{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T22:35:33Z","timestamp":1785105333780,"version":"3.55.0"},"reference-count":32,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T00:00:00Z","timestamp":1715299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: The predictive and prognostic role of BRAF alterations has been evaluated in colorectal cancer (CRC); however, BRAF alterations have not been fully characterized in non-CRC gastrointestinal (GI) malignancies. In the present study, we report the frequency and spectrum of BRAF alterations among patients with non-CRC GI malignancies. Methods: Patients with CRC and non-CRC GI malignancies who underwent somatic tumor profiling via a tissue-based or liquid-based assay were included in this study. Gain-of-function BRAF alterations were defined as pathogenic\/likely pathogenic somatic short variants (SVs), copy number amplifications \u22658, or fusions (RNA or DNA). Results: Among 51,560 patients with somatic profiling, 40% had CRC and 60% had non-CRC GI malignancies. BRAF GOF alterations were seen more frequently in CRC (8.9%) compared to non-CRC GI malignancies (2.2%) (p &lt; 0.001). Non-CRC GI malignancies with the highest prevalence of BRAF GOF alterations were bile duct cancers (4.1%) and small intestine cancers (4.0%). Among BRAF GOF alterations, class II (28% vs. 6.8%, p &lt; 0.001) and class III (23% vs. 14%, p &lt; 0.001) were more common in non-CRC GI malignancies. Among class II alterations, rates of BRAF amplifications (3.1% vs. 0.3%, p &lt; 0.001) and BRAF fusions (12% vs. 2.2%, p &lt; 0.001) were higher in non-CRC GI malignancies compared to CRC. Conclusions: Non-CRC GI malignancies demonstrate a distinct BRAF alteration profile compared to CRC, with a higher frequency of class II and III mutations, and more specifically, a higher incidence of BRAF fusions. Future studies should evaluate clinical implications for the management of non-CRC GI patients with BRAF alterations, especially BRAF fusions.<\/jats:p>","DOI":"10.3390\/cancers16101823","type":"journal-article","created":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T09:22:52Z","timestamp":1715332972000},"page":"1823","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Frequency of Common and Uncommon BRAF Alterations among Colorectal and Non-Colorectal Gastrointestinal Malignancies"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1111-8333","authenticated-orcid":false,"given":"Amit","family":"Mahipal","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1266-7393","authenticated-orcid":false,"given":"Michael H.","family":"Storandt","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5506-1749","authenticated-orcid":false,"given":"Emily A.","family":"Teslow","sequence":"additional","affiliation":[{"name":"Tempus AI, Chicago, IL 60654, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1386-614X","authenticated-orcid":false,"given":"Ellen","family":"Jaeger","sequence":"additional","affiliation":[{"name":"Tempus AI, Chicago, IL 60654, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa C.","family":"Stoppler","sequence":"additional","affiliation":[{"name":"Tempus AI, Chicago, IL 60654, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7844-5833","authenticated-orcid":false,"given":"Zhaohui","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1582-098X","authenticated-orcid":false,"given":"Sakti","family":"Chakrabarti","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"\u015amiech, M., Leszczy\u0144ski, P., Kono, H., Wardell, C., and Taniguchi, H. (2020). Emerging BRAF Mutations in Cancer Progression and Their Possible Effects on Transcriptional Networks. Genes, 11.","DOI":"10.3390\/genes11111342"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1038\/nrc1434","article-title":"Switching on kinases: Oncogenic activation of BRAF and the PDGFR family","volume":"4","author":"Dibb","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1186\/s12967-019-2036-7","article-title":"The association between BRAF mutation class and clinical features in BRAF-mutant Chinese non-small cell lung cancer patients","volume":"17","author":"Lin","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/S0092-8674(04)00215-6","article-title":"Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF","volume":"116","author":"Wan","year":"2004","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3954","DOI":"10.1158\/1078-0432.CCR-19-0311","article-title":"Class 1, 2, and 3 BRAF-Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, and Molecular Characterization","volume":"25","author":"Schirripa","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2706","DOI":"10.1200\/JCO.21.02541","article-title":"BRAF-Mutated Advanced Colorectal Cancer: A Rapidly Changing Therapeutic Landscape","volume":"40","author":"Ciombor","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1093\/annonc\/mdx401","article-title":"BRAF mutant colorectal cancer: Prognosis, treatment, and new perspectives","volume":"28","author":"Argiles","year":"2017","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1038\/s41591-023-02321-8","article-title":"Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: The phase 2 ROAR trial","volume":"29","author":"Subbiah","year":"2023","journal-title":"Nat. Med."},{"key":"ref_9","unstructured":"(2024, March 14). Tempus xT Gene Panel List and Validation. Available online: https:\/\/www.tempus.com\/wp-content\/uploads\/2023\/06\/Tempus-xT_Gene-Panel.pdf."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1038\/s41587-019-0259-z","article-title":"Integrated genomic profiling expands clinical options for patients with cancer","volume":"37","author":"Beaubier","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.18632\/oncotarget.26797","article-title":"Clinical validation of the tempus xT next-generation targeted oncology sequencing assay","volume":"10","author":"Beaubier","year":"2019","journal-title":"Oncotarget"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/s00262-022-03252-y","article-title":"Comparison of the tumor immune microenvironment and checkpoint blockade biomarkers between stage III and IV non-small cell lung cancer","volume":"72","author":"Gao","year":"2023","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/s41698-021-00202-2","article-title":"Validation of a liquid biopsy assay with molecular and clinical profiling of circulating tumor DNA","volume":"5","author":"Finkle","year":"2021","journal-title":"NPJ Precis. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e2100321","DOI":"10.1200\/PO.21.00321","article-title":"Longitudinal Shifts of Solid Tumor and Liquid Biopsy Sequencing Concordance in Metastatic Breast Cancer","volume":"6","author":"Liu","year":"2022","journal-title":"JCO Precis. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Chen, Y., Sun, H., Deng, Y., Ma, Y., Huang, H., Liu, Y., Zhang, Y., Zhang, H., Ye, S., and Mingyan, E. (2023). The clinical and genomic distinctions of Class1\/2\/3 BRAF-mutant colorectal cancer and differential prognoses. Biomark. Res., 11.","DOI":"10.1186\/s40364-022-00443-8"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1177\/1535370220959657","article-title":"Prevalence of class I\u2013III BRAF mutations among 114,662 cancer patients in a large genomic database","volume":"246","author":"Owsley","year":"2021","journal-title":"Exp. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"E231476","DOI":"10.1001\/jamanetworkopen.2023.1476","article-title":"Association of BRAF Variants with Disease Characteristics, Prognosis, and Targeted Therapy Response in Intrahepatic Cholangiocarcinoma","volume":"6","author":"Xin","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Rizzo, A., Di Federico, A., Ricci, A.D., Frega, G., Palloni, A., Pagani, R., Tavolari, S., Di Marco, M., and Brandi, G. (2020). Targeting BRAF-Mutant Biliary Tract Cancer: Recent Advances and Future Challenges. Cancer Control, 27.","DOI":"10.1177\/1073274820983013"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1016\/S1470-2045(20)30321-1","article-title":"Dabrafenib plus trametinib in patients with BRAF V600E-mutated biliary tract cancer (ROAR): A phase 2, open-label, single-arm, multicentre basket trial","volume":"21","author":"Subbiah","year":"2020","journal-title":"Lancet. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Pandya, K., Overman, M.J., and Gulhati, P. (2022). Molecular Landscape of Small Bowel Adenocarcinoma. Cancers, 14.","DOI":"10.3390\/cancers14051287"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1001\/jamaoncol.2017.1051","article-title":"Genomic Profiling of Small-Bowel Adenocarcinoma","volume":"3","author":"Schrock","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"H\u00e4nninen, U.A., Katainen, R., Tanskanen, T., Plaketti, R.M., Laine, R., Hamberg, J., Ristim\u00e4ki, A., Pukkala, E., Taipale, M., and Mecklin, J.P. (2018). Exome-wide somatic mutation characterization of small bowel adenocarcinoma. PLoS Genet., 14.","DOI":"10.1371\/journal.pgen.1007200"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"731-e1498","DOI":"10.1002\/onco.13795","article-title":"Efficacy and Safety of Trametinib in Non-V600 BRAF Mutant Melanoma: A Phase II Study","volume":"26","author":"Nebhan","year":"2021","journal-title":"Oncologist"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e2200107","DOI":"10.1200\/PO.22.00107","article-title":"Clinical Activity of Mitogen-Activated Protein Kinase-Targeted Therapies in Patients with Non-V600 BRAF-Mutant Tumors","volume":"6","author":"Dankner","year":"2022","journal-title":"JCO Precis. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3900","DOI":"10.18632\/oncotarget.27788","article-title":"MEK inhibitors in non-V600 BRAF mutations and fusions","volume":"11","author":"Johnson","year":"2020","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1158\/1078-0432.CCR-19-3443","article-title":"Trametinib Activity in Patients with Solid Tumors and Lymphomas Harboring BRAF Non-V600 Mutations or Fusions: Results from NCI-MATCH (EAY131)","volume":"26","author":"Johnson","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/PO.18.00195","article-title":"Targeted Therapy for Colorectal Cancers with Non-V600 BRAF Mutations: Perspectives for Precision Oncology","volume":"2","author":"Dankner","year":"2018","journal-title":"JCO Precis. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7089","DOI":"10.1158\/1078-0432.CCR-19-2004","article-title":"Response to Anti-EGFR Therapy in Patients with BRAF non-V600-Mutant Metastatic Colorectal Cancer","volume":"25","author":"Yaeger","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3502","DOI":"10.1158\/0008-5472.CAN-16-2745","article-title":"Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer","volume":"77","author":"Lu","year":"2017","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3183","DOI":"10.1038\/s41388-018-0171-x","article-title":"Classifying BRAF alterations in cancer: New rational therapeutic strategies for actionable mutations","volume":"37","author":"Dankner","year":"2018","journal-title":"Oncogene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1002\/ijc.29825","article-title":"The distribution of BRAF gene fusions in solid tumors and response to targeted therapy","volume":"138","author":"Ross","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1200\/JCO.2016.71.4394","article-title":"Non-V600 BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer","volume":"35","author":"Jones","year":"2017","journal-title":"J. Clin. Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/10\/1823\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:43:32Z","timestamp":1760107412000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/10\/1823"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,10]]},"references-count":32,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["cancers16101823"],"URL":"https:\/\/doi.org\/10.3390\/cancers16101823","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,10]]}}}