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Article

APC Mutation Marks an Aggressive Subtype of BRAF Mutant Colorectal Cancers

1
QIMR Berghofer Medical Research Institute, Queensland 4006, Australia
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School of Medicine, The University of Queensland, Queensland 4072, Australia
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Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Herston 4006, Australia
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Envoi Specialist Pathologists, Queensland 4059, Australia
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Department of Gastroenterology and Hepatology, The Royal Brisbane and Women’s Hospital, Queensland 4006, Australia
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(5), 1171; https://doi.org/10.3390/cancers12051171
Received: 17 April 2020 / Accepted: 1 May 2020 / Published: 6 May 2020
Background: WNT activation is a hallmark of colorectal cancer. BRAF mutation is present in 15% of colorectal cancers, and the role of mutations in WNT signaling regulators in this context is unclear. Here, we evaluate the mutational landscape of WNT signaling regulators in BRAF mutant cancers. Methods: we performed exome-sequencing on 24 BRAF mutant colorectal cancers and analyzed these data in combination with 175 publicly available BRAF mutant colorectal cancer exomes. We assessed the somatic mutational landscape of WNT signaling regulators, and performed hotspot and driver mutation analyses to identify potential drivers of WNT signaling. The effects of Apc and Braf mutation were modelled, in vivo, using the Apcmin/+ and BrafV637/Villin-CreERT2/+ mouse, respectively. Results: RNF43 was the most frequently mutated WNT signaling regulator (41%). Mutations in the beta-catenin destruction complex occurred in 48% of cancers. Hotspot analyses identified potential cancer driver genes in the WNT signaling cascade, including MEN1, GNG12 and WNT16. Truncating APC mutation was identified in 20.8% of cancers. Truncating APC mutation was associated with early age at diagnosis (p < 2 × 10−5), advanced stage (p < 0.01), and poor survival (p = 0.026). Apcmin/+/BrafV637 animals had more numerous and larger SI and colonic lesions (p < 0.0001 and p < 0.05, respectively), and a markedly reduced survival (median survival: 3.2 months, p = 8.8 × 10−21), compared to animals with Apc or Braf mutation alone. Conclusions: the WNT signaling axis is frequently mutated in BRAF mutant colorectal cancers. WNT16 and MEN1 may be novel drivers of aberrant WNT signaling in colorectal cancer. Co-mutation of BRAF and APC generates an extremely aggressive neoplastic phenotype that is associated with poor patient outcome. View Full-Text
Keywords: colorectal cancer; WNT signaling; APC; BRAF; serrated neoplasia; genomics; driver mutations colorectal cancer; WNT signaling; APC; BRAF; serrated neoplasia; genomics; driver mutations
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MDPI and ACS Style

Fennell, L.J.; Kane, A.; Liu, C.; McKeone, D.; Fernando, W.; Su, C.; Bond, C.; Jamieson, S.; Dumenil, T.; Patch, A.-M.; Kazakoff, S.H.; Pearson, J.V.; Waddell, N.; Leggett, B.; Whitehall, V.L.J. APC Mutation Marks an Aggressive Subtype of BRAF Mutant Colorectal Cancers. Cancers 2020, 12, 1171. https://doi.org/10.3390/cancers12051171

AMA Style

Fennell LJ, Kane A, Liu C, McKeone D, Fernando W, Su C, Bond C, Jamieson S, Dumenil T, Patch A-M, Kazakoff SH, Pearson JV, Waddell N, Leggett B, Whitehall VLJ. APC Mutation Marks an Aggressive Subtype of BRAF Mutant Colorectal Cancers. Cancers. 2020; 12(5):1171. https://doi.org/10.3390/cancers12051171

Chicago/Turabian Style

Fennell, Lochlan J., Alexandra Kane, Cheng Liu, Diane McKeone, Winnie Fernando, Chang Su, Catherine Bond, Saara Jamieson, Troy Dumenil, Ann-Marie Patch, Stephen H. Kazakoff, John V. Pearson, Nicola Waddell, Barbara Leggett, and Vicki L.J. Whitehall 2020. "APC Mutation Marks an Aggressive Subtype of BRAF Mutant Colorectal Cancers" Cancers 12, no. 5: 1171. https://doi.org/10.3390/cancers12051171

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