Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes
Background: Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown si...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/112518 |
| Acceso en línea: | https://hdl.handle.net/10171/112518 |
| Access Level: | acceso abierto |
| Palabra clave: | CDH1 germline variants Cancer phenotypes |
| id |
ES_9c9fc8b4b04bc7311a4b3aaa4043b9e2 |
|---|---|
| oai_identifier_str |
oai:dadun.unav.edu:10171/112518 |
| network_acronym_str |
ES |
| network_name_str |
España |
| repository_id_str |
|
| dc.title.none.fl_str_mv |
Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes |
| title |
Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes |
| spellingShingle |
Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes Garcia-Pelaez, J. (José)|||/items/4ff0ba0e-f074-464e-9f86-2336e4d79183 CDH1 germline variants Cancer phenotypes |
| title_short |
Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes |
| title_full |
Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes |
| title_fullStr |
Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes |
| title_full_unstemmed |
Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes |
| title_sort |
Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes |
| dc.creator.none.fl_str_mv |
Garcia-Pelaez, J. (José)|||/items/4ff0ba0e-f074-464e-9f86-2336e4d79183 Barbosa-Matos, R. (Rita)|||/items/d871a5df-4f64-447a-80f4-c55410079929 Lobo, S. (Silvana)|||/items/f02eefc5-f669-4893-a48a-9915be170b53 Dias, A. (Alexandre)|||/items/4643dbe6-9c68-4189-b8a8-e9c6ea6a3d84 Garrido, L. (Luzia)|||/items/3a65b9e5-93a4-4f73-b30c-d1c4228616fd Castedo, S. (Sérgio)|||/items/609140ee-1ee8-4fcf-aa26-477aa4f1cb7c Sousa, S. (Sónia)|||/items/3c883b68-c83d-47af-a0e4-2f0845d58134 Pinheiro, H. (Hugo)|||/items/6838e27a-b2a5-4fcb-b1da-f6dcd14f8fec Sousa, L. (Liliana)|||/items/2d904271-b6eb-44a2-9343-bea4fabecdc8 Monteiro, R. (Rita)|||/items/3f96fb07-32e5-4769-a090-84c20a21d3be Maqueda, J.J. (Joaquin J.)|||/items/836cd693-7159-4659-8a04-ad0da52a4026 Fernandes, S. (Susana)|||/items/1ad3f3be-0141-4efa-a163-e2cf4961da34 Carneiro, F. (Fátima)|||/items/c33b3332-29db-4d6e-af52-5351a53a596b Pinto, N. (Nádia)|||/items/0588e380-ae3b-43a6-92a3-c0a43ccc04f7 Lemos, C. (Carolina)|||/items/ebacf663-7c04-4679-aa08-b2d4c861dd75 Pinto, C. (Carla)|||/items/aee89133-1d3d-4347-833f-c32a6b00a725 Teixeira, M.R. (Manuel R.)|||/items/6cfab3a7-7789-44e0-8b9f-36a1eeac0c1a Aretz, S. (Stefan)|||/items/7c1e7c27-3d70-4f50-8882-805241f2dd97 Patiño-García, A. (Ana)|||/items/d68c74f1-df22-4e04-9b77-9cf48fd87b46 Bajalica-Lagercrantz, S. (Svetlana)|||/items/c0618ea2-c93a-40cd-8cf3-ee72e93830ea Balmaña, J. (Judith)|||/items/cbc11b02-1f64-4172-857c-74bc11e5b912 Blatnik, A. (Ana)|||/items/6d8c7e08-ba34-46f3-911d-a7c9704025f5 Benusiglio, P.R. (Patrick R.)|||/items/ed34ad72-d00a-4e20-8a34-55d7dde278b0 Blanluet, M. (Maud)|||/items/4fb24a4e-b781-498d-8599-4eeb50548920 Bours, V. (Vincent)|||/items/f452b402-5f40-46c4-bb50-fc07da305089 Brems, H. (Hilde)|||/items/69908ea5-3baa-4d3f-b94d-a4da6a050d4f Brunet, J. (Joan)|||/items/77cac85b-1652-4413-9934-9f1551eb84eb Calistri, D. (Daniele)|||/items/b544a21b-00c4-4923-9013-286caf97527f Capellá, G. (Gabriel)|||/items/6f09e72c-ca17-44c1-b547-eab67312bd8d Carrera, S. (Sergio)|||/items/ad321484-8e60-4279-8add-9ed6742ea5f4 Colas, C. (Chrystelle)|||/items/f64697d8-57cf-42ab-ac5e-942afe8c5894 Dahan, K. (Karin)|||/items/817e5bb1-1ff4-4a8e-b0bd-8a8ba9d7f066 Putter, R. (Robin) de|||/items/f981c384-35cb-4a16-b272-fba50599aece Desseignés, C. (Camille)|||/items/601fd9b7-4ed4-41c1-b9f6-972f3f69b4b6 |
| author |
Garcia-Pelaez, J. (José)|||/items/4ff0ba0e-f074-464e-9f86-2336e4d79183 |
| author_facet |
Garcia-Pelaez, J. (José)|||/items/4ff0ba0e-f074-464e-9f86-2336e4d79183 Barbosa-Matos, R. (Rita)|||/items/d871a5df-4f64-447a-80f4-c55410079929 Lobo, S. (Silvana)|||/items/f02eefc5-f669-4893-a48a-9915be170b53 Dias, A. (Alexandre)|||/items/4643dbe6-9c68-4189-b8a8-e9c6ea6a3d84 Garrido, L. (Luzia)|||/items/3a65b9e5-93a4-4f73-b30c-d1c4228616fd Castedo, S. (Sérgio)|||/items/609140ee-1ee8-4fcf-aa26-477aa4f1cb7c Sousa, S. (Sónia)|||/items/3c883b68-c83d-47af-a0e4-2f0845d58134 Pinheiro, H. (Hugo)|||/items/6838e27a-b2a5-4fcb-b1da-f6dcd14f8fec Sousa, L. (Liliana)|||/items/2d904271-b6eb-44a2-9343-bea4fabecdc8 Monteiro, R. (Rita)|||/items/3f96fb07-32e5-4769-a090-84c20a21d3be Maqueda, J.J. (Joaquin J.)|||/items/836cd693-7159-4659-8a04-ad0da52a4026 Fernandes, S. (Susana)|||/items/1ad3f3be-0141-4efa-a163-e2cf4961da34 Carneiro, F. (Fátima)|||/items/c33b3332-29db-4d6e-af52-5351a53a596b Pinto, N. (Nádia)|||/items/0588e380-ae3b-43a6-92a3-c0a43ccc04f7 Lemos, C. (Carolina)|||/items/ebacf663-7c04-4679-aa08-b2d4c861dd75 Pinto, C. (Carla)|||/items/aee89133-1d3d-4347-833f-c32a6b00a725 Teixeira, M.R. (Manuel R.)|||/items/6cfab3a7-7789-44e0-8b9f-36a1eeac0c1a Aretz, S. (Stefan)|||/items/7c1e7c27-3d70-4f50-8882-805241f2dd97 Patiño-García, A. (Ana)|||/items/d68c74f1-df22-4e04-9b77-9cf48fd87b46 Bajalica-Lagercrantz, S. (Svetlana)|||/items/c0618ea2-c93a-40cd-8cf3-ee72e93830ea Balmaña, J. (Judith)|||/items/cbc11b02-1f64-4172-857c-74bc11e5b912 Blatnik, A. (Ana)|||/items/6d8c7e08-ba34-46f3-911d-a7c9704025f5 Benusiglio, P.R. (Patrick R.)|||/items/ed34ad72-d00a-4e20-8a34-55d7dde278b0 Blanluet, M. (Maud)|||/items/4fb24a4e-b781-498d-8599-4eeb50548920 Bours, V. (Vincent)|||/items/f452b402-5f40-46c4-bb50-fc07da305089 Brems, H. (Hilde)|||/items/69908ea5-3baa-4d3f-b94d-a4da6a050d4f Brunet, J. (Joan)|||/items/77cac85b-1652-4413-9934-9f1551eb84eb Calistri, D. (Daniele)|||/items/b544a21b-00c4-4923-9013-286caf97527f Capellá, G. (Gabriel)|||/items/6f09e72c-ca17-44c1-b547-eab67312bd8d Carrera, S. (Sergio)|||/items/ad321484-8e60-4279-8add-9ed6742ea5f4 Colas, C. (Chrystelle)|||/items/f64697d8-57cf-42ab-ac5e-942afe8c5894 Dahan, K. (Karin)|||/items/817e5bb1-1ff4-4a8e-b0bd-8a8ba9d7f066 Putter, R. (Robin) de|||/items/f981c384-35cb-4a16-b272-fba50599aece Desseignés, C. (Camille)|||/items/601fd9b7-4ed4-41c1-b9f6-972f3f69b4b6 |
| author_role |
author |
| author2 |
Barbosa-Matos, R. (Rita)|||/items/d871a5df-4f64-447a-80f4-c55410079929 Lobo, S. (Silvana)|||/items/f02eefc5-f669-4893-a48a-9915be170b53 Dias, A. (Alexandre)|||/items/4643dbe6-9c68-4189-b8a8-e9c6ea6a3d84 Garrido, L. (Luzia)|||/items/3a65b9e5-93a4-4f73-b30c-d1c4228616fd Castedo, S. (Sérgio)|||/items/609140ee-1ee8-4fcf-aa26-477aa4f1cb7c Sousa, S. (Sónia)|||/items/3c883b68-c83d-47af-a0e4-2f0845d58134 Pinheiro, H. (Hugo)|||/items/6838e27a-b2a5-4fcb-b1da-f6dcd14f8fec Sousa, L. (Liliana)|||/items/2d904271-b6eb-44a2-9343-bea4fabecdc8 Monteiro, R. (Rita)|||/items/3f96fb07-32e5-4769-a090-84c20a21d3be Maqueda, J.J. (Joaquin J.)|||/items/836cd693-7159-4659-8a04-ad0da52a4026 Fernandes, S. (Susana)|||/items/1ad3f3be-0141-4efa-a163-e2cf4961da34 Carneiro, F. (Fátima)|||/items/c33b3332-29db-4d6e-af52-5351a53a596b Pinto, N. (Nádia)|||/items/0588e380-ae3b-43a6-92a3-c0a43ccc04f7 Lemos, C. (Carolina)|||/items/ebacf663-7c04-4679-aa08-b2d4c861dd75 Pinto, C. (Carla)|||/items/aee89133-1d3d-4347-833f-c32a6b00a725 Teixeira, M.R. (Manuel R.)|||/items/6cfab3a7-7789-44e0-8b9f-36a1eeac0c1a Aretz, S. (Stefan)|||/items/7c1e7c27-3d70-4f50-8882-805241f2dd97 Patiño-García, A. (Ana)|||/items/d68c74f1-df22-4e04-9b77-9cf48fd87b46 Bajalica-Lagercrantz, S. (Svetlana)|||/items/c0618ea2-c93a-40cd-8cf3-ee72e93830ea Balmaña, J. (Judith)|||/items/cbc11b02-1f64-4172-857c-74bc11e5b912 Blatnik, A. (Ana)|||/items/6d8c7e08-ba34-46f3-911d-a7c9704025f5 Benusiglio, P.R. (Patrick R.)|||/items/ed34ad72-d00a-4e20-8a34-55d7dde278b0 Blanluet, M. (Maud)|||/items/4fb24a4e-b781-498d-8599-4eeb50548920 Bours, V. (Vincent)|||/items/f452b402-5f40-46c4-bb50-fc07da305089 Brems, H. (Hilde)|||/items/69908ea5-3baa-4d3f-b94d-a4da6a050d4f Brunet, J. (Joan)|||/items/77cac85b-1652-4413-9934-9f1551eb84eb Calistri, D. (Daniele)|||/items/b544a21b-00c4-4923-9013-286caf97527f Capellá, G. (Gabriel)|||/items/6f09e72c-ca17-44c1-b547-eab67312bd8d Carrera, S. (Sergio)|||/items/ad321484-8e60-4279-8add-9ed6742ea5f4 Colas, C. (Chrystelle)|||/items/f64697d8-57cf-42ab-ac5e-942afe8c5894 Dahan, K. (Karin)|||/items/817e5bb1-1ff4-4a8e-b0bd-8a8ba9d7f066 Putter, R. (Robin) de|||/items/f981c384-35cb-4a16-b272-fba50599aece Desseignés, C. (Camille)|||/items/601fd9b7-4ed4-41c1-b9f6-972f3f69b4b6 |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
CDH1 germline variants Cancer phenotypes |
| topic |
CDH1 germline variants Cancer phenotypes |
| description |
Background: Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype–phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. Methods. This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype–phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. Findings: From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1–93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66–57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18–29·39], p=0·0017) and gastric cancer (7·81 [2·03–29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004). Interpretation: CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 2023-01-01 2023 2023-01-01 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/112518 |
| url |
https://hdl.handle.net/10171/112518 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier |
| publisher.none.fl_str_mv |
Elsevier |
| dc.source.none.fl_str_mv |
reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
| instname_str |
Universidad de Navarra |
| reponame_str |
Dadun. Depósito Académico Digital de la Universidad de Navarra |
| collection |
Dadun. Depósito Académico Digital de la Universidad de Navarra |
| repository.name.fl_str_mv |
|
| repository.mail.fl_str_mv |
|
| _version_ |
1869414674593742848 |
| spelling |
Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk SyndromesGarcia-Pelaez, J. (José)|||/items/4ff0ba0e-f074-464e-9f86-2336e4d79183Barbosa-Matos, R. (Rita)|||/items/d871a5df-4f64-447a-80f4-c55410079929Lobo, S. (Silvana)|||/items/f02eefc5-f669-4893-a48a-9915be170b53Dias, A. (Alexandre)|||/items/4643dbe6-9c68-4189-b8a8-e9c6ea6a3d84Garrido, L. (Luzia)|||/items/3a65b9e5-93a4-4f73-b30c-d1c4228616fdCastedo, S. (Sérgio)|||/items/609140ee-1ee8-4fcf-aa26-477aa4f1cb7cSousa, S. (Sónia)|||/items/3c883b68-c83d-47af-a0e4-2f0845d58134Pinheiro, H. (Hugo)|||/items/6838e27a-b2a5-4fcb-b1da-f6dcd14f8fecSousa, L. (Liliana)|||/items/2d904271-b6eb-44a2-9343-bea4fabecdc8Monteiro, R. (Rita)|||/items/3f96fb07-32e5-4769-a090-84c20a21d3beMaqueda, J.J. (Joaquin J.)|||/items/836cd693-7159-4659-8a04-ad0da52a4026Fernandes, S. (Susana)|||/items/1ad3f3be-0141-4efa-a163-e2cf4961da34Carneiro, F. (Fátima)|||/items/c33b3332-29db-4d6e-af52-5351a53a596bPinto, N. (Nádia)|||/items/0588e380-ae3b-43a6-92a3-c0a43ccc04f7Lemos, C. (Carolina)|||/items/ebacf663-7c04-4679-aa08-b2d4c861dd75Pinto, C. (Carla)|||/items/aee89133-1d3d-4347-833f-c32a6b00a725Teixeira, M.R. (Manuel R.)|||/items/6cfab3a7-7789-44e0-8b9f-36a1eeac0c1aAretz, S. (Stefan)|||/items/7c1e7c27-3d70-4f50-8882-805241f2dd97Patiño-García, A. (Ana)|||/items/d68c74f1-df22-4e04-9b77-9cf48fd87b46Bajalica-Lagercrantz, S. (Svetlana)|||/items/c0618ea2-c93a-40cd-8cf3-ee72e93830eaBalmaña, J. (Judith)|||/items/cbc11b02-1f64-4172-857c-74bc11e5b912Blatnik, A. (Ana)|||/items/6d8c7e08-ba34-46f3-911d-a7c9704025f5Benusiglio, P.R. (Patrick R.)|||/items/ed34ad72-d00a-4e20-8a34-55d7dde278b0Blanluet, M. (Maud)|||/items/4fb24a4e-b781-498d-8599-4eeb50548920Bours, V. (Vincent)|||/items/f452b402-5f40-46c4-bb50-fc07da305089Brems, H. (Hilde)|||/items/69908ea5-3baa-4d3f-b94d-a4da6a050d4fBrunet, J. (Joan)|||/items/77cac85b-1652-4413-9934-9f1551eb84ebCalistri, D. (Daniele)|||/items/b544a21b-00c4-4923-9013-286caf97527fCapellá, G. (Gabriel)|||/items/6f09e72c-ca17-44c1-b547-eab67312bd8dCarrera, S. (Sergio)|||/items/ad321484-8e60-4279-8add-9ed6742ea5f4Colas, C. (Chrystelle)|||/items/f64697d8-57cf-42ab-ac5e-942afe8c5894Dahan, K. (Karin)|||/items/817e5bb1-1ff4-4a8e-b0bd-8a8ba9d7f066Putter, R. (Robin) de|||/items/f981c384-35cb-4a16-b272-fba50599aeceDesseignés, C. (Camille)|||/items/601fd9b7-4ed4-41c1-b9f6-972f3f69b4b6CDH1 germline variantsCancer phenotypesBackground: Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype–phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. Methods. This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype–phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. Findings: From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1–93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66–57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18–29·39], p=0·0017) and gastric cancer (7·81 [2·03–29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004). Interpretation: CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria.ElsevierDadun. Depósito Académico Digital Universidad de Navarra20232023-01-0120232023-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/112518reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/1125182026-06-21T12:47:57Z |
| score |
15,812429 |