Cancer risks by sex and variant type in PTEN Hamartoma Tumor Syndrome

Linda A J Hendricks; Nicoline Hoogerbrugge; Arjen R Mensenkamp; Joan Brunet; Roser Lleuger-Pujol; Hildegunn Høberg-Vetti; Marianne Tveit Haavind; Giovanni Innella; Daniela Turchetti; Stefan Aretz; Isabel Spier; Marc Tischkowitz; Arne Jahn; Thera P Links; Maran J W Olderode-Berends; Ana Blatnik; Edward M Leter; D Gareth Evans; Emma R Woodward; Verena Steinke-Lange; Violetta C Anastasiadou; Chrystelle Colas; Marie-Charlotte Villy; Patrick R Benusiglio; Anna Gerasimenko; Valeria Barili; Maud Branchaud; Claude Houdayer; Bianca Tesi; M Omer Yazicioglu; Rachel S van der Post; Janneke H M Schuurs-Hoeijmakers; PTEN Study Group; Janet R Vos

doi:10.1093/jnci/djac188

Cancer risks by sex and variant type in PTEN Hamartoma Tumor Syndrome

Linda A J Hendricks, Nicoline Hoogerbrugge, Arjen R Mensenkamp, Joan Brunet, Roser Lleuger-Pujol, Hildegunn Høberg-Vetti, Marianne Tveit Haavind, Giovanni Innella, Daniela Turchetti, Stefan Aretz, Isabel Spier, Marc Tischkowitz, Arne Jahn, Thera P Links, Maran J W Olderode-Berends, Ana Blatnik, Edward M Leter, D Gareth Evans, Emma R Woodward, Verena Steinke-LangeVioletta C Anastasiadou, Chrystelle Colas, Marie-Charlotte Villy, Patrick R Benusiglio, Anna Gerasimenko, Valeria Barili, Maud Branchaud, Claude Houdayer, Bianca Tesi, M Omer Yazicioglu, Rachel S van der Post, Janneke H M Schuurs-Hoeijmakers, PTEN Study Group, Janet R Vos^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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), 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: 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 (SIR) were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses.

RESULTS: 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 year, IQR : 3-10), and 159/281 females and 39/174 males with cancer. By age 60, 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%CI 43.0-66.4) to 75.8% (95%CI 60.7-88.4), with two-to-three-fold increased risks for PTEN truncating and about two-fold for phosphatase domain variants. EC risks ranged from 6.4% (95%CI 2.1-18.6) to 22.1% (95%CI 11.6-39.6), and TC risks from 8.9% (95%CI 5.1-15.3) to 20.5% (95%CI 11.3-35.4). Colorectal cancer, renal cancer and melanoma risks were each below 10.0%.

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

Original language	English
Journal	Journal of the National Cancer Institute
DOIs	https://doi.org/10.1093/jnci/djac188
Publication status	E-pub ahead of print - 28 Sept 2022

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10.1093/jnci/djac188

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Hendricks, L. A. J., Hoogerbrugge, N., Mensenkamp, A. R., Brunet, J., Lleuger-Pujol, R., Høberg-Vetti, H., Haavind, M. T., Innella, G., Turchetti, D., Aretz, S., Spier, I., Tischkowitz, M., Jahn, A., Links, T. P., Olderode-Berends, M. J. W., Blatnik, A., Leter, E. M., Evans, D. G., Woodward, E. R., ... Vos, J. R. (2022). Cancer risks by sex and variant type in PTEN Hamartoma Tumor Syndrome. Journal of the National Cancer Institute. https://doi.org/10.1093/jnci/djac188

@article{f3630f3af3af4c929bd4b59efd9de145,

title = "Cancer risks by sex and variant type in PTEN Hamartoma Tumor Syndrome",

abstract = "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), 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: 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 (SIR) were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses.RESULTS: 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 year, IQR : 3-10), and 159/281 females and 39/174 males with cancer. By age 60, 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%CI 43.0-66.4) to 75.8% (95%CI 60.7-88.4), with two-to-three-fold increased risks for PTEN truncating and about two-fold for phosphatase domain variants. EC risks ranged from 6.4% (95%CI 2.1-18.6) to 22.1% (95%CI 11.6-39.6), and TC risks from 8.9% (95%CI 5.1-15.3) to 20.5% (95%CI 11.3-35.4). Colorectal cancer, renal cancer and melanoma risks were each below 10.0%.CONCLUSION: Females have a different breast cancer risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of breast (females), endometrial and thyroid cancer. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.",

author = "Hendricks, {Linda A J} and Nicoline Hoogerbrugge and Mensenkamp, {Arjen R} and Joan Brunet and Roser Lleuger-Pujol and Hildegunn H{\o}berg-Vetti and Haavind, {Marianne Tveit} and Giovanni Innella and Daniela Turchetti and Stefan Aretz and Isabel Spier and Marc Tischkowitz and Arne Jahn and Links, {Thera P} and Olderode-Berends, {Maran J W} and Ana Blatnik and Leter, {Edward M} and Evans, {D Gareth} and Woodward, {Emma R} and Verena Steinke-Lange and Anastasiadou, {Violetta C} and Chrystelle Colas and Marie-Charlotte Villy and Benusiglio, {Patrick R} and Anna Gerasimenko and Valeria Barili and Maud Branchaud and Claude Houdayer and Bianca Tesi and Yazicioglu, {M Omer} and {van der Post}, {Rachel S} and Schuurs-Hoeijmakers, {Janneke H M} and {PTEN Study Group} and Vos, {Janet R}",

note = "{\textcopyright} The Author(s) 2022. Published by Oxford University Press.",

year = "2022",

month = sep,

day = "28",

doi = "10.1093/jnci/djac188",

language = "English",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

}

Hendricks, LAJ, Hoogerbrugge, N, Mensenkamp, AR, Brunet, J, Lleuger-Pujol, R, Høberg-Vetti, H, Haavind, MT, Innella, G, Turchetti, D, Aretz, S, Spier, I, Tischkowitz, M, Jahn, A, Links, TP, Olderode-Berends, MJW, Blatnik, A, Leter, EM, Evans, DG, Woodward, ER, Steinke-Lange, V, Anastasiadou, VC, Colas, C, Villy, M-C, Benusiglio, PR, Gerasimenko, A, Barili, V, Branchaud, M, Houdayer, C, Tesi, B, Yazicioglu, MO, van der Post, RS, Schuurs-Hoeijmakers, JHM, PTEN Study Group & Vos, JR 2022, 'Cancer risks by sex and variant type in PTEN Hamartoma Tumor Syndrome', Journal of the National Cancer Institute. https://doi.org/10.1093/jnci/djac188

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

PY - 2022/9/28

Y1 - 2022/9/28

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), 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: 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 (SIR) were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses.RESULTS: 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 year, IQR : 3-10), and 159/281 females and 39/174 males with cancer. By age 60, 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%CI 43.0-66.4) to 75.8% (95%CI 60.7-88.4), with two-to-three-fold increased risks for PTEN truncating and about two-fold for phosphatase domain variants. EC risks ranged from 6.4% (95%CI 2.1-18.6) to 22.1% (95%CI 11.6-39.6), and TC risks from 8.9% (95%CI 5.1-15.3) to 20.5% (95%CI 11.3-35.4). Colorectal cancer, renal cancer and melanoma risks were each below 10.0%.CONCLUSION: Females have a different breast cancer risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of breast (females), endometrial and thyroid cancer. 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), 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: 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 (SIR) were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses.RESULTS: 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 year, IQR : 3-10), and 159/281 females and 39/174 males with cancer. By age 60, 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%CI 43.0-66.4) to 75.8% (95%CI 60.7-88.4), with two-to-three-fold increased risks for PTEN truncating and about two-fold for phosphatase domain variants. EC risks ranged from 6.4% (95%CI 2.1-18.6) to 22.1% (95%CI 11.6-39.6), and TC risks from 8.9% (95%CI 5.1-15.3) to 20.5% (95%CI 11.3-35.4). Colorectal cancer, renal cancer and melanoma risks were each below 10.0%.CONCLUSION: Females have a different breast cancer risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of breast (females), endometrial and thyroid cancer. 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

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

ER -