{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:39:13Z","timestamp":1760150353109,"version":"build-2065373602"},"reference-count":53,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T00:00:00Z","timestamp":1699401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico (FONDECYT)","doi-asserted-by":"publisher","award":["1200049","1220353","85220068"],"award-info":[{"award-number":["1200049","1220353","85220068"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ANID Subvenci\u00f3n a Instalaci\u00f3n en la Academia Convocatoria a\u00f1o 2022 (SIA)","award":["1200049","1220353","85220068"],"award-info":[{"award-number":["1200049","1220353","85220068"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cancer is a genomic disease, with driver mutations contributing to tumorigenesis. These potentially heritable variants influence risk and underlie familial breast cancer (BC). This study evaluated associations between BC risk and 13 SNPs in driver genes MAP3K1, SF3B1, SMAD4, ARID2, ATR, KMT2C, MAP3K13, NCOR1, and TBX3, in BRCA1\/2-negative Chilean families. SNPs were genotyped using TaqMan Assay in 492 cases and 1285 controls. There were no associations between rs75704921:C&gt;T (ARID2); rs2229032:A&gt;C (ATR); rs3735156:C&gt;G (KMT2C); rs2276738:G&gt;C, rs2293906:C&gt;T, rs4075943T:&gt;A, rs13091808:C&gt;T (MAP3K13); rs178831:G&gt;A (NCOR1); or rs3759173:C&gt;A (TBX3) and risk. The MAP3K1 rs832583 A allele (C\/A+A\/A) showed a protective effect in families with moderate BC history (OR = 0.7 [95% CI 0.5\u20130.9] p = 0.01). SF3B1 rs16865677-T (G\/T+T\/T) increased risk in sporadic early-onset BC (OR = 1.4 [95% CI 1.0\u20132.0] p = 0.01). SMAD4 rs3819122-C (A\/C+C\/C) increased risk in cases with moderate family history (OR = 2.0 [95% CI 1.3\u20132.9] p \u2264 0.0001) and sporadic cases diagnosed \u226450 years (OR = 1.6 [95% CI 1.1\u20132.2] p = 0.006). SMAD4 rs12456284:A&gt;G increased BC risk in G-allele carriers (A\/G + G\/G) in cases with \u22652 BC\/OC cases and early-onset cases (OR = 1.2 [95% CI 1.0\u20131.6] p = 0.04 and OR = 1.4 [95% CI 1.0\u20131.9] p = 0.03, respectively). Our study suggests that specific germline variants in driver genes MAP3K1, SF3B1, and SMAD4 contribute to BC risk in Chilean population.<\/jats:p>","DOI":"10.3390\/ijms242216076","type":"journal-article","created":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T07:02:05Z","timestamp":1699426925000},"page":"16076","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Association of Germline Variation in Driver Genes with Breast Cancer Risk in Chilean Population"],"prefix":"10.3390","volume":"24","author":[{"given":"Sebasti\u00e1n","family":"Morales-Pison","sequence":"first","affiliation":[{"name":"Centro de Oncolog\u00eda de Precisi\u00f3n (COP), Facultad de Medicina y Ciencias de la Salud, Universidad Mayor, Las Condes, Santiago 7560908, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1678-2708","authenticated-orcid":false,"given":"Julio C.","family":"Tapia","sequence":"additional","affiliation":[{"name":"Laboratorio de Transformaci\u00f3n Celular, Programa de Biolog\u00eda Celular y Molecular, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia, Santiago 783090, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2022-029X","authenticated-orcid":false,"given":"Sarai","family":"Morales-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica Humana, Programa de Gen\u00e9tica Humana, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia, Santiago 783090, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edio","family":"Maldonado","sequence":"additional","affiliation":[{"name":"Programa de Biolog\u00eda Celular y Molecular, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia, Santiago 783090, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00f3nica","family":"Acu\u00f1a","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica Humana, Programa de Gen\u00e9tica Humana, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia, Santiago 783090, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gloria M.","family":"Calaf","sequence":"additional","affiliation":[{"name":"Instituto de Alta Investigaci\u00f3n, Universidad de Tarapac\u00e1, Arica 1010069, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lilian","family":"Jara","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica Humana, Programa de Gen\u00e9tica Humana, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia, Santiago 783090, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"891824","DOI":"10.3389\/fonc.2022.891824","article-title":"Global Burden of Female Breast Cancer: Age-Period-Cohort Analysis of Incidence Trends From 1990 to 2019 and Forecasts for 2035","volume":"12","author":"Li","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_3","unstructured":"Government of Chile, Ministerio de Salud (2018). Plan Nacional de C\u00e1ncer 2018\u20132028."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1186\/bcr448","article-title":"Familial risks of breast cancer","volume":"4","author":"Easton","year":"2002","journal-title":"Breast Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1002\/1097-0142(19920915)70:4+<1747::AID-CNCR2820701616>3.0.CO;2-E","article-title":"Genetic predisposition to breast cancer","volume":"70","author":"Skolnick","year":"1992","journal-title":"Cancer"},{"key":"ref_6","first-page":"232","article-title":"Genetic analysis of breast cancer in the cancer and steroid hormone study","volume":"48","author":"Claus","year":"1991","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Jara, L., Morales, S., de Mayo, T., Gonzalez-Hormazabal, P., Carrasco, V., and Godoy, R. (2017). Mutations in BRCA1, BRCA2 and other breast and ovarian cancer susceptibility genes in Central and South American populations. Biol. Res., 50.","DOI":"10.1186\/s40659-017-0139-2"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"74233","DOI":"10.18632\/oncotarget.18815","article-title":"BRCA1 and BRCA2 founder mutations account for 78% of germline carriers among hereditary breast cancer families in Chile","volume":"8","author":"Alvarez","year":"2017","journal-title":"Oncotarget"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7531","DOI":"10.1007\/s11033-022-07561-4","article-title":"BRCA1 and BRCA2 screening of nine Chilean founder mutations through allelic-discrimination and real-time PCR in breast\/ovarian cancer patients","volume":"49","author":"Alvarez","year":"2022","journal-title":"Mol. Biol. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Apostolou, P., and Fostira, F. (2013). Hereditary breast cancer: The era of new susceptibility genes. Biomed. Res. Int., 2013.","DOI":"10.1155\/2013\/747318"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2692","DOI":"10.1002\/ijc.32309","article-title":"Recurrent moderate-risk mutations in Finnish breast and ovarian cancer patients","volume":"145","author":"Nurmi","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/nature07943","article-title":"The cancer genome","volume":"458","author":"Stratton","year":"2009","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1126\/science.1204040","article-title":"Exploring the genomes of cancer cells: Progress and promise","volume":"331","author":"Stratton","year":"2011","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nature11017","article-title":"The landscape of cancer genes and mutational processes in breast cancer","volume":"486","author":"Stephens","year":"2012","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/nrg3445","article-title":"Cancer genome-sequencing study design","volume":"14","author":"Mwenifumbo","year":"2013","journal-title":"Nat. Rev. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1038\/nature08987","article-title":"International network of cancer genome projects","volume":"464","author":"Hudson","year":"2010","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1016\/j.cell.2018.07.034","article-title":"Comprehensive Characterization of Cancer Driver Genes and Mutations","volume":"174","author":"Bailey","year":"2018","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/ng.2764","article-title":"The Cancer Genome Atlas Pan-Cancer analysis project","volume":"45","author":"Weinstein","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13073-018-0531-8","article-title":"Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterations","volume":"10","author":"Tamborero","year":"2018","journal-title":"Genome Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/s41568-020-0290-x","article-title":"A compendium of mutational cancer driver genes","volume":"20","author":"Muinos","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/nature11154","article-title":"Sequence analysis of mutations and translocations across breast cancer subtypes","volume":"486","author":"Banerji","year":"2012","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/nature11143","article-title":"Whole-genome analysis informs breast cancer response to aromatase inhibition","volume":"486","author":"Ellis","year":"2012","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/nature10933","article-title":"The clonal and mutational evolution spectrum of primary triple-negative breast cancers","volume":"486","author":"Shah","year":"2012","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s10552-017-0849-3","article-title":"Functional germline variants in driver genes of breast cancer","volume":"28","author":"Gohler","year":"2017","journal-title":"Cancer Causes Control"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1056\/NEJMoa1008433","article-title":"ARID1A mutations in endometriosis-associated ovarian carcinomas","volume":"363","author":"Wiegand","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Fernandez-Moya, A., Morales, S., Arancibia, T., Gonzalez-Hormazabal, P., Tapia, J.C., Godoy-Herrera, R., Reyes, J.M., Gomez, F., Waugh, E., and Jara, L. (2020). Germline Variants in Driver Genes of Breast Cancer and Their Association with Familial and Early-Onset Breast Cancer Risk in a Chilean Population. Cancers, 12.","DOI":"10.3390\/cancers12010249"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Morales-Pison, S., Gonzalez-Hormazabal, P., Tapia, J.C., Salas-Burgos, A., Ampuero, S., Gomez, F., Waugh, E., Reyes, J.M., and Jara, L. (2022). Heritable genomic diversity in breast cancer driver genes and associations with risk in a Chilean population. Biol. Res., 55.","DOI":"10.1186\/s40659-022-00384-4"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2650","DOI":"10.1038\/srep02650","article-title":"Comprehensive identification of mutational cancer driver genes across 12 tumor types","volume":"3","author":"Tamborero","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1158\/0008-5472.CAN-07-5283","article-title":"Prediction of cancer driver mutations in protein kinases","volume":"68","author":"Torkamani","year":"2008","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1186\/bcr2236","article-title":"The breast cancer somatic \u2018muta-ome\u2019: Tackling the complexity","volume":"11","author":"Teschendorff","year":"2009","journal-title":"Breast Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Nguyen, K., Tran, M.N., Rivera, A., Cheng, T., Windsor, G.O., Chabot, A.B., Cavanaugh, J.E., Collins-Burow, B.M., Lee, S.B., and Drewry, D.H. (2022). MAP3K Family Review and Correlations with Patient Survival Outcomes in Various Cancer Types. Front. Biosci. (Landmark Ed.), 27.","DOI":"10.31083\/j.fbl2705167"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1177\/1947601913513950","article-title":"MAP3K1: Genomic Alterations in Cancer and Function in Promoting Cell Survival or Apoptosis","volume":"4","author":"Pham","year":"2013","journal-title":"Genes Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/s41422-018-0044-4","article-title":"MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models","volume":"28","author":"Xue","year":"2018","journal-title":"Cell Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1007\/s13402-023-00805-w","article-title":"MAP3K1 expression is associated with progression and poor prognosis of hormone receptor-positive, HER2-negative early-stage breast cancer","volume":"46","author":"Kuo","year":"2023","journal-title":"Cell Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3892\/ol.2022.13187","article-title":"Spectrum of MAP3K1 mutations in breast cancer is luminal subtype-predominant and related to prognosis","volume":"23","author":"Li","year":"2022","journal-title":"Oncol. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"115018","DOI":"10.18632\/oncotarget.22983","article-title":"SF3B1 mutation is a poor prognostic indicator in luminal B and progesterone receptor-negative breast cancer patients","volume":"8","author":"Fu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1038\/leu.2014.73","article-title":"Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia","volume":"28","author":"Matsunawa","year":"2014","journal-title":"Leukemia"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1002\/path.4483","article-title":"SF3B1 mutations constitute a novel therapeutic target in breast cancer","volume":"235","author":"Maguire","year":"2015","journal-title":"J. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.3892\/ol.2015.3442","article-title":"SMAD4 expression in breast ductal carcinoma correlates with prognosis","volume":"10","author":"Liu","year":"2015","journal-title":"Oncol. Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4396","DOI":"10.1038\/sj.onc.1203798","article-title":"Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4","volume":"19","author":"Moren","year":"2000","journal-title":"Oncogene"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1093\/jnci\/92.17.1388","article-title":"Role of transforming growth factor-beta signaling in cancer","volume":"92","author":"Piek","year":"2000","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1200\/JCO.2002.08.125","article-title":"Assessment of molecular markers of clinical sensitivity to single-agent taxane therapy for metastatic breast cancer","volume":"20","author":"Tan","year":"2002","journal-title":"J. Clin. Oncol."},{"key":"ref_43","first-page":"1039","article-title":"Twenty-year results of the Naples GUN randomized trial: Predictive factors of adjuvant tamoxifen efficacy in early breast cancer","volume":"9","author":"Carlomagno","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1038\/sj.onc.1201017","article-title":"DPC4 (SMAD4) mediates transforming growth factor-beta1 (TGF-beta1) induced growth inhibition and transcriptional response in breast tumour cells","volume":"14","author":"Roelen","year":"1997","journal-title":"Oncogene"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.1039\/c0mb00016g","article-title":"Proteomics of Smad4 regulated transforming growth factor-beta signalling in colon cancer cells","volume":"6","author":"Ali","year":"2010","journal-title":"Mol. Biosyst."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1093\/annonc\/mds333","article-title":"The prognostic role of TGF-beta signaling pathway in breast cancer patients","volume":"24","author":"Dekker","year":"2013","journal-title":"Ann. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"52","DOI":"10.14449\/jbd.2019.7.2.52","article-title":"Clinicopathological significance of SMAD4 expression in breast cancer","volume":"7","author":"Woo","year":"2019","journal-title":"J. Breast Dis."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Stuelten, C.H., Buck, M.B., Dippon, J., Roberts, A.B., Fritz, P., and Knabbe, C. (2006). Smad4-expression is decreased in breast cancer tissues: A retrospective study. BMC Cancer, 6.","DOI":"10.1186\/1471-2407-6-25"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/1476-4598-8-111","article-title":"Dual effects of TGF-beta on ERalpha-mediated estrogenic transcriptional activity in breast cancer","volume":"8","author":"Ren","year":"2009","journal-title":"Mol. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Marouf, C., Gohler, S., Filho, M.I., Hajji, O., Hemminki, K., Nadifi, S., and Forsti, A. (2016). Analysis of functional germline variants in APOBEC3 and driver genes on breast cancer risk in Moroccan study population. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2210-8"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s10689-022-00289-x","article-title":"Juvenile polyposis diagnosed with an integrated histological, immunohistochemical and molecular approach identifying new SMAD4 pathogenic variants","volume":"21","author":"Mafficini","year":"2022","journal-title":"Fam. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"599719","DOI":"10.3389\/fonc.2021.599719","article-title":"Genetic Variations in the Transforming Growth Factor-beta1 Pathway May Improve Predictive Power for Overall Survival in Non-small Cell Lung Cancer","volume":"11","author":"Zhang","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nprot.2006.83","article-title":"The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: Twenty-something years on","volume":"1","author":"Chomczynski","year":"2006","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16076\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:19:18Z","timestamp":1760131158000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16076"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,8]]},"references-count":53,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242216076"],"URL":"https:\/\/doi.org\/10.3390\/ijms242216076","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,11,8]]}}}