{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T06:07:35Z","timestamp":1779170855487,"version":"3.51.4"},"reference-count":30,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":137,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["88887.136405\/2017-00"],"award-info":[{"award-number":["88887.136405\/2017-00"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["465682\/2014-6"],"award-info":[{"award-number":["465682\/2014-6"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2014\/50943-1 2022\/05162-8 2023\/01303-9"],"award-info":[{"award-number":["2014\/50943-1 2022\/05162-8 2023\/01303-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Biallelic pathogenic variants in\n                    <jats:italic>MUTYH<\/jats:italic>\n                    cause\n                    <jats:italic>MUTYH<\/jats:italic>\n                    \u2010associated polyposis (MAP), a rare recessive colorectal cancer (CRC) predisposition syndrome characterized by somatic G:C\u2009&gt;\u2009T:A transversions. The hotspot somatic mutations\n                    <jats:italic>KRAS<\/jats:italic>\n                    \u2010G12C and\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    \u2010Q546K are highly enriched in MAP CRCs, and are rarely observed in sporadic cases, suggesting their potential utility in supporting the reclassification of variants of uncertain significance (VUS) in\n                    <jats:italic>MUTYH<\/jats:italic>\n                    . This study is aimed at evaluating the frequency of\n                    <jats:italic>KRAS<\/jats:italic>\n                    \u2010G12C and\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    \u2010Q546K in adenomas and CRC from MAP patients and to demonstrate their relevance to reclassify\n                    <jats:italic>MUTYH<\/jats:italic>\n                    VUS. These hotspot mutations were evaluated using targeted NGS in adenomas and CRC tissues from 16 previously diagnosed MAP patients and three patients suspected of MAP, who harbored a VUS in either homozygosity or compound heterozygosity with a germline pathogenic\n                    <jats:italic>MUTYH<\/jats:italic>\n                    variant.\n                    <jats:italic>KRAS<\/jats:italic>\n                    \u2010G12C and\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    \u2010Q546K were identified in 92.3% and 38.4% of 13 MAP adenocarcinomas, respectively.\n                    <jats:italic>KRAS<\/jats:italic>\n                    \u2010G12C was also present in 47% of 17 MAP adenomas, whereas none of them harbored\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    \u2010Q546K. The detection of either mutation in CRC showed 100% sensitivity and 97% specificity for MAP (\n                    <jats:italic>p<\/jats:italic>\n                    = 0.00001). Among the three\u2010suspected MAP cases with VUS, two harbored somatic\n                    <jats:italic>KRAS<\/jats:italic>\n                    \u2010G12C and\/or\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    \u2010Q546K, providing sufficient evidence to reclassify\n                    <jats:italic>MUTYH<\/jats:italic>\n                    VUS p.Pro301Arg and p.Trp113Arg as likely pathogenic based on ACMG\/AMP criteria. These findings support the use of\n                    <jats:italic>KRAS<\/jats:italic>\n                    \u2010G12C and\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    \u2010Q546K as cost\u2010effective, accessible tumor biomarkers for aiding in MAP diagnosis and\n                    <jats:italic>MUTYH<\/jats:italic>\n                    VUS reclassification, particularly in settings with limited access to whole\u2010exome\/genome mutational signature analysis.\n                  <\/jats:p>","DOI":"10.1155\/humu\/6589780","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T05:29:15Z","timestamp":1779168555000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Frequent Detection of\n                    <i>KRAS<\/i>\n                    \u2010G12C and\n                    <i>PIK3CA<\/i>\n                    \u2010Q546K Mutations in MAP Tumors Highlights their Role in\n                    <i>MUTYH<\/i>\n                    Variants of Uncertain Significance Reclassification"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1050-0741","authenticated-orcid":false,"given":"Ana Beatriz Deleame","family":"Medeiros","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3733-965X","authenticated-orcid":false,"given":"Vanessa Nascimento","family":"Kozak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9711-6362","authenticated-orcid":false,"given":"Clarissa Gondim","family":"Pican\u00e7o-Albuquerque","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederico Guilherme Keche Virmond","family":"Neto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1891-9221","authenticated-orcid":false,"given":"Gabriel Oliveira","family":"dos Santos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel Aguiar","family":"Junior","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1838-2153","authenticated-orcid":false,"given":"Jos\u00e9 Claudio","family":"Casali-da-Rocha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5667-1418","authenticated-orcid":false,"given":"Dirce Maria","family":"Carraro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8659-5329","authenticated-orcid":false,"given":"Giovana Tardin","family":"Torrezan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng828"},{"key":"e_1_2_12_2_2","volume-title":"GeneReviews [Internet]","author":"Nielsen M.","year":"2012"},{"key":"e_1_2_12_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)13805-6"},{"key":"e_1_2_12_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2017.04.022"},{"key":"e_1_2_12_5_2","doi-asserted-by":"publisher","DOI":"10.1155\/2024\/8520275"},{"key":"e_1_2_12_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2019-320462"},{"key":"e_1_2_12_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2017.9"},{"key":"e_1_2_12_8_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.595675"},{"key":"e_1_2_12_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30916-1"},{"key":"e_1_2_12_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_12_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-021-01004-8"},{"key":"e_1_2_12_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23640"},{"key":"e_1_2_12_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2024.102266"},{"key":"e_1_2_12_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03758-y"},{"key":"e_1_2_12_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28648-3"},{"key":"e_1_2_12_16_2","unstructured":"MedeirosA. B. D. KRAS-G12C: um biomarcador negligenciado para detectar indiv\u00edduos com Polipose Associada ao MUTYH [dissertation] 2025 A.C.Camargo Cancer Center https:\/\/accamargo.phlnet.com.br\/MESTRADO\/2024\/MEDEIROSABD\/MEDEIROSABD.pdf."},{"key":"e_1_2_12_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"key":"e_1_2_12_18_2","article-title":"MUTYH-Associated Polyposis: The Irish Experience","volume":"109","author":"McVeigh T. 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