APC Mutation Marks an Aggressive Subtype of BRAF Mutant Colorectal Cancers

Lochlan J Fennell; 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; Vicki L J Whitehall

doi:10.3390/cancers12051171

APC Mutation Marks an Aggressive Subtype of BRAF Mutant Colorectal Cancers

Cancers (Basel). 2020 May 6;12(5):1171. doi: 10.3390/cancers12051171.

Authors

Lochlan J Fennell^{1

2}, Alexandra Kane^{1

2

3}, Cheng Liu^{1

2

4}, Diane McKeone¹, Winnie Fernando¹, Chang Su^{1

2}, Catherine Bond¹, Saara Jamieson¹, Troy Dumenil¹, Ann-Marie Patch¹, Stephen H Kazakoff¹, John V Pearson¹, Nicola Waddell^{1

2}, Barbara Leggett^{1

2

5}, Vicki L J Whitehall^{1

2

3}

Affiliations

¹ QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
² School of Medicine, The University of Queensland, Herston, QLD 4072, Australia.
³ Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Herston, QLD 4006, Australia.
⁴ Envoi Specialist Pathologists, Kelvin Grove, QLD 4059, Australia.
⁵ Department of Gastroenterology and Hepatology, The Royal Brisbane and Women's Hospital, Herston, QLD 4006, Australia.

Abstract

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 Apc^min/+ and Braf^V637/Villin-Cre^ERT2/+ 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). Apc^min/+/Braf^V637 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.

Keywords: APC; BRAF; WNT signaling; colorectal cancer; driver mutations; genomics; serrated neoplasia.