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Mutational Mechanisms That Activate Wnt Signaling and Predict Outcomes in Colorectal Cancer Patients William Hankey1, Michael A

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Mutational Mechanisms That Activate Wnt Signaling and Predict Outcomes in Colorectal Cancer Patients William Hankey1, Michael A Published OnlineFirst December 6, 2017; DOI: 10.1158/0008-5472.CAN-17-1357 Cancer Genome and Epigenome Research Mutational Mechanisms That Activate Wnt Signaling and Predict Outcomes in Colorectal Cancer Patients William Hankey1, Michael A. McIlhatton1, Kenechi Ebede2, Brian Kennedy3, Baris Hancioglu3, Jie Zhang4, Guy N. Brock3, Kun Huang4, and Joanna Groden1 Abstract APC biallelic loss-of-function mutations are the most prevalent also exhibiting unique changes in pathways related to prolifera- genetic changes in colorectal tumors, but it is unknown whether tion, cytoskeletal organization, and apoptosis. Apc-mutant ade- these mutations phenocopy gain-of-function mutations in the nomas were characterized by increased expression of the glial CTNNB1 gene encoding b-catenin that also activate canonical nexin Serpine2, the human ortholog, which was increased in WNT signaling. Here we demonstrate that these two mutational advanced human colorectal tumors. Our results support the mechanisms are not equivalent. Furthermore, we show how hypothesis that APC-mutant colorectal tumors are transcription- differences in gene expression produced by these different ally distinct from APC-wild-type colorectal tumors with canonical mechanisms can stratify outcomes in more advanced human WNT signaling activated by other mechanisms, with possible colorectal cancers. Gene expression profiling in Apc-mutant and implications for stratification and prognosis. Ctnnb1-mutant mouse colon adenomas identified candidate Significance: These findings suggest that colon adenomas genes for subsequent evaluation of human TCGA (The Cancer driven by APC mutations are distinct from those driven by WNT Genome Atlas) data for colorectal cancer outcomes. Transcrip- gain-of-function mutations, with implications for identifying tional patterns exhibited evidence of activated canonical Wnt at-risk patients with advanced disease based on gene expression signaling in both types of adenomas, with Apc-mutant adenomas patterns. Cancer Res; 78(3); 617–30. Ó2017 AACR. Introduction mutations activate canonical WNT signaling and occur in a mutually exclusive fashion (4). Mutational data show that Personalized medicine has permitted stratification of tumors CTNNB1 mutations become less prevalent in the tumor spectrum into subtypes distinguishable by molecular characteristics asso- from small adenomas to large adenomas and adenocarcinomas, ciated with different prognoses or therapeutic responses. In colo- while APC mutations remain well-represented (5). This difference rectal cancer, activating mutations in the KRAS gene, for example, in prevalence may be explained by WNT-independent functions correlate strongly with poor prognosis (1) and guide therapeutic of the APC tumor suppressor protein for which loss significantly decision-making (2). Development of additional markers is contributes to colorectal tumor progression (6–15), and retention needed, however, to define stage-specific characteristics associated in CTNNB1-mutant tumors may impair progression. with clinical outcomes. Nuclear APC and chromatin-associated APC interact with The most prevalent genetic changes in colorectal tumors are b-catenin to inhibit canonical WNT signaling, but may mediate biallelic APC mutations; although they have an unclear relation- b-catenin–independent transcriptional changes as well. Previous ship to outcome (3), they drive dramatic changes in both gene transcriptional profiling studies of human and murine colon expression and cellular phenotype. We asked whether biallelic tumors have assumed the equivalence of APC and CTNNB1 loss-of-function APC mutations are equivalent to gain-of-func- mutations in their effects on gene transcription. Our previous tion mutations in the CTNNB1 gene encoding b-catenin, as both work described a transcriptional profiling of adenomas from four murine models of intestinal cancer, focused on the shared char- 1Department of Cancer Biology and Genetics, College of Medicine, The Ohio acteristics of activated canonical WNT signaling between colon Min/þ State University, Columbus, Ohio. 2Department of Anesthesiology, University of tumors from Apc mice and azoxymethane- and dextran Florida, Gainesville, Florida. 3Department of Biomedical Informatics, College of sulfate sodium- (AOM/DSS)–treated mice now known to harbor 4 Medicine, The Ohio State University, Columbus, Ohio. Department of Medical Ctnnb1 mutations (16, 17). The transcriptional evidence of acti- and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, vated canonical WNT signaling in these Apc- and Ctnnb1-mutant Indiana. tumors stood out in comparison with colon adenomas from Note: Supplementary data for this article are available at Cancer Research mouse models with aberrant Smad/TGFb1 signaling (16, 17). Online (http://cancerres.aacrjournals.org/). Subtle differences between APC and CTNNB1-mutant colorectal Corresponding Author: Joanna Groden, The Ohio State University, 986 BRT 460 tumors were not examined. W. 12th Ave., Columbus, OH 43210. Phone: 614-688-4301; Fax: 614-688-8675; This study tests the hypothesis that APC-mutant colon tumors E-mail: [email protected] exhibit a set of changes in gene expression that overlap with those doi: 10.1158/0008-5472.CAN-17-1357 in CTNNB1-mutant tumors, as well as a unique set of changes in Ó2017 American Association for Cancer Research. gene expression due to the loss of chromatin-associated APC and www.aacrjournals.org 617 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst December 6, 2017; DOI: 10.1158/0008-5472.CAN-17-1357 Hankey et al. absent from CTNNB1-mutant tumors where such binding is using a HiSeq 2500 instrument (Illumina, Inc.). Data processing retained. These differences in gene expression patterns were first and analysis were performed by The Ohio State University Bio- identified by a comparison of transcriptional profiles of mouse medical Informatics Shared Resource. The transcript expression colon adenomas bearing either biallelic Apc mutations (from levels were quantified in FPKM units. Data were normalized by þ ApcMin/ mice) or an activating Ctnnb1 mutation (from mice dividing the FPKM measurement for each adenoma by that of treated with AOM/DSS). Transcriptome profiling (mRNA-seq) its corresponding adjacent nonadenoma tissue. Differentially þ of colon adenomas from each mouse model was performed to expressed transcripts between Apc-deficient (ApcMin/ ) and generate a list of up- and downregulated transcripts for each Apc-wild-type (AOM/DSS) colon adenomas were identified type of adenoma. Transcriptional changes in Apc-deficient ade- using the two-tailed Student t test to compare the fold changes nomas exhibited significant overlap with AOM/DSS adenomas, over nonadenoma tissue between three adenomas of each but also included unique changes related to the regulation of type. Adenomas from AOM/DSS–treated mice were confirmed proliferation, apoptosis, and cytoskeletal organization. Adeno- to express degradation-resistant b-catenin as reported pre- þ mas from ApcMin/ mice are characterized by increased expression viously (19), indicating that they were Apc-wild-type (4). of Serpine2 in comparison with adenomas with Ctnnb1 mutations. Sanger sequencing was done by reverse transcribing an RNA Expression of its human ortholog is directly correlated with stage sample from each adenoma from AOM/DSS–treated mice and in human colorectal tumors. Future studies will test the clinical from the adjacent nonadenoma sample using SuperScript II utility of this candidate marker in identifying at-risk patients with reverse transcriptase (Thermo Fisher Scientific, catalog no. potentially more advanced disease and will characterize the 18064022). The Ctnnb1 gene was then PCR-amplified using the relationship between its expression and chromatin-associated primers Ctnnb1S (GCTGACCTGATGGAGTTGGA) and Ctnnb1AS functions of APC. (GCTACTTGCTCTTGCGTGAA), and Sanger sequenced from each side using the same primers. The point mutations observed were all between codons 32 through 41 and consistent with Materials and Methods previous reports (19). The raw and processed mRNA-seq data are þ Generation of ApcMin/ and AOM/DSS–treated mouse colon available through NCBI's Gene Expression Omnibus (accession adenomas number GSE98496, https://www.ncbi.nlm.nih.gov/geo/query/ AOM/DSS mice were treated as follows: 6- to 7-week-old acc.cgi?acc=GSE103895). C57BL/6J mice were given a single intraperitoneal injection of AOM (10 mg/kg body weight). One week later mice were In silico analysis of gene expression data from mouse colon treated with 2% DSS (in drinking water), followed by two tumors weeks on water alone. They received 3 cycles of DSS/water. Approximately half of the genes listed in the RNA-seq analysis Mice were sacrificed seventy days after AOM was administered. (14,301 out of 31,189 total) were considered to have sufficient Min/þ Apc mice on a C57BL/6J background were sacrificed at counts (an average > 32 across the 8 sequenced samples) to enable 110–120 days old. Whole mouse colons were harvested from reliable expression analysis. FPKM measurements were used to Min/þ sacrificed Apc and AOM/DSS–treated mice and immedi- calculate fold changes for each adenoma relative to matched ately stored in RNAlater solution (Thermo Fisher Scientific, nonadenomatous colon tissue. A total of 3,097 transcripts were catalog no. AM7020) to protect RNA quality. Single adenomas differentially expressed by at least 2-fold
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