TY - JOUR
T1 - Cancer risks by sex and variant type in PTEN Hamartoma Tumor Syndrome
AU - Hendricks, Linda A J
AU - Hoogerbrugge, Nicoline
AU - Mensenkamp, Arjen R
AU - Brunet, Joan
AU - Lleuger-Pujol, Roser
AU - Høberg-Vetti, Hildegunn
AU - Haavind, Marianne Tveit
AU - Innella, Giovanni
AU - Turchetti, Daniela
AU - Aretz, Stefan
AU - Spier, Isabel
AU - Tischkowitz, Marc
AU - Jahn, Arne
AU - Links, Thera P
AU - Olderode-Berends, Maran J W
AU - Blatnik, Ana
AU - Leter, Edward M
AU - Evans, D Gareth
AU - Woodward, Emma R
AU - Steinke-Lange, Verena
AU - Anastasiadou, Violetta C
AU - Colas, Chrystelle
AU - Villy, Marie-Charlotte
AU - Benusiglio, Patrick R
AU - Gerasimenko, Anna
AU - Barili, Valeria
AU - Branchaud, Maud
AU - Houdayer, Claude
AU - Tesi, Bianca
AU - Yazicioglu, M Omer
AU - van der Post, Rachel S
AU - Schuurs-Hoeijmakers, Janneke H M
AU - PTEN Study Group
AU - Vos, Janet R
N1 - Funding Information:
Acknowledgements: This research is supported (not financially) by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS)—Project ID No 739547. ERN GENTURIS is partly cofunded by the European Union within the framework of the Third Health Programme “ERN-2016— Framework Partnership Agreement 2017-2021”.
Funding Information:
This work was supported by the PTEN Research Foundation (grant number 17-001 to L.A.J.H and J.R.V.); and the National Institute for Health Research (NIHR) Biomedical Research Centre Manchester (Grant Reference Number 1215-200074 to D.G.E. and E.R.W.).
Publisher Copyright:
© The Author(s) 2022. Published by Oxford University Press.
PY - 2023/1/10
Y1 - 2023/1/10
N2 - 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 ¼ 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] ¼ 43.0% to 66.4%) to 75.8% (95% CI ¼ 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 ¼ 2.1% to 18.6%) to 22.1% (95% CI ¼ 11.6% to 39.6%) and TC risks from 8.9% (95% CI ¼ 5.1% to 15.3%) to 20.5% (95% CI ¼ 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.
AB - 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 ¼ 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] ¼ 43.0% to 66.4%) to 75.8% (95% CI ¼ 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 ¼ 2.1% to 18.6%) to 22.1% (95% CI ¼ 11.6% to 39.6%) and TC risks from 8.9% (95% CI ¼ 5.1% to 15.3%) to 20.5% (95% CI ¼ 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.
U2 - 10.1093/jnci/djac188
DO - 10.1093/jnci/djac188
M3 - Article
C2 - 36171661
SN - 0027-8874
VL - 115
SP - 93
EP - 103
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 1
ER -