Impact of <scp><i>PPM1D</i></scp> mutations in patients with myelodysplastic syndrome and deletion of chromosome 5q

Panagiota, Victoria; Meggendorfer, Manja; Kubasch, Anne Sophie; Gabdoulline, Razif; Krönke, Jan; Mies, Anna; Shahswar, Rabia; Kandziora, Christian; Klement, Piroska; Schiller, Johannes; Göhring, Gudrun; Haferlach, Claudia; Ganster, Christina; Shirneshan, Katayoon; Gutermuth, Annika; Thiede, Christian; Germing, Ulrich; Schroeder, Thomas; Kobbe, Guido; Klesse, Sabrina; Koenecke, Christian; Schlegelberger, Brigitte; Haase, Detlef; Döhner, Konstanze; Sperr, Wolfgang R.; Valent, Peter; Ganser, Arnold; Thol, Felicitas; Haferlach, Torsten; Platzbecker, Uwe; Heuser, Michael

doi:10.1002/ajh.26162

Cited by 2 publications

(1 citation statement)

References 6 publications

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“…PPM1D is known to be a negative regulator of p53 and other tumor suppressors, and somatic variants are found in multiple malignancies (Graf et al, 2022; Khadka et al, 2022). There are several individuals with stop gain variants designated as ClinVar pathogenic/likely pathogenic in gnomAD, though at least one is present in an older individual; these may represent somatic variants acquired in the setting of clonal hematopoiesis of indeterminate potential, as has been reported with this gene, particularly in association with myelodysplastic syndromes (Panagiota et al, 2021; Zink et al, 2017) and has been previously seen in other highly penetrant, autosomal dominant conditions (Carlston et al, 2017). To our knowledge, there are no reports of individuals with JdVS and concurrent malignancies.…”

Section: Discussionmentioning

confidence: 99%

Jansen‐de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families

Wojcik

Srivastava

Agrawal

et al. 2023

American J of Med Genetics Pt A

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Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.

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Section: Discussionmentioning

confidence: 99%

Jansen‐de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families

Wojcik

Srivastava

Agrawal

et al. 2023

American J of Med Genetics Pt A

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PPM1D in Solid and Hematologic Malignancies: Friend and Foe?

Zhang

Hsu

Goodell

2022

Molecular Cancer Research

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In the face of constant genomic insults, the DNA damage response (DDR) is initiated to preserve genome integrity; its disruption is a classic hallmark of cancer. Protein phosphatase Mg2+/Mn2+–dependent 1D (PPM1D) is a central negative regulator of the DDR that is mutated or amplified in many solid cancers. PPM1D overexpression is associated with increased proliferative and metastatic behavior in multiple solid tumor types and patients with PPM1D-mutated malignancies have poorer prognoses. Recent findings have sparked an interest in the role of PPM1D in hematologic malignancies. Acquired somatic mutations may provide hematopoietic stem cells with a competitive advantage, leading to a substantial proportion of mutant progeny in the peripheral blood, an age-associated phenomenon termed “clonal hematopoiesis” (CH). Recent large-scale genomic studies have identified PPM1D to be among the most frequently mutated genes found in individuals with CH. While PPM1D mutations are particularly enriched in patients with therapy-related myeloid neoplasms, their role in driving leukemic transformation remains uncertain. Here, we examine the mechanisms through which PPM1D overexpression or mutation may drive malignancy by suppression of DNA repair, cell-cycle arrest, and apoptosis. We also discuss the divergent roles of PPM1D in the oncogenesis of solid versus hematologic cancers with a view to clinical implications and new therapeutic avenues.

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Impact of PPM1D mutations in patients with myelodysplastic syndrome and deletion of chromosome 5q

Cited by 2 publications

References 6 publications

Jansen‐de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families

Jansen‐de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families

PPM1D in Solid and Hematologic Malignancies: Friend and Foe?

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