The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS)

Linda A J Hendricks¹, Katja C J Verbeek¹, Janneke H M Schuurs-Hoeijmakers², Mirjam M de Jong³, Thera P Links⁴, Hilde Brems⁵, Mio Aerden⁵, Joan Brunet⁶, Roser Lleuger-Pujol⁶, Robert Hüneburg⁷, Stefan Aretz⁸, Chrystelle Colas⁹, Marie-Charlotte Villy¹⁰, Emma R Woodward¹¹, D Gareth Evans¹¹, Daniëlle G M Bosch¹², Stephany H Donze¹², Lenka Foretová¹³, Ana Blatnik¹⁴, Edward M Leter¹⁵, Marc Tischkowitz¹⁶, Arne Jahn¹⁷, Robin de Putter¹⁸, Juliette Dupont¹⁹, Siri Briskemyr²⁰, Verena Steinke-Lange²¹, Margherita Baldassarri²², Violetta C Anastasiadou²³, Arvīds Irmejs²⁴, Carla Oliveira²⁵, Rachel S van der Post²⁶, Arjen R Mensenkamp¹, Bianca Tesi²⁷, Ninni Mu²⁸, Patrick R Benusiglio²⁹, Anna Gerasimenko³⁰, Giovanni Innella³¹, Daniela Turchetti³¹, Claude Houdayer³², Maud Branchaud³², Hildegunn Høberg Vetti³³, Marianne Tveit Haavind³⁴, Judith Balmaña³⁵, Maite Torres³⁵, Maurizio Genuardi³⁶, Arianna Panfili³⁷, Kjersti Jørgensen³⁸, Lovise Mæhle³⁸, Nicoline Hoogerbrugge¹, Janet R Vos³⁹

Affiliations

¹ Department of Human Genetics, Radboudumc expert center for PHTS, Radboud university medical center, Nijmegen, The Netherlands; Radboud university medical center, Radboud Institute for Medical Innovation, Nijmegen, The Netherlands.
² Department of Human Genetics, Radboudumc expert center for PHTS, Radboud university medical center, Nijmegen, The Netherlands.
³ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁴ Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁵ Center for Human Genetics, University Hospital Leuven, University of Leuven, Leuven, Belgium.
⁶ Hereditary Cancer Program, Catalan Institute of Oncology, ONCOBELL-IDIBELL-IDIBGI-IGTP, CIBERONC, Barcelona, Spain.
⁷ Center for Hereditary Tumor Syndromes, University Hospital of Bonn, Bonn, Germany; Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.
⁸ Center for Hereditary Tumor Syndromes, University Hospital of Bonn, Bonn, Germany; Institute of Human Genetics, Medical Faculty, University of Bonn, Germany.
⁹ Institut Curie, Service de Génétique, Paris, France; Inserm U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe Labellisée Par la Ligue Nationale Contre le Cancer, Paris, France.
¹⁰ Institut Curie, Service de Génétique, Paris, France.
¹¹ Manchester Centre for Genomic Medicine, St Mary's Hospital, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, United Kingdom.
¹² Department of Clinical Genetics, Erasmus MC Rotterdam, The Netherlands.
¹³ Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
¹⁴ Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
¹⁵ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
¹⁶ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom.
¹⁷ Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; ERN-GENTURIS, Hereditary Cancer Syndrome Center Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.
¹⁸ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
¹⁹ Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.
²⁰ Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway.
²¹ Medical Genetics Center, Germany; Arbeitsgruppe Erbliche Gastrointestinale Tumore, Medizinische Klinik und Poliklinik IV-Campus Innenstadt, Klinikum der Universität München, Germany.
²² Medical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.
²³ Karaiskakio Foundation, Nicosia Cyprus, and Archbishop Makarios III Children's Hospital, Nicosia, Cyprus.
²⁴ Institute of Oncology, Riga Stradins University, Riga, Latvia; Breast Unit, Pauls Stradins Clinical University Hospital, Riga, Latvia.
²⁵ Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; Department of Pathology, University of Porto, Porto, Portugal.
²⁶ Radboud university medical center, Radboud Institute for Medical Innovation, Nijmegen, The Netherlands; Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
²⁷ Department of Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
²⁸ Department of Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
²⁹ Department of Medical Genetics, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France.
³⁰ Sorbonne University, Paris Brain Institute-ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, Paris, France; APHP Sorbonne University, GH Pitié Salpêtrière et Trousseau, Department of Genetics, Centre de référence "déficiences intellectuelles de causes rares", Paris, France.
³¹ Department of Medical and Surgical Sciences, Center for Studies on Hereditary Cancer, University of Bologna, Bologna, Italy; Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
³² Univ Rouen Normandie, INSERM U1245, FHU-G4 Génomique and CHU Rouen, Department of Genetics, Rouen, France.
³³ Western Norway Familial Cancer Center, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway; Faculty of Health Studies, VID Specialized University, Bergen, Norway.
³⁴ Western Norway Familial Cancer Center, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
³⁵ Medical Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain.
³⁶ Medical Genetics Section, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Laboratory and Infectious Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
³⁷ Department of Laboratory and Infectious Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
³⁸ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
³⁹ Department of Human Genetics, Radboudumc expert center for PHTS, Radboud university medical center, Nijmegen, The Netherlands; Radboud university medical center, Radboud Institute for Medical Innovation, Nijmegen, The Netherlands. Electronic address: janet.vos@radboudumc.nl.

PMID: 40433764
DOI: 10.1016/j.gim.2025.101467

Free article

The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS)

Linda A J Hendricks et al. Genet Med. 2025 Oct.

Free article

. 2025 Oct;27(10):101467.

doi: 10.1016/j.gim.2025.101467. Epub 2025 May 24.

Authors

Affiliations

¹ Department of Human Genetics, Radboudumc expert center for PHTS, Radboud university medical center, Nijmegen, The Netherlands; Radboud university medical center, Radboud Institute for Medical Innovation, Nijmegen, The Netherlands.
² Department of Human Genetics, Radboudumc expert center for PHTS, Radboud university medical center, Nijmegen, The Netherlands.
³ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁴ Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁵ Center for Human Genetics, University Hospital Leuven, University of Leuven, Leuven, Belgium.
⁶ Hereditary Cancer Program, Catalan Institute of Oncology, ONCOBELL-IDIBELL-IDIBGI-IGTP, CIBERONC, Barcelona, Spain.
⁷ Center for Hereditary Tumor Syndromes, University Hospital of Bonn, Bonn, Germany; Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.
⁸ Center for Hereditary Tumor Syndromes, University Hospital of Bonn, Bonn, Germany; Institute of Human Genetics, Medical Faculty, University of Bonn, Germany.
⁹ Institut Curie, Service de Génétique, Paris, France; Inserm U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe Labellisée Par la Ligue Nationale Contre le Cancer, Paris, France.
¹⁰ Institut Curie, Service de Génétique, Paris, France.
¹¹ Manchester Centre for Genomic Medicine, St Mary's Hospital, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, United Kingdom.
¹² Department of Clinical Genetics, Erasmus MC Rotterdam, The Netherlands.
¹³ Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
¹⁴ Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
¹⁵ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
¹⁶ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom.
¹⁷ Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; ERN-GENTURIS, Hereditary Cancer Syndrome Center Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany.
¹⁸ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
¹⁹ Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.
²⁰ Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway.
²¹ Medical Genetics Center, Germany; Arbeitsgruppe Erbliche Gastrointestinale Tumore, Medizinische Klinik und Poliklinik IV-Campus Innenstadt, Klinikum der Universität München, Germany.
²² Medical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.
²³ Karaiskakio Foundation, Nicosia Cyprus, and Archbishop Makarios III Children's Hospital, Nicosia, Cyprus.
²⁴ Institute of Oncology, Riga Stradins University, Riga, Latvia; Breast Unit, Pauls Stradins Clinical University Hospital, Riga, Latvia.
²⁵ Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; Department of Pathology, University of Porto, Porto, Portugal.
²⁶ Radboud university medical center, Radboud Institute for Medical Innovation, Nijmegen, The Netherlands; Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
²⁷ Department of Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
²⁸ Department of Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
²⁹ Department of Medical Genetics, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France.
³⁰ Sorbonne University, Paris Brain Institute-ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, Paris, France; APHP Sorbonne University, GH Pitié Salpêtrière et Trousseau, Department of Genetics, Centre de référence "déficiences intellectuelles de causes rares", Paris, France.
³¹ Department of Medical and Surgical Sciences, Center for Studies on Hereditary Cancer, University of Bologna, Bologna, Italy; Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
³² Univ Rouen Normandie, INSERM U1245, FHU-G4 Génomique and CHU Rouen, Department of Genetics, Rouen, France.
³³ Western Norway Familial Cancer Center, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway; Faculty of Health Studies, VID Specialized University, Bergen, Norway.
³⁴ Western Norway Familial Cancer Center, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
³⁵ Medical Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain.
³⁶ Medical Genetics Section, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Laboratory and Infectious Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
³⁷ Department of Laboratory and Infectious Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
³⁸ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
³⁹ Department of Human Genetics, Radboudumc expert center for PHTS, Radboud university medical center, Nijmegen, The Netherlands; Radboud university medical center, Radboud Institute for Medical Innovation, Nijmegen, The Netherlands. Electronic address: janet.vos@radboudumc.nl.

PMID: 40433764
DOI: 10.1016/j.gim.2025.101467

Abstract

Purpose: Patients with PTEN Hamartoma Tumor Syndrome (PHTS) have high hereditary cancer risks for breast, endometrial, and thyroid cancer. Patients develop multiple primary cancers, but these risks remain uncertain. We aimed to provide the second primary cancer risk.

Methods: This European cohort study assessed second primary cancer risks with Kaplan-Meier analyses using data from medical files, registries and/or patient questionnaires.

Results: Overall, 279 adult PHTS patients with (a history of) cancer were included (80% female). Among females, 106 (54%) developed a PHTS-related second primary cancer after a PHTS-related first primary cancer, whereas 10 (29%) males developed a PHTS-related second primary cancer after a PHTS-related first primary cancer. The 5- and 10-year PHTS-related second primary cancer risks were 24.5% (95% CI = 18.1-32.5) and 45.7% (95% CI = 36.9-55.4) in females and 14.5% (95% CI = 5.7-34.1) and 19.8% (95% CI = 8.6-41.9) in males, respectively. Furthermore, 5- and 10-year risks for a second primary breast cancer after a first primary breast cancer were 23.3% (95% CI = 14.9-35.2) and 45.6% (95% CI = 33.0-60.2) in females, respectively.

Conclusion: This study demonstrated that PHTS patients have high second primary cancer risks, which is driven by breast cancer in females. Hence, identifying patients with PHTS before or at first primary cancer diagnosis is essential to enable potential early detection or prevention of a second primary cancer through surveillance or risk-reducing surgery.

Keywords: PTEN; PTEN Hamartoma Tumor Syndrome; hereditary cancer; second primary cancer risk.

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Conflict of interest statement

Conflict of Interest Arjen R. Mensenkamp received funds from AstraZeneca for contribution to sponsored quality assessment and variant interpretation of variants of uncertain significance in BRCA1 and BRCA2. This funding was not related to this study. Judith Balmaña received funding support from GSK for an educational activity unrelated to this study. Arne Jahn received an honorarium from AstraZeneca for work unrelated to this study. All other authors declare no conflicts of interest.

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The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS)

Affiliations

The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS)

Authors

Affiliations

Abstract

Conflict of interest statement

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LinkOut - more resources

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Research Materials