A high prevalence of myeloid malignancies in progeria with Werner syndrome is associated with p53 insufficiency

Kato, Hisaya; Maezawa, Yoshiro; Nishijima, Dai; Iwamoto, Eisuke; Takeda, June; Kanamori, Takashi; Yamaga, Masaya; Mishina, Tatsuzo; Takeda, Yusuke; Izumi, Shintaro; Hino, Yutaro; Nishi, Hiroyuki; Ishiko, Jun; Takeuchi, Masahiro; Kaneko, Hiromi; Koshizaka, Masaya; Mimura, Naoya; Kuzuya, Masafumi; Sakaida, Emiko; Takemoto, Minoru; Shiraishi, Yuichi; Miyano, Satoru; Ogawa, Seishi; Iwama, Atsushi; Sanada, Masashi; Yokote, Koutaro

doi:10.1016/j.exphem.2022.02.005

Cited by 6 publications

(5 citation statements)

References 24 publications

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“…The Werner syndrome ATP-dependent helicase (WRN) is a RecQ enzyme involved in the maintenance of genome integrity. WRN is associated with Werner syndrome and a predisposition to multiple cancers, such as multiple myeloma [ 28 ], myelodysplastic syndrome/acute myeloid leukemia [ 29 ], colorectal cancer [ 30 ], breast cancer [ 31 ], and ovarian cancer [ 32 ]. WRN contributes to chromosomal stability for survival in both normal and cancer cells [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry

Maeda

Koshizaka

Shoji

et al. 2023

Aging

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Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease. Fifty-one patients were enrolled and registered in the Werner Syndrome Registry. Their data were collected annually following registration. A cross-sectional analysis at registration and a longitudinal analysis between the baseline and each subsequent year was performed. Pearson's chi-squared and Wilcoxon signed-rank tests were used. Malignant neoplasms were observed from the fifth decade of life (mean onset: 49.7 years) and were observed in approximately 30% of patients during the 3-year survey period. Regarding renal function, the mean estimated glomerular filtration rate calculated from serum creatinine (eGFRcre) and eGFRcys, which were calculated from cystatin C in the first year, were 98.3 and 83.2 mL/min/1.73 m 2 , respectively, and differed depending on the index used. In longitudinal analysis, the average eGFRcre for the first and fourth years was 74.8 and 63.4 mL/min/1.73 m 2 , showing a rapid decline. Secular changes in Werner syndrome in multiple patients were identified. The prevalence of malignant neoplasms is high, and renal function may decline rapidly. It is, therefore, necessary to carry out active and detailed examinations and pay attention to the type and dose of the drugs used.

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Section: Discussionmentioning

confidence: 99%

Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry

Maeda

Koshizaka

Shoji

et al. 2023

Aging

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“…Interestingly, while haematological tumour deaths have been declining as well (2005, 22.4 per 100,000; 2019, 19.5 per 100,000), their share of total tumour deaths have increased slightly (2005, 16.0%; 2019, 17.3%) [ 18 ]. However, this prevalence is far smaller than the percentage of haematological tumour deaths in WS; tumour development in WS, unlike atherosclerotic disease, might depend on a WS-specific mechanism [ 19 ].…”

Section: Discussion/conclusionmentioning

confidence: 99%

Lifetime extension and the recent cause of death in Werner syndrome: a retrospective study from 2011 to 2020

Kato

Koshizaka

Kaneko

et al. 2022

Orphanet J Rare Dis

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Background Werner syndrome (WS) is an autosomal recessive premature ageing disease that causes accelerated ageing-like symptoms after puberty. Previous studies conducted in the late 2000s reported that malignant neoplasms and atherosclerotic diseases were the two leading causes of death, with life expectancies in the mid-50 s. However, the recent lifespan and cause of death in patients with WS remain unclear. Objective To clarify the latest lifespan and causes of death in patients with WS. Method We conducted a questionnaire-based survey in 2020 among the primary doctors of WS patients who were identified in previous nationwide surveys in Japan and clarified the following: the age of WS patients (age of death, if the patient had already died), sex, and cause of death. Patients who died in 2010 or earlier were excluded from the analysis. Results A total of 123 living patients were identified at the time of the survey in 2020. Fourteen WS patients died between 2011 and 2020, with a mean age of 59.0 ± 8.9 years (mean ± SD). The most common cause of death was non-epithelial tumours, accounting for eight deaths, while no patient died of atherosclerotic diseases. Conclusions Compared to previous studies, this study suggests that the lifespan of patients with WS has been extended. Although there were no deaths due to atherosclerotic diseases, non-epithelial tumours were still the leading cause of death. Further development of screening and treatment methods for these tumours is required.

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“…Werner syndrome patients with WRN mutations were easy to obtain p53 gene mutations or related chromosomal abnormalities, and this was different from other MDS/AML patients' changes in cellular or molecular genetic material. In hematopoietic stem cells, WRN function loss could result in p53 inactivation and acquirer of competitive fitness and then develop into myeloid malignancies (12), which may increase chemosensitivity. CHK1-related homologous recombination repair (HRR) in WRN defection cells was the key approach for repairing double-strand breaks (DSB) caused by ionizing radiation, which resulted in hyper-radiosensitization (13).…”

Section: Discussionmentioning

confidence: 99%

Case Report: A novel WRN mutation in Werner syndrome patient with diabetic foot disease and myelodysplastic syndrome

et al. 2022

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Werner syndrome is an autosomal recessive rare disease caused by a WRN gene mutation, which is rarely reported in the Chinese population. We report the clinical and genetic data of a Chinese patient with Werner syndrome. The proband was a 40-year-old male patient who presented with diabetic foot ulcers, accompanied by short stature, cataracts, hypogonadism, and hair thinning, and myelodysplastic syndrome (MDS) occurred after 18 months. Genetic sequencing showed there were compound heterozygous mutations as c.3384-1G>C and c.3744dupA in the WRN gene. The c.3744dupA mutation is a novel pathogenic variation for Werner syndrome.

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A high prevalence of myeloid malignancies in progeria with Werner syndrome is associated with p53 insufficiency

Cited by 6 publications

References 24 publications

Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry

Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry

Lifetime extension and the recent cause of death in Werner syndrome: a retrospective study from 2011 to 2020

Case Report: A novel WRN mutation in Werner syndrome patient with diabetic foot disease and myelodysplastic syndrome

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