Werner syndrome (WS) is an autosomal recessive premature aging disorder caused by mutations in the WRN gene. It is characterized by the development of age‐related diseases, such as juvenile bilateral cataracts, gray hair, hair loss, insulin‐resistant diabetes mellitus, atherosclerosis, and cancer after adolescence. The leading causes of death in patients with WS are coronary heart disease and cancer. Owing to improvements in the management of diabetes and dyslipidemia, deaths from atherosclerotic disease have decreased dramatically, and life expectancy has extended to 59 years. 1
The average age of cancer onset has increased in patients with WS, from 36.9 years in 1966 to 49.7 years in 2023. 2 , 3 However, because the average age at the onset of cancer is younger in patients with WS than in healthy individuals, early detection and treatment are critical. 3 The median ages (range) at the diagnosis of cancer in patients with WS are as follows: meningioma, 39 (22–67) years; thyroid cancer, 40 (20–57) years; soft tissue sarcoma, 43 (26–58) years; skin melanoma, 44 (34–59) years; leukemia, 45 (28–62) years; osteosarcoma, 49 (20–57) years. 4
In patients with WS, the morbidity of non‐epithelial tumors, such as malignant melanoma, meningioma, soft tissue sarcomas, osteosarcomas, and hematologic tumors (myelodysplastic syndrome and multiple myeloma), is higher than that in the general population, and the frequency of multiple primary cancers is higher. 2 , 4 , 5 The ratio of epithelial to non‐epithelial tumors is 1:1.5 in patients with WS, compared with 10:1 in the general population. 3 However, recent reports indicate that the incidence of epithelial tumors, such as thyroid, lung, and breast cancers, is increasing, and the ratio of epithelial to non‐epithelial tumors is 1.6:1. This change may reflect the increased life expectancy of patients with WS. 2
The guidelines for cancer screening in patients with WS are insufficient. Ultrasound screening for thyroid cancer and annual full‐body skin examinations are recommended for malignant melanomas. 6 The most common types of malignant melanoma in patients with WS are acral lentiginous melanoma and mucosal melanoma, particularly in nasal mucosa, palms, and soles. 4 Neurological evaluations of signs and symptoms are also important to screen for intracranial tumors. 7
For this study, we propose a strategy for cancer screening and surveillance in patients with WS, as shown in Table 1 . Cancer types were selected according to previous reports, with those accounting for the top two‐thirds of all cancers classified as “High” frequency. 4 Screening interval was based on recommendations for cancer screening in Japan and for other progeroid syndromes. 8 Evidence on the optimal timing of screening is scarce, but the average age of cancer diagnosis is in the 40s, with some cases reported in the 20s. Therefore, screening should begin at least at age 40, preferably earlier.
Table 1
Recommendations for cancer screening and surveillance in patients with Werner syndrome (2024)
| Cancer type | Frequency | Screening type | Interval/timing | Notes |
| Thyroid cancer | High | Palpation, ultrasound | Annual | |
| Lung cancer | Less | Chest X‐ray | Annual | Avoid smoking |
| Breast cancer | Less | Breast ultrasound | Every 2 years | Avoid excessive alcohol intake |
| Meningioma | High | Interviews for headache, dizziness, and neurological symptoms. Brain MRI | Interviews, every 6 months. MRI, if necessary | |
| Soft tissue sarcoma, osteosarcoma | High | Soft tissue visual inspection and palpation | Annual | |
| Interviews for bone pain | ||||
| Malignant melanoma | High | Skin visual inspection | Annual | Avoid excessive exposure to ultraviolet light. Use of sunscreen is recommended |
| Leukemia, myelodysplastic syndromes | High | Blood cell counts | Every 3 months | |
| Pancreatic cancer | Less | Abdominal ultrasound | If diabetes develops or there is sudden glycemic control deterioration | |
| Gastric and colorectal cancer | Less | Fecal occult blood tests | Annual | Upper gastrointestinal endoscopy is preferred over gastric fluoroscopy |
In general, recommendations for cancer screening in Japan include radiography or endoscopy for gastric cancer, fecal occult blood tests for colorectal cancer, radiography or sputum cytology for lung cancer, mammography and palpation for breast cancer, and cytology or human papillomavirus (HPV) tests for cervical cancer. The World Health Organization also strongly recommends HPV tests for cervical cancer. 9 WS cells are susceptible to X‐ray‐induced chromosomal aberrations, 10 and although there is no clinical evidence, one should consider the risks and benefits of X‐rays in clinical testing. Interview and physical examination should also be performed assuming non‐epithelial tumors, which are more common in WS.
For cancer screening in young‐onset progeria syndromes, such as Bloom syndrome, characterized by abnormal DNA repair mechanisms arising from mutations in the BLM gene, ultrasound and magnetic resonance imaging (MRI) are preferred over X‐rays and computed tomography scans. 8 Blood cell counts to screen for hematologic tumors, and routine skin examinations with minimal UV exposure to screen for skin cancers are also recommended. The benefits of routine screening for osteosarcoma have yet to be established, and imaging should be considered as necessary, with attention to signs and symptoms. Therefore, the proposed cancer screening for WS includes the use of ultrasound and MRI, rather than X‐rays.
Patients with WS can receive chemotherapy and surgery, similar to other patients with cancer. Treatments for cancer are advancing, and early detection may prolong survival. Although we have provided recommendations for cancer screening in WS for the first time, there is a lack of information on the effectiveness of the screening program, including the age of initiation, the appropriateness of the intervals, and cost‐effectiveness. Therefore, further studies are warranted.
We expect that the newly proposed malignancy screening strategy will improve the quality of life and prognosis of patients with WS.
Disclosure statement
The authors declare no conflict of interest.
Author contributions
YM, H. Kato, and KY managed the project. YM and KA drafted and revised the manuscript. KA, YM, H. Kato, H. Kaneko, YK, TT, TO, SM, HN, AT, KW, MT, MK, and KY critically reviewed the manuscript. All the authors contributed to, reviewed, and approved the final manuscript.
Ethics statement
The study adhered to the tenets of the Declaration of Helsinki. The study received approval from the Ethics Board of Chiba University on 27 July 2016 (approval number: 278) and from the Ethics Board of Kyoto University on 29 January 2020 (approval number: R2370). Written informed consent was obtained from patients before enrollment.
Acknowledgements
This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI under grant numbers JP22K15682 (H. Kato), JP22K20844 (H. Kaneko), JP21K19437 (KY), JP23H00417 (KY); Advanced Research and Development Programs for Medical Innovation (AMED) under grant numbers JP21jm0210096 (KY), JP22ym0126066 (KY), JP23ek0109622 (KY); and a Ministry of Health, Labour and Welfare (MHLW) Health Labour Sciences Research Grant, 21FC1016 (KY).
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
References
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