TY - JOUR
T1 - First estimates of diffuse gastric cancer risks for carriers of CTNNA1 germline pathogenic variants
AU - Coudert, Marie
AU - Drouet, Youenn
AU - Delhomelle, H. lène
AU - Svrcek, Magali
AU - Benusiglio, Patrick R.
AU - Coulet, Florence
AU - Clark, Dana Farengo
AU - Katona, Bryson W.
AU - van Hest, Liselotte P.
AU - van der Kolk, Lizet E.
AU - Cats, Annemieke
AU - van Dieren, Jolanda M.
AU - Nehoray, Bita
AU - Slavin, Thomas
AU - Spier, Isabel
AU - Hüneburg, Robert
AU - Lobo, Silvana
AU - Oliveira, Carla
AU - Boussemart, Lise
AU - Masson, Laure
AU - Chiesa, Jean
AU - Schwartz, Mathias
AU - Buecher, Bruno
AU - Golmard, Lisa
AU - Bouvier, Anne-Marie
AU - Bonadona, Valérie
AU - Stoppa-Lyonnet, Dominique
AU - Lasset, Christine
AU - Colas, Chrystelle
N1 - Funding Information: Funding This research is supported by the European Reference on Genetic Tumour Risk Syndromes (ERN GENTURIS)-Project ID No 739547. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme 'ERN-2016- Framework Partnership Agreement 2017-2021'. The work was also supported by the project PTDC/BTM-TEC/ 6706/2020 (LEGOH) funded by ERDF funds through the COMPETE 2020-POCI, Portugal 2020, and by The Portuguese Foundation for Science and Technology (FCT). SL was supported by the PhD fellowship Ref. 2020.05773.BD. Funding Information: This research is supported by the European Reference on Genetic Tumour Risk Syndromes (ERN GENTURIS)—Project ID No 739547. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme ‘ERN-2016-Framework Partnership Agreement 2017-2021’. The work was also supported by the project PTDC/BTM-TEC/6706/2020 (LEGOH) funded by ERDF funds through the COMPETE 2020—POCI, Portugal 2020, and by The Portuguese Foundation for Science and Technology (FCT). SL was supported by the PhD fellowship Ref. 2020.05773.BD. Publisher Copyright: © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2022/8/29
Y1 - 2022/8/29
N2 - Background: Pathogenic variants (PV) of CTNNA1 are found in families fulfilling criteria for hereditary diffuse gastric cancer (HDGC) but no risk estimates were available until now. The aim of this study is to evaluate diffuse gastric cancer (DGC) risks for carriers of germline CTNNA1 PV. Methods: Data from published CTNNA1 families were updated and new families were identified through international collaborations. The cumulative risk of DGC by age for PV carriers was estimated with the genotype restricted likelihood (GRL) method, taking into account non-genotyped individuals and conditioning on all observed phenotypes and genotypes of the index case to obtain unbiased estimates. A non-parametric (NP) and the Weibull functions were used to model the shape of penetrance function with the GRL. Kaplan-Meier incidence curve and standardised incidence ratios were also computed. A 'leave-one-out' strategy was used to evaluate estimate uncertainty. Results: Thirteen families with 46 carriers of PV were included. The cumulative risks of DGC at 80 years for carriers of CTNNA1 PV are 49% and 57%, respectively with the Weibull GRL and NP GRL methods. Risk ratios to population incidence reach particularly high values at early ages and decrease with age. At 40 years, they are equal to 65 and 833, respectively with the Weibull GRL and NP GRL. Conclusion: This is the largest series of CTNNA1 families that provides the first risk estimates of GC. These data will help to improve management and surveillance for these patients and support inclusion of CTNNA1 in germline testing panels.
AB - Background: Pathogenic variants (PV) of CTNNA1 are found in families fulfilling criteria for hereditary diffuse gastric cancer (HDGC) but no risk estimates were available until now. The aim of this study is to evaluate diffuse gastric cancer (DGC) risks for carriers of germline CTNNA1 PV. Methods: Data from published CTNNA1 families were updated and new families were identified through international collaborations. The cumulative risk of DGC by age for PV carriers was estimated with the genotype restricted likelihood (GRL) method, taking into account non-genotyped individuals and conditioning on all observed phenotypes and genotypes of the index case to obtain unbiased estimates. A non-parametric (NP) and the Weibull functions were used to model the shape of penetrance function with the GRL. Kaplan-Meier incidence curve and standardised incidence ratios were also computed. A 'leave-one-out' strategy was used to evaluate estimate uncertainty. Results: Thirteen families with 46 carriers of PV were included. The cumulative risks of DGC at 80 years for carriers of CTNNA1 PV are 49% and 57%, respectively with the Weibull GRL and NP GRL methods. Risk ratios to population incidence reach particularly high values at early ages and decrease with age. At 40 years, they are equal to 65 and 833, respectively with the Weibull GRL and NP GRL. Conclusion: This is the largest series of CTNNA1 families that provides the first risk estimates of GC. These data will help to improve management and surveillance for these patients and support inclusion of CTNNA1 in germline testing panels.
KW - gastroenterology
KW - genetic counseling
KW - genetic predisposition to disease
KW - medical oncology
UR - http://www.scopus.com/inward/record.url?scp=85137865988&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/jmg-2022-108740
DO - https://doi.org/10.1136/jmg-2022-108740
M3 - Article
C2 - 36038258
SN - 0022-2593
VL - 59
SP - 1189
EP - 1195
JO - Journal of medical genetics
JF - Journal of medical genetics
IS - 12
M1 - 108740
ER -