims-lifras 2024-07-14 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2024–07–14
seven papers selected by
Joanna Zawacka, Karolinska Institutet

The Crucial Role of Hereditary Cancer Panel Testing in Unaffected Individuals with a Strong Family History of Cancer: A Retrospective Study of a Cohort of 103 Healthy Subjects.
Germline rare variants in HER2-positive breast cancer predisposition: a systematic review and meta-analysis.
Disparate Rates of Germline Variants in Cancer Predisposition Genes in African American/Black Compared With Non-Hispanic White Individuals Between 2015 and 2022.
BRCA-associated hereditary male cancers: can gender affect the prevalence and spectrum of germline pathogenic variants?
Germline ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition.
Genotype matters: Personalized screening recommendations for germline CHEK2 variants.
Germline Sequencing of DNA Damage Repair Genes in Two Hereditary Prostate Cancer Cohorts Reveals New Disease Risk-Associated Gene Variants.

Cancers (Basel). 2024 Jun 25. pii: 2327. [Epub ahead of print]16(13):

The Crucial Role of Hereditary Cancer Panel Testing in Unaffected Individuals with a Strong Family History of Cancer: A Retrospective Study of a Cohort of 103 Healthy Subjects.

Lucrezia Pilenzi, Federico Anaclerio, Anastasia Dell'Elice, Maria Minelli, Roberta Giansante, Michela Cicirelli, Nicola Tinari, Antonino Grassadonia, Andrea Pantalone, Simona Grossi, Nicole Canale, Annalisa Bruno, Giuseppe Calabrese, Patrizia Ballerini, Liborio Stuppia, Ivana Antonucci.

  Hereditary cancer syndromes caused by germline mutations account for 5-10% of all cancers. The finding of a genetic mutation could have far-reaching consequences for pharmaceutical therapy, personalized prevention strategies, and cascade testing. According to the National Comprehensive Cancer Network's (NCCN) and the Italian Association of Medical Oncology (AIOM) guidelines, unaffected family members should be tested only if the affected one is unavailable. This article explores whether germline genetic testing may be offered to high-risk families for hereditary cancer even if a living affected relative is missing. A retrospective study was carried out on 103 healthy subjects tested from 2017 to 2023. We enrolled all subjects with at least two first- or second-degree relatives affected by breast, ovarian, pancreatic, gastric, prostate, or colorectal cancer. All subjects were tested by Next Generation Sequencing (NGS) multi-gene panel of 27 cancer-associated genes. In the study population, 5 (about 5%) pathogenic/likely pathogenic variants (PVs/LPVs) were found, while 40 (42%) had a Variant of Uncertain Significance (VUS). This study highlights the importance of genetic testing for individuals with a strong family history of hereditary malignancies. This approach would allow women who tested positive to receive tailored treatment and prevention strategies based on their personal mutation status.

Keywords:  NGS multigene panel; hereditary cancer; unaffected family member

DOI:  https://doi.org/10.3390/cancers16132327
Front Oncol. 2024 ;14 1395970

Germline rare variants in HER2-positive breast cancer predisposition: a systematic review and meta-analysis.

Angelica Cerveira de Baumont, Nathan Araujo Cadore, Luana Giongo Pedrotti, Giovana Dallaio Curzel, Jaqueline Bohrer Schuch, Marina Bessel, Cláudia Bordignon, Mahira Lopes Rosa, Gabriel de Souza Macedo, Daniela Dornelles Rosa.

   Introduction: Approximately 10% of breast cancer (BC) cases result from hereditary causes. Genetic testing has been widely implemented in BC care to determine hereditary cancer syndromes and personalized medicine. Thus, identification of individuals carrying germline pathogenic variants could be useful to provide appropriate prophylactic or screening measures for each BC subtype, however, there are few formal recommendations for genetic testing in this sense so far. In this study, we assessed rare germline variants in a specific group of genes in order to determine the association with human epidermal growth factor 2 enriched (HER2+) BC phenotype through a systematic review and meta-analysis comparing subtypes overexpressing HER2 with other clinically recognized subtypes of BC. This review was registered with PROSPERO (ID: CRD42023447571).
Methods: We conducted an online literature search in PubMed (MEDLINE), Scopus, and EMBASE databases. We included original studies that investigated germline variants in HER2+ BC patients and selected the studies that reported only rare and/or pathogenic germline variants. We assessed the risk of bias and quality of the studies using the Joanna Briggs Institute Critical Appraisal checklists and the Modified Newcastle-Ottawa Scale for Genetic Studies, respectively. Considering hormone receptor and HER2 expression status, we compared gene-based risks initially in HR-HER2-, HR+HER2-, HR+HER2+, and HR-HER2+ groups, conducting separate meta-analyses using the random effects model for each comparison, and within them for each gene.
Results: Of the total 36 studies describing germline variants, 11 studies provided information on the prevalence of variants in the different clinically relevant BC subtypes and allowed comparisons. Germline variants within eight genes showed significant differences when meta-analyzed between the BC groups: BRCA1, BRCA2, TP53, ATM, CHEK2, PALB2, RAD51C, and BARD1. Notably, TP53, ATM, and CHEK2 germline variants were identified as predisposing factors for HER2+ subtypes, whereas BRCA1, BRCA2, PALB2, RAD51C, and BARD1 germline variants were associated with a predisposition to low HER2 expression. Main concerns about bias and quality assessment were the lack of confounding factors control; and comparability or outcome assessment, respectively.
Discussion: Our findings underscore the connection between germline variants and differential expression of the HER2 protein and BC subtypes.
Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023447571.

Keywords:  BRCA; HER2+; Hereditary breast cancer; TP53; pathogenic variants

DOI:  https://doi.org/10.3389/fonc.2024.1395970
JCO Precis Oncol. 2024 Jul;8 e2300715

Disparate Rates of Germline Variants in Cancer Predisposition Genes in African American/Black Compared With Non-Hispanic White Individuals Between 2015 and 2022.

Rachel B Wyatt Castillo, Sarah M Nielsen, Elaine Chen, Brandie Heald, Rachel E Ellsworth, Edward D Esplin, Gail E Tomlinson.

PURPOSE: African American/Black (AA/B) individuals are under-represented in genomic databases and thus less likely to receive definitive information from germline genetic testing (GGT) than non-Hispanic White (NHW) individuals. With nearly 500,000 AA/B and NHW individuals having undergone multigene panel testing (MGPT) for hereditary cancer risk at a single commercial laboratory, to our knowledge, we present the largest study to date investigating cancer GGT results in AA/B and NHW individuals.
METHODS: MGPT results from a retrospective cohort of AA/B (n = 48,684) and NHW (n = 444,831) patients were evaluated. Frequencies of pathogenic germline variants (PGVs) and variants of uncertain significance (VUS) were compared between AA/B and NHW individuals. Changes in frequency of VUS over time were determined. Pearson's chi-squared test was used to compare categorical variables among groups. All significance tests were two-tailed, and P < .05 was considered statistically significant.
RESULTS: Between 2015 and 2022, rates of VUS decreased 2.3-fold in AA/B and 1.8-fold in NHW individuals; however, frequencies of VUS and PGV remained significantly higher (46% v 32%; P < .0001) and lower (9% v 13%; P < .0001) in AA/B compared with NHW individuals. Rates of VUS in ATM, BRCA1, BRCA2, PALB2, and PMS2 were significantly higher in AA/B compared with NHW individuals, whereas rates of PGV in BRCA1, BRCA2, and PALB2 were higher in AA/B compared with NHW individuals (P < .001).
CONCLUSION: Despite reductions in VUS frequencies over time, disparities in definitive GGT results persist. Increasing inclusion of AA/B populations in both testing and research will further increase knowledge of genetic variants across these racial groups.

DOI: https://doi.org/10.1200/PO.23.00715
Front Oncol. 2024 ;14 1414343

BRCA-associated hereditary male cancers: can gender affect the prevalence and spectrum of germline pathogenic variants?

Daniele Fanale, Lidia Rita Corsini, Chiara Brando, Ugo Randazzo, Marco Bono, Erika Pedone, Alessandro Perez, Roberta Sciacchitano, Daniela Cancelliere, Paola Piraino, Ambra Giurintano, Tancredi Didier Bazan Russo, Pietro Ferraro, Gaetana Rinaldi, Valeria Spinnato, Vincenzo Gennusa, Gianfranco Pernice, Salvatore Vieni, Gianni Pantuso, Antonio Russo, Viviana Bazan.

   Introduction: Although hereditary male neoplasms are quite rare, individuals harbouring germline BRCA1/2 pathogenic variants (PVs) may have a risk of developing tumours associated with Hereditary Breast and Ovarian Cancer (HBOC) syndrome, including male breast (MBC), prostate (PCa) and pancreatic (PC) cancers, and melanoma. Women and men showed a comparable genetic architecture of cancer susceptibility, but there are some gender-specific features. Since little is known about cancer genetic susceptibility in male population, our study was aimed at investigating the frequency of BRCA1/2 PVs in men with HBOC syndrome-associated tumors, in order to understand whether differences in gender may reflect in the prevalence and spectrum of germline alterations.
Patients and methods: We retrospectively collected and analysed clinical information of 352 HBOC-associated male cancer patients genetically tested for germline BRCA1/2 PVs by Next-Generation Sequencing analysis, enrolled, from February 2018 to January 2024, at the "Regional Center for the prevention, diagnosis and treatment of rare and heredo-familial tumors of adults" of the University-Hospital Policlinico "P. Giaccone" of Palermo (Italy).
Results: Our investigation revealed that 7.4% of patients was carrier of a germline BRCA PV, with an almost total prevalence of BRCA2 alterations. In particular, 65.4% of BRCA-positive patients developed MBC, 19.2% had PC, 11.6% developed PCa, and only 3.8% had melanoma. Specifically, MBC individuals showed a BRCA-associated genetic predisposition in 17% of cases, whereas patients with PCa or PC exhibited a lower frequency of BRCA2 PVs, taking into account the current national criteria for access to germline genetic testing.
Discussion: Our study showed a high heterogeneity in prevalence of germline BRCA2 PVs among men which could reflect a potential gender-specific genetic heterogeneity. Therefore, BRCA-associated male tumours could be due to BRCA2 PVs different from those usually detected in women. In the event that it is demonstrated, in future, that male cancers are genetically distinct entities from those female this could improve personalized risk evaluation and guide therapeutic choices for patients of both sexes, in order to obtain a gender equality in cancer care.

Keywords:  BRCA1; BRCA2; HBOC; germline pathogenic variants; male breast cancer; melanoma; pancreatic cancer; prostate cancer

DOI:  https://doi.org/10.3389/fonc.2024.1414343
Blood. 2024 Jul 11. pii: blood.2024024607. [Epub ahead of print]

Germline ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition.

Jiarna Rose Zerella, Claire C Homan, Peer Arts, Xuzhu Lin, Sam John Spinelli, Parvathy Venugopal, Milena Babic, Peter Brautigan, Lynda Truong, Luis Alberto Arriola-Martinez, Sarah Moore, Rachel Hollins, Wendy Parker, Hung Nguyen, Karin S Kassahn, Susan Branford, Simone K Feurstein, Lise Larcher, Flore Sicre de Fontbrune, Serwet Demirdas, Sonja de Munnik, Hélène A Poirel, Benedicte Brichard, Sahar Mansour, Kristiana Gordon, Erg Variants Research Network, Marcin W Wlodarski, Ashwin Lakshman Koppayi, Sara Dobbins, Pim G N J Mutsaers, Kim E Nichols, Ninad Oak, Desiree DeMille, Rong Mao, Ali Crawford, Julie McCarrier, Donald Basel, Josue Flores-Daboub, Michael W Drazer, Kerry Phillips, Nicola Poplawski, Graeme M Birdsey, Daniela Pirri, Pia Ostergaard, Annet Simons, Lucy A Godley, David M Ross, Devendra K Hiwase, Jean Soulier, Anna L Brown, Catherine L Carmichael, Hamish S Scott, Christopher N Hahn.

The genomics era has facilitated discovery of new genes predisposing to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ERG as a novel autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor critical for definitive hematopoiesis, stem cell function and platelet maintenance. ERG colocalizes with other transcription factors including RUNX1 and GATA2 on promoters/enhancers of genes orchestrating hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 thrombocytopenic individuals from one family and 14 additional ERG variants in unrelated individuals with BMF/HM including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germline ERG variants included cytopenias (thrombocytopenia, neutropenia, pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense, 1 truncating) including 3 missense population variants were functionally characterized. Thirteen potentially pathogenic ETS domain missense variants displayed loss-of-function characteristics disrupting transcriptional transactivation, DNA-binding and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture, and to promote acute erythroleukemia when transplanted into mice, concordant with these variants being loss-of-function. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germline ERG variants has clinical implications for patient/family diagnosis, counselling, surveillance, and treatment strategies including selection of bone marrow donors or cell/gene therapy.

DOI: https://doi.org/10.1182/blood.2024024607
Oncotarget. 2024 Jul 10. 15 459-460

Genotype matters: Personalized screening recommendations for germline CHEK2 variants.

Adela Rodriguez Hernandez, Rochelle Scheib, Judy E Garber, Huma Q Rana, Brittany L Bychkovsky.



Keywords:  CHEK2; germline; pathogenic or likely pathogenic variants

DOI:  https://doi.org/10.18632/oncotarget.28604
Cancers (Basel). 2024 Jul 07. pii: 2482. [Epub ahead of print]16(13):

Germline Sequencing of DNA Damage Repair Genes in Two Hereditary Prostate Cancer Cohorts Reveals New Disease Risk-Associated Gene Variants.

Georgea R Foley, James R Marthick, Sionne E Lucas, Kelsie Raspin, Annette Banks, Janet L Stanford, Elaine A Ostrander, Liesel M FitzGerald, Joanne L Dickinson.

  Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (MQLS) undertaken. In the combined datasets, rare ERCC3 (rs145201970, p = 2.57 × 10-4) and BRIP1 (rs4988345, p = 0.025) variants were significantly associated with PrCa risk. A PARP2 (rs200603922, p = 0.028) variant in the Australian dataset and a MUTYH (rs36053993, p = 0.031) variant in the North American dataset were also associated with risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies.

Keywords:  DNA repair; genetic susceptibility; germline variants; prostate cancer; rare high-risk genes

DOI:  https://doi.org/10.3390/cancers16132482