A deep intronic recurrent CHEK2 variant c.1009-118_1009-87delinsC affects pre-mRNA splicing and contributes to hereditary breast cancer predisposition

Zemankova, Petra; Cerna, Marta; Horackova, Klara; Ernst, Corinna; Soukupova, Jana; Borecka, Marianna; Blümcke, Britta; Cerna, Leona; Cerna, Monika; Curtisova, Vaclava; Dolezalova, Tatana; Duskova, Petra; Dvorakova, Lenka; Foretova, Lenka; Havranek, Ondrej; Hauke, Jan; Hahnen, Eric; Hodulova, Miloslava; Hovhannisyan, Milena; Hruskova, Lucie; Janatova, Marketa; Janikova, Maria; Jelinkova, Sandra; Just, Pavel; Kosarova, Marcela; Koudova, Monika; Krutilkova, Vera; Machackova, Eva; Matejkova, Katerina; Michalovska, Renata; Misove, Adela; Nehasil, Petr; Nemcova, Barbora; Novotny, Jan; Panczak, Ales; Pesek, Pavel; Scheinost, Ondrej; Springer, Drahomira; Stastna, Barbora; Stranecky, Viktor; Subrt, Ivan; Tavandzis, Spiros; Tureckova, Eva; Vesela, Kamila; Vlckova, Zdenka; Vocka, Michal; Wappenschmidt, Barbara; Zima, Tomas; Kleibl, Zdenek; Kleiblova, Petra

doi:10.1016/j.breast.2024.103721

The Breast

2024

DOI: 10.1016/j.breast.2024.103721

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A deep intronic recurrent CHEK2 variant c.1009-118_1009-87delinsC affects pre-mRNA splicing and contributes to hereditary breast cancer predisposition

Petra Zemankova,

Marta Cerna,

Klara Horackova

et al.

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Cited by 2 publications

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A comprehensive analysis of germline predisposition to early-onset ovarian cancer

Horackova,

Zemankova,

Nehasil

et al. 2024

Sci Rep

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The subset of ovarian cancer (OC) diagnosed ≤ 30yo represents a distinct subgroup exhibiting disparities from late-onset OC in many aspects, including indefinite germline cancer predisposition. We performed DNA/RNA-WES with HLA-typing, PRS assessment and survival analysis in 123 early-onset OC-patients compared to histology/stage-matched late-onset and unselected OC-patients, and population-matched controls. Only 6/123(4.9%) early-onset OC-patients carried a germline pathogenic variant (GPV) in high-penetrance OC-predisposition genes. Nevertheless, our comprehensive germline analysis of early-onset OC-patients revealed two divergent trajectories of potential germline susceptibility. Firstly, overrepresentation analysis highlighted a connection to breast cancer (BC) that was supported by the CHEK2 GPV enrichment in early-onset OC(p = 1.2 × 10–4), and the presumably BC-specific PRS313, which successfully stratified early-onset OC-patients from controls(p = 0.03). The second avenue pointed towards the impaired immune response, indicated by LY75-CD302 GPV(p = 8.3 × 10–4) and diminished HLA diversity compared with controls(p = 3 × 10–7). Furthermore, we found a significantly higher overall GPV burden in early-onset OC-patients compared to controls(p = 3.8 × 10–4). The genetic predisposition to early-onset OC appears to be a heterogeneous and complex process that goes beyond the traditional Mendelian monogenic understanding of hereditary cancer predisposition, with a significant role of the immune system. We speculate that rather a cumulative overall GPV burden than specific GPV may potentially increase OC risk, concomitantly with reduced HLA diversity.

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A comprehensive analysis of germline predisposition to early-onset ovarian cancer

Horackova,

Zemankova,

Nehasil

et al. 2024

Sci Rep

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Understanding genetic variations associated with familial breast cancer

Pal,

Das,

Pandey

2024

World J Surg Onc

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Background Breast cancer is the most frequent cancer among women. Genetics are the main risk factor for breast cancer. Statistics show that 15–25% of breast cancers are inherited among those with cancer-prone relatives. BRCA1, BRCA2, TP53, CDH1, PTEN, and STK11 are the most frequent genes for familial breast cancer, which occurs 80% of the time. In rare situations, moderate-penetrance gene mutations such CHEK2, BRIP1, ATM, and PALB2 contribute 2–3%. Methods A search of the PubMed database was carried out spanning from 2005 to July 2024, yielding a total of 768 articles that delve into the realm of familial breast cancer, concerning genes and genetic syndromes. After exclusion 150 articles were included in the final review. Results We report on a set of 20 familial breast cancer -associated genes into high, moderate, and low penetrance levels. Additionally, 10 genetic disorders were found to be linked with familial breast cancer. Conclusion Familial breast cancer has been linked to several genetic diseases and mutations, according to studies. Screening for genetic disorders is recommended by National Comprehensive Cancer Network recommendations. Evaluation of breast cancer candidate variations and risk loci may improve individual risk assessment. Only high- and moderate-risk gene variations have clinical guidelines, whereas low-risk gene variants require additional investigation. With increasing use of NGS technology, more linkage with rare genes is being discovered.

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A deep intronic recurrent CHEK2 variant c.1009-118_1009-87delinsC affects pre-mRNA splicing and contributes to hereditary breast cancer predisposition

Cited by 2 publications

References 23 publications

A comprehensive analysis of germline predisposition to early-onset ovarian cancer

A comprehensive analysis of germline predisposition to early-onset ovarian cancer

Understanding genetic variations associated with familial breast cancer

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