Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragen


  • Radboud University Medical Center
  • Bellvitge Biomedical Research Institute (IDIBELL)
  • Haukeland University Hospital
  • Università degli Studi di Bologna
  • Universitätsklinikum Bonn
  • University of Cambridge
  • University of Groningen
  • Institute of Oncology Ljubljana
  • Maastricht University
  • University of Manchester
  • Center for Medical Genetics and Primary Health Care
  • Archbishop Makarios III Hospital
  • Institut Curie
  • DNA Repair and Uveal Melanoma (D.R.U.M.)
  • UF d'oncogénétique Clinique
  • University of Parma
  • Karolinska-Universitätskrankenhaus


BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks.

METHODS: This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses.

RESULTS: A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%.

CONCLUSIONS: Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.


Seiten (von - bis)93-103
FachzeitschriftJournal of the National Cancer Institute
PublikationsstatusVeröffentlicht - 10 Jan. 2023

Externe IDs

Scopus 85149012016


Ziele für nachhaltige Entwicklung


  • Adult, Male, Humans, Female, Middle Aged, Hamartoma Syndrome, Multiple/epidemiology, Cohort Studies, Prospective Studies, Thyroid Neoplasms, PTEN Phosphohydrolase/genetics, Kidney Neoplasms/epidemiology, Germ-Line Mutation