Germline mutations in<i>WNK2</i>could be associated with serrated polyposis syndrome

Lima, Yasmin Soares de; Arnau‐Collell, Coral; Muñoz, Jenifer; Herrera‐Pariente, Cristina; Moreira, Letícia; Ocaña, Teresa; Díaz‐Gay, Marcos; Franch-Expósito, Sebastià; Cuatrecasas, Míriam; Carballal, Sabela; López-Novo, Anael; Moreno, Lorena; Fernàndez, Guerau; Bustamante, Aránzazu Díaz de; Peters, Sophia; Sommer, Anna; Spier, Isabel; Paske, Iris B A W Te; Herwaarden, Yasmijn van; Castells, Antoni; Bujanda, Luís; Capellà, Gabriel; Steinke‐Lange, Verena; Mahmood, Khalid; Joo, Jihoon E.; Arnold, Julie; Parry, Susan; Macrae, Finlay; Winship, Ingrid; Rosty, Christophe; Cubiella, Joaquín; Rodríguez‐Alcalde, Daniel; Holinski‐Feder, Elke; Voer, Richarda M. de; Buchanan, Daniel D.; Aretz, Stefan; Ruíz-Ponte, Clara; Valle, Laura; Balaguer, Francesc; Bonjoch, Laia; Castellví–Bel, Sergi

doi:10.1136/jmg-2022-108684

Cited by 4 publications

(1 citation statement)

References 51 publications

(108 reference statements)

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“…Polyposis-related genes are not commonly altered in SPS patients ( Clendenning et al, 2013 ); but some isolated SPS cases harbor putatively pathogenic variants in MUTYH ( Chow et al, 2006 ; Boparai et al, 2008 ; Murphy et al, 2022 ), SMAD4, CHEK2 and POLD1 ( Murphy et al, 2022 ). Our research group has conducted germline sequencing analyses and has proposed new potential high-penetrance genes ( Toma et al, 2020 ; Soares de Lima et al, 2021 ; 2022 ) and low-penetrance variants ( Arnau-Collell et al, 2020 ) that could be associated with SPS susceptibility.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome

Bonjoch

Lima²,

Díaz‐Gay³

et al. 2023

Front. Mol. Biosci.

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Serrated polyposis syndrome (SPS) is one of the most frequent polyposis syndromes characterized by an increased risk for developing colorectal cancer (CRC). Although SPS etiology has been mainly associated with environmental factors, germline predisposition to SPS could also be relevant for cases with familial aggregation or a family history of SPS/CRC. After whole-exome sequencing of 39 SPS patients from 16 families, we identified a heterozygous germline frameshift variant in the POLD1 gene (c.1941delG, p.(Lys648fs*46)) in a patient with SPS and CRC. Tumor presented an ultra-hypermutated phenotype and microsatellite instability. The POLD1 germline variant segregated in three additional SPS-affected family members. We attempted to create yeast and cellular models for this variant but were no viable. Alternatively, we generated patient-derived organoids (PDOs) from healthy rectal tissue of the index case, as well as from a control donor. Then, we challenged PDOs with a DNA-damaging agent to induce replication stress. No significant differences were observed in the DNA damage response between control and POLD1-Lys648fs PDOs, nor specific mutational signatures were observed. Our results do not support the pathogenicity of the analyzed POLD1 frameshift variant. One possible explanation is that haplosufficiency of the wild-type allele may be compensating for the absence of expression of the frameshift allele. Overall, future work is required to elucidate if functional consequences could be derived from POLD1 alterations different from missense variants in their proofreading domain. To our knowledge, our study presents the first organoid model for germline POLD1 variants and establishes the basis for its use as a model for disease in SPS, CRC and other malignancies.

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Section: Introductionmentioning

confidence: 99%

Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome

Bonjoch

Lima²,

Díaz‐Gay³

et al. 2023

Front. Mol. Biosci.

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Genetic predisposition to gastrointestinal polyposis: syndromes, tumour features, genetic testing, and clinical management

Valle,

Monahan

2024

The Lancet Gastroenterology & Hepatology

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Modifiable factors of development and recurrence of adenomatous colorectal polyps (literature review)

Gataullin,

Sakhabetdinov,

Valitov

et al. 2024

vmirvz

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Relevance. Adenomatous colorectal polyps are associated with a high risk of developing a malignant tumor. They are considered precancerous conditions and can lead to the development of colorectal cancer. To date, colorectal cancer ranks third in the world in frequency of occurrence among all malignant neoplasms.Objective. Improving the results of diagnosis and surgical treatment of patients with colorectal adenomatous neoplasms by identifying development factors and identifying risk groups for this nosology.Materials and methods. Analysis of literary data.Results. Among the factors leading to the development of colorectal polyps, it is worth noting a genetic predisposition, so by immunoblotting, PCR sequencing of the entire exome in cases of patients with familial dentate polyposis, rare variants of the germ line in the WNK2 gene were identified. Functional studies have shown that variants of the WINK2 germ line affect protein function in the context of the MAPK pathway, a molecular trait of this disease. Also, in the course of many domestic and foreign randomized clinical trials, the following modifiable factors for the development of adenomatous colorectal polyps were identified.Conclusion. The study revealed the factors of development and recurrence of colorectal neoplasms and identified risk groups for this nosology. The study revealed low compliance of patients with respect to changes in certain living conditions (the use of ethyl alcohol and products containing it, tobacco smoking, both active and passive, the fight against obesity and inactivity), which leads to recurrence and increases the risks of malignancy of colorectal polyps.

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Germline mutations inWNK2could be associated with serrated polyposis syndrome

Cited by 4 publications

References 51 publications

Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome

Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome

Genetic predisposition to gastrointestinal polyposis: syndromes, tumour features, genetic testing, and clinical management

Modifiable factors of development and recurrence of adenomatous colorectal polyps (literature review)

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