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Activating mutations in codons 12 and 13 of the <jats:italic>KRAS<\/jats:italic> gene are the only established negative predictors of response to anti-EGFR therapy and patients whose tumors harbor such mutations are not candidates for therapy. However, 40 to 60% of wild-type cases do not respond to anti-EGFR therapy, suggesting the involvement of other genes that act downstream of EGFR in the RAS-RAF-MAPK and PI3K-AKT pathways or activating <jats:italic>KRAS<\/jats:italic> mutations at other locations of the gene.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>DNA was obtained from a consecutive series of 201 mCRC cases (FFPE tissue), wild-type for <jats:italic>KRAS<\/jats:italic> exon 2 (codons 12 and 13). Mutational analysis of <jats:italic>KRAS<\/jats:italic> (exons 3 and 4), <jats:italic>BRAF<\/jats:italic> (exons 11 and 15), and <jats:italic>PIK3CA<\/jats:italic> (exons 9 and 20) was performed by high resolution melting (HRM) and positive cases were then sequenced.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>One mutation was present in 23.4% (47\/201) of the cases and 3.0% additional cases (6\/201) had two concomitant mutations. A total of 53 cases showed 59 mutations, with the following distribution: 44.1% (26\/59) in <jats:italic>KRAS<\/jats:italic> (13 in exon 3 and 13 in exon 4), 18.6% (11\/59) in <jats:italic>BRAF<\/jats:italic> (two in exon 11 and nine in exon 15) and 37.3% (22\/59) in <jats:italic>PIK3CA<\/jats:italic> (16 in exon 9 and six in exon 20). In total, 26.4% (53\/201) of the cases had at least one mutation and the remaining 73.6% (148\/201) were wild-type for all regions studied. Five of the mutations we report, four in <jats:italic>KRAS<\/jats:italic> and one in <jats:italic>BRAF<\/jats:italic>, have not previously been described in CRC. <jats:italic>BRAF<\/jats:italic> and <jats:italic>PIK3CA<\/jats:italic> mutations were more frequent in the colon than in the sigmoid or rectum: 20.8% <jats:italic>vs.<\/jats:italic> 1.6% <jats:italic>vs.<\/jats:italic> 0.0% (<jats:italic>P=<\/jats:italic>0.000) for <jats:italic>BRAF<\/jats:italic> and 23.4% <jats:italic>vs.<\/jats:italic> 12.1% <jats:italic>vs.<\/jats:italic> 5.4% (<jats:italic>P<\/jats:italic>=0.011) for <jats:italic>PIK3CA<\/jats:italic> mutations.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>About one fourth of mCRC cases wild-type for <jats:italic>KRAS<\/jats:italic> codons 12 and 13 present other mutations either in <jats:italic>KRAS<\/jats:italic>, <jats:italic>BRAF<\/jats:italic>, or <jats:italic>PIK3CA<\/jats:italic>, many of which may explain the lack of response to anti-EGFR therapy observed in a significant proportion of these patients.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2407-13-169","type":"journal-article","created":{"date-parts":[[2013,4,1]],"date-time":"2013-04-01T18:14:04Z","timestamp":1364840044000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["High resolution melting analysis of KRAS, BRAF and PIK3CA in KRASexon 2 wild-type metastatic colorectal cancer"],"prefix":"10.1186","volume":"13","author":[{"given":"Joana G","family":"Guedes","sequence":"first","affiliation":[]},{"given":"Isabel","family":"Veiga","sequence":"additional","affiliation":[]},{"given":"Patr\u00edcia","family":"Rocha","sequence":"additional","affiliation":[]},{"given":"Pedro","family":"Pinto","sequence":"additional","affiliation":[]},{"given":"Carla","family":"Pinto","sequence":"additional","affiliation":[]},{"given":"Manuela","family":"Pinheiro","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Peixoto","sequence":"additional","affiliation":[]},{"given":"Maria","family":"Fragoso","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Raimundo","sequence":"additional","affiliation":[]},{"given":"Paula","family":"Ferreira","sequence":"additional","affiliation":[]},{"given":"Manuela","family":"Machado","sequence":"additional","affiliation":[]},{"given":"Nuno","family":"Sousa","sequence":"additional","affiliation":[]},{"given":"Paula","family":"Lopes","sequence":"additional","affiliation":[]},{"given":"Ant\u00f3nio","family":"Ara\u00fajo","sequence":"additional","affiliation":[]},{"given":"Joana","family":"Macedo","sequence":"additional","affiliation":[]},{"given":"Fernando","family":"Alves","sequence":"additional","affiliation":[]},{"given":"Camila","family":"Coutinho","sequence":"additional","affiliation":[]},{"given":"Rui","family":"Henrique","sequence":"additional","affiliation":[]},{"given":"L\u00facio L","family":"Santos","sequence":"additional","affiliation":[]},{"given":"Manuel R","family":"Teixeira","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2013,4,1]]},"reference":[{"issue":"2","key":"3799_CR1","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1056\/NEJMra044389","volume":"353","author":"DS Krause","year":"2005","unstructured":"Krause DS, Van Etten RA: Tyrosine kinases as targets for cancer therapy. 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