{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:48:55Z","timestamp":1790887735619,"version":"4.1.0"},"reference-count":36,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82103153"],"award-info":[{"award-number":["82103153"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172617"],"award-info":[{"award-number":["82172617"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172665"],"award-info":[{"award-number":["82172665"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National High Level Hospital Clinical Research Funding","award":["2024CX23"],"award-info":[{"award-number":["2024CX23"]}]},{"name":"National High Level Hospital Clinical Research Funding","award":["2024YC03"],"award-info":[{"award-number":["2024YC03"]}]},{"name":"Beijing Natural Science Foundation","award":["7232176"],"award-info":[{"award-number":["7232176"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2026,3,4]]},"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>\n                      von Hippel-Lindau (VHL) syndrome-related renal cell carcinoma (RCC) is the most prevalent hereditary RCC and exhibits clinical heterogeneity, complicating patient management. While\n                      <jats:italic>VHL<\/jats:italic>\n                      gene inactivation is the primary driver, the impact of co-occurring germline mutations in other renal cancer predisposition genes on clinical phenotype remains poorly understood. This study aimed to investigate whether such co-mutations define a distinct clinical and molecular subgroup of patients with VHL syndrome.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      115 patients with VHL syndrome were enrolled in this study. All patients underwent germline sequencing of a 39-gene panel for hereditary RCC. Pathogenic\/likely pathogenic variants of the\n                      <jats:italic>VHL<\/jats:italic>\n                      gene were identified, and patients were stratified into a VHL single-mutation group and a VHL co-mutation group. Clinical characteristics, tumour manifestations, renal lesion growth kinetics and age-related tumour risks were compared.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      42.6% of patients harboured germline co-mutations. The co-mutation group exhibited a greater proportion of symptomatic patients (95.9% vs 78.7%, p=0.012) and increased penetrance of RCC (79.6% vs 57.6%, p=0.013) and pancreatic cystic tumours (77.6% vs 48.5%, p=0.002). This group had a lower incidence of positive family history (40.8% vs 69.7%, p=0.002). Co-mutation status is an independent predictor for RCC development (HR 1.798, p=0.016), and their RCC lesions exhibited significantly faster linear (0.376\u2009cm\/year vs 0.225\u2009cm\/year, p=0.022) and volumetric (3.132 cm\n                      <jats:sup>3<\/jats:sup>\n                      \/year vs 1.167 cm\n                      <jats:sup>3<\/jats:sup>\n                      \/year, p=0.049) growth metrics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Germline co-mutations are prevalent in VHL syndrome and define a clinically distinct subset of patients characterised by higher disease penetrance and a more aggressive RCC phenotype. Our findings suggest that co-mutation status is a critical determinant of clinical heterogeneity and a powerful biomarker for risk stratification.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2025-111303","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T17:20:31Z","timestamp":1773940831000},"page":"361-367","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Comparison of clinical characteristics between patients with single mutation and co-mutation in hereditary renal cancer: a retrospective analysis of 115 patients with von Hippel-Lindau syndrome"],"prefix":"10.1136","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-6478-7902","authenticated-orcid":false,"given":"Tao","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Urology, Peking University First Hospital, Beijing, China"},{"name":"Institute of Urology, Peking University, 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