<i>APC</i>Mutation marks an aggressive subtype of<i>BRAF</i>mutant colorectal cancers

Fennell, Lochlan J.; Kane, Alexandra; Liu, Cheng; McKeone, Diane; Fernando, Winnie; Su, Chang; Bond, Catherine; Jamieson, Saara; Dumenil, Troy; Patch, Ann‐Marie; Kazakoff, Stephen H.; Pearson, John V.; Waddell, Nicola; Leggett, Barbara A.; Whitehall, Vicki

doi:10.1101/2020.02.16.942904

Cited by 8 publications

(14 citation statements)

References 43 publications

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“… 24 Therefore, BRAF -mutated CRC harbored more RNF43 mutations and fewer APC alterations compared to BRAF wild-type CRC. 25 In addition, the mutual exclusivity between RNF43 and APC mutations in BRAF V600E-mutant CRC was consistently observed in our and others’ studies. 25 Fennell et al have shown that APC mutations could induce aggressive biological behaviors and poor prognosis in BRAF V600E-mutant CRC, whereas RNF43 mutations were associated with prolonged OS.…”

Section: Discussionsupporting

confidence: 81%

Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR/BRAF inhibitors

Wang

et al. 2022

Ther Adv Med Oncol

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Background: Combinatorial inhibition of epidermal growth factor receptor (EGFR) and BRAF shows remarkable clinical benefits in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC). However, the tumor may inevitably develop resistance to the targeted therapy, thereby limiting the response rate and durability. This study aimed to determine the genetic alterations associated with intrinsic and acquired resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC. Methods: Targeted sequencing of 520 cancer-related genes was performed in tumor tissues and in plasma samples collected from patients with BRAF V600E-mutant mCRC, who were treated with EGFR/BRAF ± MEK inhibitors, before and after the targeted treatment. Clinical benefit was defined as an objective response or a stable disease lasting longer than the median progression-free survival (PFS). Results: In all, 25 patients with BRAF V600E-mutant mCRC were included in this study. Those with RNF43 mutations ( n = 8) were more likely to achieve clinical benefit from EGFR/BRAF inhibitors than those with wild-type RNF43 (87.5% versus 37.5%, p = 0.034). Genetic alterations in receptor tyrosine kinase genes ( n = 6) were associated with worse PFS ( p = 0.005). Among the 23 patients whose disease progressed after the EGFR/BRAF-targeted therapy, at least one acquired resistance-related mutation was detected in 12 patients. Acquired mutations were most frequently observed in the mitogen-activated protein kinase pathway-related genes ( n = 9), including KRAS (G12D and Q61H/R), NRAS (Q61L/R/K and amplification), BRAF (amplification), and MEK1 (K57T). MET amplification and PIK3R1 Q579fs mutation emerged in three patients and one patient, respectively, after disease progression. Conclusion: Multiple genetic alterations are associated with clinical benefits and resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC. Our findings provide novel insights into strategies for overcoming resistance to EGFR/BRAF inhibitors in patients with BRAF V600E-mutant mCRC.

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Section: Discussionsupporting

confidence: 81%

Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR/BRAF inhibitors

Wang

et al. 2022

Ther Adv Med Oncol

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“…The model genes APC and BRAF were selected to demonstrate the utility of this presented pipeline. APC and BRAF mutation assessment have been useful and expedient in prognosis of CRC and their relative expression levels and mutational status have been implicated in treatment response 7,9 . In the present study our analysis of existing clinical datasets shows a significant reduction in APC mRNA expression levels that occurs in distinct anatomical regions of colon tumour tissue when compared to healthy colon tissue (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“…Two genes important in CRC are the tumour suppressor gene adenomatous polyposis coli (APC) and the oncogene B-Raf proto-oncogene (BRAF), implicated in CRC development 7,9 . The most common CRC activation pathway, which is responsible for 70-80% of all CRC diagnoses, is triggered due to inactivation of the tumour suppressor gene APC, which has an important role in the wnt signalling pathway, intercellular adhesion, cytoskeleton stabilisation, cell cycle regulation and apoptosis [10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

Development of an accessible gene expression bioinformatics pipeline to study driver mutations of colorectal cancer

Driest

Johnson

Rattray

et al. 2021

Preprint

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Colorectal cancer (CRC) is a global cause of cancer-related mortality driven by genetic and environmental factors which influence therapeutic outcomes. The emergence of next-generation sequencing technologies enables the rapid and extensive collection and curation of genetic data for each cancer type into clinical gene expression biobanks.In this study we used a combination of bioinformatics tools to investigate the expression patterns and prognostic significance of two genes, adenomatous polyposis coli (APC) and B-Raf proto-oncogene (BRAF), that are commonly dysregulated in colon cancer. Subsequently, we investigated the pathways and biomolecular effectors implicated in APC and BRAF function.Our results show mutation types, frequency, anatomical location and differential expression patterns for APC and BRAF between colorectal tumour and matched healthy tissue. The prognostic values of APC and BRAF was investigated as a function of expression level in CRC and other cancer types.In the era of precision medicine and with significant advancements in biobanking and data curation, there is significant scope to use existing clinical datasets for evaluating the role of mutational drivers in carcinogenesis. This offers the potential for studying combinations of less well-known genes and the discovery of novel biomarkers or studying the association between various effector proteins and pathways.

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“…The top three most statistically different genomic alterations specific to APC mut-CRCs were PTPRK-RSPO3 gene fusions (p = 1.3 x 10 -5 ), RNF43 mutations (p = 4.7 x 10 -5 ) and BRAF mutations (p = 1.9 x 10 -4 ). These genetic alterations have been identified in CRC previously with evidence for mutual exclusivity with APC mutations [27][28][29][30] . (The RNF43 mutation G659Vfs*41, which is associated with MSI CRCs, was not present in the tumors analyzed here 31 .)…”

Section: Wnt Signaling Mutations In Apc Mut-crcsmentioning

confidence: 95%

Molecular Drivers of Tumor Progression in Microsatellite Stable APC Mutation-Negative Colorectal Cancers

Grant

Xicola

Nguyen

et al. 2021

Preprint

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Background: The tumor suppressor gene adenomatous polyposis coli (APC) is the initiating mutation in approximately 80% of all colorectal cancers (CRC), underscoring the importance of aberrant regulation of intracellular WNT signaling in CRC development. Recent studies have found that early-onset CRC exhibits an increased proportion of tumors lacking an APC mutation. We set out to identify mechanisms underlying APC mutation-negative (APCmut-) CRCs. Methods: We analyzed data from The Cancer Genome Atlas to compare clinical phenotypes, somatic mutations, copy number variations, gene fusions, RNA expression, and DNA methylation profiles between APCmut- and APC mutation-positive (APCmut+) microsatellite stable CRCs. Results: Transcriptionally, APCmut- CRCs clustered into two approximately equal groups. Cluster One was associated with enhanced mitochondrial activation. Cluster Two was strikingly associated with genetic inactivation or decreased RNA expression of the WNT antagonist RNF43, increased expression of the WNT agonist RSPO3, activating mutation of BRAF, or increased methylation and decreased expression of AXIN2. APCmut- CRCs exhibited evidence of increased immune cell infiltration, with significant correlation between M2 macrophages and RSPO3. Conclusions: APCmut- CRCs comprise two groups of tumors characterized by enhanced mitochondrial activation or increased sensitivity to extracellular WNT, suggesting that they could be respectively susceptible to inhibition of these pathways.

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APCMutation marks an aggressive subtype ofBRAFmutant colorectal cancers

Cited by 8 publications

References 43 publications

Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR/BRAF inhibitors

Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR/BRAF inhibitors

Development of an accessible gene expression bioinformatics pipeline to study driver mutations of colorectal cancer

Molecular Drivers of Tumor Progression in Microsatellite Stable APC Mutation-Negative Colorectal Cancers

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