BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis

Cremolini, Chiara; Bartolomeo, Maria Di; Amatu, Alessio; Antoniotti, Carlotta; Moretto, Roberto; Berenato, Rosa; Perrone, Francesco; Tamborini, Elena; Aprile, Giuseppe; Lonardi, Sara; Sartore-Bianchi, Andrea; Fontanini, Gabriella; Milione, Massimo; Lauricella, Calogero; Siena, Salvatore; Falcone, Alfredo; Braud, Filippo de; Loupakis, Fotios; Pietrantonio, Filippo

doi:10.1093/annonc/mdv290

Cited by 145 publications

(142 citation statements)

References 22 publications

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“…The frequency of BRAF D594G mutations in colorectal cancers has been reported as 0.3-2.3% of colorectal cancers [13,14,15,16,17,18,19,20,21]. To date, 22 colorectal cancers with BRAF D594G mutations have been registered in the COSMIC database (http://cancer.sanger.ac.uk/cosmic); however, since BRAF D594G mutations are rare in colorectal cancer, it is difficult to draw conclusions based on these data.…”

Section: Discussionmentioning

confidence: 99%

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Colorectal Cancer with BRAF D594G Mutation Is Not Associated with Microsatellite Instability or Poor Prognosis

Amaki-Takao

Yamaguchi²,

Natsume³

et al. 2016

Oncology

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Objective:BRAF D594G mutations in colorectal cancer patients are not clearly understood. We retrospectively investigated the clinicopathological features of colorectal cancers with BRAF D594G mutations. Methods: We selected 908 colorectal cancer patients who underwent surgical resection from January 2008 to January 2013, and assessed BRAF, KRAS, microsatellite instability, and CpG island methylator phenotype (CIMP). Results: We detected BRAF D594G in 7 patients and BRAF V600E in 45 patients. The clinicopathological features of cancers with BRAF D594G mutation were similar to those with BRAF wild-type, but differed from those with BRAF V600E mutations. Regarding microsatellite instability status, 44.4% of cases with BRAF V600E mutations exhibited high microsatellite instability, compared to 14.3% of those with BRAF D594G mutations and 4.4% of those with BRAF wild-type. There were no CIMP-positive tumors in cancers with BRAF D594G mutations, whereas 67.8% of tumors with BRAF V600E mutations were CIMP-positive. In stage IV cancers, the survival rates of patients at 2 years were 8.5, 50.0, and 68.2% in the BRAF V600E mutation, BRAF D594G mutation, and BRAF wild-type groups, respectively. Conclusion: Colorectal cancers with BRAF D594G mutations exhibit similar clinicopathological features, microsatellite instability status, and prognosis as those with BRAF wild-type.

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Section: Discussionmentioning

confidence: 99%

“…A recent report demonstrated that colorectal cancers with rare BRAF mutations, including in codons 594 and 596, were MSS in MSI status and showed favorable prognoses compared to those with BRAF V600E mutations [21]. Moreover, the kinase activity of BRAF mutations at codon 594 was reported to be low [22,23,24].…”

Section: Discussionmentioning

confidence: 99%

Colorectal Cancer with BRAF D594G Mutation Is Not Associated with Microsatellite Instability or Poor Prognosis

Amaki-Takao

Yamaguchi²,

Natsume³

et al. 2016

Oncology

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“…Dagegen waren die BRAF-594-und 596-Mutationen häu-figer mit rektalen und nicht-muzinösen Tumoren ohne peritoneale Metastasierung assoziiert. Die untersuchten BRAF-594-und 596-Tumoren waren alle Mikrosatelliten-stabil und waren darüber hinaus mit erheblich längeren Überlebenszeiten (Median 62,0 vs. 12,6 Monate; HR 0,36, p = 0,002) verbunden [1060].…”

Section: Braf-mutationunclassified

“…Quellen: [1060,1117] Konsens Hintergrund Eine BRAF-V600-Mutation wird bei 8 -12 % der mKRK-Patienten beobachtet. Häufiger sind Frauen betroffen, das Erkankungsalter ist meist höher.…”

Section: Level Of Evidenceunclassified

S3-Leitlinie – Kolorektales Karzinom

Schmiegel

Buchberger

Follmann³

et al. 2017

Z Gastroenterol

151

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“…The coexistence of both KRAS and BRAF is uncommon in CRC patients. In the present study, patients ID 3 and 19 carried 2 different BRAF mutations: Val600Glu (A>T, rs113488022) [54] and Gly596Val (C>A), both variants are pathogenic with different molecular, pathological characteristics and clinical outcomes [55]. These two patients could be benefit from anti-BRAF in combination with anti-EGFR or anti-MAPK [56].…”

Section: Tp53 Showed the Highest Percentage Of Germline Inherited Mutmentioning

confidence: 85%

Genetic Variations of Selected Genes Using Target Deep Sequencing in Colorectal Cancer Patients

Farghal¹,

Saied²,

Ghaith³

et al. 2017

J Cancer Sci Ther

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Background: Colorectal carcinoma (CRC) is a burden problem in a developing country like Egypt since patients are usually admitted in late stage with bad prognosis and short overall survival. Because of genetic predisposition of CRC and introduction of advanced molecular techniques, efforts are directed to screen for potential pathogenic or disease-causing variants in CRC patients Methods: DNA was isolated from formalin fixed paraffin embedded tissue sections collected from 24 CRC confirmed diagnosed patients. TruSight CRC panel (Illumina) was used for detection of different variants in 15 genes. The generated reads were obtained from Illumina Miseq were clustered into single nucleotide polymorphism (SNPs) and small insertions/deletions (Indels). Further pathogenic variants with somatic and germline mutations were identified according to the recommended criteria. Some CRC patients were subjected to anti-EGFR target therapy.Results: Most of the variants were detected in TP53 gene 140 variants (65%); 105 short deletions none of them was pathogenic, 29 missense mutations and 6 SNPs at splicing sites. Next, ERBB2 has got 17 variants (8.8%) (missense and splicing), 8 of them were damaging disease causing variants. Besides, 16 pathogenic variants were identified in 12 patients (6 in TP53 and 7 in KRAS). Some pathogenic variants were not reported before in CRC e.g. TP53 C>A, rs121912654, Val157Phe. Additionally, patients carried different KRAS wild mutations showed variable response to anti-EGFR target therapy. Conclusion:The most affected pathway in CRC was TP53 pathway followed by ERBB2, NRAS, KRAS and PIK3CA genes. Variable response to target therapy suggested dependence on the type of pathogenic variant identified, also a possible role of ERBB2 which had a significant variant frequency.NRAS. The prevalence rate of TP53 mutation in Arab population is 52.5% compared to 47.5% in matched Western population [7]. TP53 mutations have roles in determining progression, invasiveness and also metastasis of CRC. So, CRC patients with mutant TP53 have more progressive phenotype and poorer survival than those with TP53 wild type [8]. The phosphatidylinositol 3-kinase/Akt/mammalian target of

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BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis

Cited by 145 publications

References 22 publications

Colorectal Cancer with <b><i>BRAF</i></b> D594G Mutation Is Not Associated with Microsatellite Instability or Poor Prognosis

Colorectal Cancer with <b><i>BRAF</i></b> D594G Mutation Is Not Associated with Microsatellite Instability or Poor Prognosis

S3-Leitlinie – Kolorektales Karzinom

Genetic Variations of Selected Genes Using Target Deep Sequencing in Colorectal Cancer Patients

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