{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T11:30:28Z","timestamp":1775129428832,"version":"3.50.1"},"reference-count":29,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"3","license":[{"start":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T00:00:00Z","timestamp":1614211200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Commun"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Lynch syndrome (LS) is a hereditary condition characterized by a high risk of colorectal cancer, endometrial cancer, and other neoplasia associated with germline alterations in DNA mismatch repair genes. The classical genetic diagnostic strategy for LS consists of the Sanger sequencing of genes associated with the suspected syndrome. Next\u2010generation sequencing (NGS) enables the simultaneous sequencing of a large number of hereditary cancer genes. Here, we aimed to study whether other germline pathogenic variants of hereditary cancer genes are present in patients with LS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">A cohort of 84 probands with a previous genetic diagnosis of LS by Sanger sequencing was reanalyzed using NGS via a commercial panel of 94 hereditary cancer genes by hybrid capture. The American College of Medical Genetics and Genomics criteria were used to classify the clinical significance of the variants. The findings of NGS were confirmed by Sanger sequencing. When possible, genetic analyses of the new findings in the proband's relatives were also performed by Sanger sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      We identified five families (6%), out of 84, with at least two germline pathogenic variants conferring to high or moderate risk in different dominant cancer\u2010predisposing genes: [\n                      <jats:italic toggle=\"yes\">MLH1\u2010BRCA2\u2010NBN<\/jats:italic>\n                      ], [\n                      <jats:italic toggle=\"yes\">MLH1\u2010BRCA1<\/jats:italic>\n                      ], [\n                      <jats:italic toggle=\"yes\">MSH2\u2010ATM<\/jats:italic>\n                      ], [\n                      <jats:italic toggle=\"yes\">MSH6\u2010NF1<\/jats:italic>\n                      ], and [\n                      <jats:italic toggle=\"yes\">MLH1\u2010FANCA<\/jats:italic>\n                      ]. Interestingly, only one out of these five families exhibited a clinical phenotype associated with the new pathogenic variants. The family with three pathogenic variants of the [\n                      <jats:italic toggle=\"yes\">MLH1\u2010BRCA2\u2010NBN<\/jats:italic>\n                      ] genes showed a high aggregation of tumors associated with LS and breast and ovarian cancer syndrome.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Our results showed that the co\u2010occurrence of more than one pathogenic variant in cancer\u2010predisposing genes was remarkable among cases of LS. In most cases, no clinicial manifestations were associated with the secondary pathogenic variants. Further studies are needed to confirm these findings and elucidate their clinical impact. Reanalysis of LS families should be considered only in families with mixed clinical phenotypes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.12134","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T09:54:30Z","timestamp":1614246870000},"page":"218-228","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Co\u2010occurrence of germline pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome"],"prefix":"10.34133","volume":"41","author":[{"given":"Rosario","family":"Ferrer\u2010Avargues","sequence":"first","affiliation":[{"name":"FISABIO\u2010 Elche Health Department","place":["Elche, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Isabel","family":"Castillejo","sequence":"additional","affiliation":[{"name":"FISABIO\u2010 Elche Health Department","place":["Elche, Spain"]},{"name":"Molecular Genetics Unit. Elche University Hospital","place":["Elche, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Estela","family":"D\u00e1maso","sequence":"additional","affiliation":[{"name":"FISABIO\u2010 Elche Health Department","place":["Elche, Spain"]},{"name":"Molecular Genetics Unit. Elche University Hospital","place":["Elche, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia","family":"D\u00edez\u2010Obrero","sequence":"additional","affiliation":[{"name":"FISABIO\u2010 Elche Health Department","place":["Elche, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noem\u00ed","family":"Garrigos","sequence":"additional","affiliation":[{"name":"Immunological Center of Alicante","place":["San Juan\u2010Alicante, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana","family":"Molina","sequence":"additional","affiliation":[{"name":"Immunological Center of Alicante","place":["San Juan\u2010Alicante, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"Codo\u00f1er\u2010Alejos","sequence":"additional","affiliation":[{"name":"FISABIO\u2010 Elche Health Department","place":["Elche, Spain"]},{"name":"Molecular Genetics Unit. Elche University Hospital","place":["Elche, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1ngel","family":"Segura","sequence":"additional","affiliation":[{"name":"Cancer Genetic Counseling Unit. La Fe University Hospital","place":["Valencia, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Beatriz","family":"S\u00e1nchez\u2010Heras","sequence":"additional","affiliation":[{"name":"FISABIO\u2010 Elche Health Department","place":["Elche, Spain"]},{"name":"Cancer Genetic Counseling Unit. Elche University Hospital","place":["Elche, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adela","family":"Castillejo","sequence":"additional","affiliation":[{"name":"FISABIO\u2010 Elche Health Department","place":["Elche, Spain"]},{"name":"Molecular Genetics Unit. Elche University Hospital","place":["Elche, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0234-9188","authenticated-orcid":false,"given":"Jos\u00e9 Luis","family":"Soto","sequence":"additional","affiliation":[{"name":"FISABIO\u2010 Elche Health Department","place":["Elche, Spain"]},{"name":"Molecular Genetics Unit. Elche University Hospital","place":["Elche, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"221","published-online":{"date-parts":[[2021,2,25]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3878"},{"issue":"3","key":"e_1_3_2_3_2","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1002\/humu.22262","article-title":"Cancer Risks for MLH1 and MSH2 Mutation Carriers","volume":"34","author":"Dowty JG","year":"2013","unstructured":"Dowty JG, Win AK, Buchanan DD, Lindor NM, Macrae FA, Clendenning M, et\u00a0al. 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