The clinical significance of adenomatous polyposis coli (APC) and catenin Beta 1 (CTNNB1) genetic aberrations in patients with melanoma

Background Melanoma-intrinsic activated β-catenin pathway, the product of the catenin beta 1 (CTNNB1) gene, has been associated with low/absent tumor-infiltrating lymphocytes, accelerated tumor growth, metastases development, and resistance to anti-PD-L1/anti-CTLA-4 agents in mouse melanoma models. Little is known about the association between the adenomatous polyposis coli (APC) and CTNNB1 gene mutations in stage IV melanoma with immunotherapy response and overall survival (OS). Methods We examined the prognostic significance of somatic APC/CTNNB1 mutations in the Cancer Genome Atlas Project for Skin Cutaneous Melanoma (TCGA-SKCM) database. We assessed APC/CTNNB1 mutations as predictors of response to immunotherapies in a clinicopathologically annotated metastatic patient cohort from three US melanoma centers. Results In the TCGA-SKCM patient cohort (n = 434) presence of a somatic APC/CTNNB1 mutation was associated with a worse outcome only in stage IV melanoma (n = 82, median OS of APC/CTNNB1 mutants vs. wild-type was 8.15 vs. 22.8 months; log-rank hazard ratio 4.20, p = 0.011). APC/CTNNB1 mutation did not significantly affect lymphocyte distribution and density. In the 3-melanoma institution cohort, tumor tissues underwent targeted panel sequencing using two standards of care assays. We identified 55 patients with stage IV melanoma and APC/CTNNB1 genetic aberrations (mut) and 169 patients without (wt). At a median follow-up of more than 25 months for both groups, mut compared with wt patients had slightly more frequent (44% vs. 39%) and earlier (66% vs. 45% within six months from original diagnosis of stage IV melanoma) development of brain metastases. Nevertheless, time-to-development of brain metastases was not significantly different between the two groups. Fortunately, mut patients had similar clinical benefits from PD-1 inhibitor-based treatments compared to wt patients (median OS 26.1 months vs. 29.9 months, respectively, log-rank p = 0.23). Less frequent mutations in the NF1, RAC1, and PTEN genes were seen in the mut compared with wt patients from the 3-melanoma institution cohort. Analysis of brain melanoma tumor tissues from a separate craniotomy patient cohort (n = 55) showed that melanoma-specific, activated β-catenin (i.e., nuclear localization) was infrequent (n = 3, 6%) and not prognostic in established brain metastases. Conclusions APC/CTNNB1 mutations are associated with a worse outcome in stage IV melanoma and early brain metastases independent of tumor-infiltrating lymphocyte density. However, PD1 inhibitor-based treatments provide comparable benefits to both mut and wt patients with stage IV melanoma.

HISTOPATOLOGIA DA POLIPOSE ADENOMATOSA FAMILIAR E SUA ASSOCIAÇÃO COM O ADENOCARCINOMA COLORRETAL

Introdução: Adenomas são lesões precursoras com potencial evolutivo para malignidade entre 5 e 15 anos. Doenças como a polipose adenomatosa familiar (PAF) aumentam o risco de desenvolvimento do câncer colorretal. Objetivos: Descrever a histologia colorretal, correlacionando à PAF e sua evolução para adenocarcinoma colorretal. Material e métodos: Pesquisa bibliográfica nas bases Pubmed e Scielo, com os descritores: “familial adenomatous polyposis” e “colorectal neoplasms”. Foram utilizados: Robbins Patologia Básica 9ª Ed.; Junqueira e Carneiro Histologia Básica 13ª Ed. Resultados: O intestino grosso possui mucosa de tecido epitelial simples cilíndrico com células caliciformes e criptas de Lieberküng, lâmina própria de tecido conjuntivo frouxo e muscular da mucosa. A submucosa contém tecido conjuntivo denso e plexo de Meissner. A muscular própria possui duas subcamadas musculares lisas: circular interna, longitudinal externa, e plexo de Auerbach. Por fim, a serosa/adventícia possui tecido conjuntivo frouxo e adiposo. A PAF é uma doença autossômica dominante caracterizada pelo desenvolvimento de adenomas entéricos. Ela resulta da mutação no supressor tumoral adenomatous polyposis coli, responsável pela estabilidade genômica e apoptose. Se não tratados precocemente, 100% dos pacientes acometidos desenvolverá câncer colorretal. Na forma clássica, apresenta inúmeros adenomas, que evoluem para câncer rapidamente. Na atenuada, há menos adenomas, menor agressividade e progressão lenta. Estruturalmente, os adenomas são tubulares, vilosos ou túbulo-vilosos, classificação essencial para conhecimento do potencial maligno. A displasia epitelial de baixo grau nos adenomas possui núcleos alongados e pseudoestratificados, com pequenos nucléolos, enquanto a de alto grau apresenta núcleos redondos, estratificação e nucléolo proeminente. No cólon proximal, os adenocarcinomas são polipóides e exofíticos, raramente causando obstrução. Já no distal, são lesões anulares com estreitamento luminal e oclusão. Clinicamente, no cólon direito ocorre anemia ferropriva e no esquerdo sangramento oculto, alterações intestinais e cólicas. Microscopicamente, os adenocarcinomas bem diferenciados possuem células colunares altas, semelhantes aos adenomas, com componente invasivo causador de resposta desmoplásica, ocasionando consistência firme. Os pouco diferenciados formam glândulas e produzem mucina. Ainda, estas neoplasias podem apresentar diferenciação neuroendócrina. Conclusão: As características da PAF explicam sua correlação com o desenvolvimento de carcinomas colorretais. Assim, destaca-se a importância do estudo histopatológico, facilitando a compreensão evolutiva adenomas-câncer neste grupo populacional.

Adenomatous Polyposis Coli loss controls cell cycle regulators and response to paclitaxel in MDA-MB-157 metaplastic breast cancer cells

Adenomatous Polyposis Coli (APC) is lost in approximately 70% of sporadic breast cancers, with an inclination towards triple negative breast cancer (TNBC). TNBC is treated with traditional chemotherapy, such as paclitaxel (PTX); however, tumors often develop drug resistance. We previously created APC knockdown cells (APC shRNA1) using the human TNBC cells, MDA-MB-157, and showed that APC loss induces PTX resistance. To understand the mechanisms behind APC-mediated PTX response, we performed cell cycle analysis and analyzed cell cycle related proteins. Cell cycle analysis indicated increased G2/M population in both PTX-treated APC shRNA1 and parental cells, suggesting that APC expression does not alter PTX-induced G2/M arrest. We further studied the subcellular localization of the G2/M transition proteins, cyclin B1 and CDK1. The APC shRNA1 cells had increased CDK1, which was preferentially localized to the cytoplasm, and increased baseline CDK6. RNA-sequencing was performed to gain a global understanding of changes downstream of APC loss and identified a broad mis-regulation of cell cycle-related genes in APC shRNA1 cells. Our studies are the first to show an interaction between APC and taxane response in breast cancer. The implications include designing combination therapy to re-sensitize APC-mutant breast cancers to taxanes using the specific cell cycle alterations.

A Rare Case of Serrated Polyposis Syndrome with the MSH6 and SMARCA4 variants

Serrated polyposis syndrome (SPS) is the most common form of polyposis syndrome and has been shown to increase the risk of colorectal cancer (CRC). The genetic pathway of CRC in SPS is different from the classic adenomatous polyposis coli (APC) pathway, which accounts for 70–80% of cases of CRC. Most commonly, SPS mutations include BRAF and KRAS, with activation of the RAS-RAF-MAP kinase pathway involved in the pathogenesis of serrated lesions. We present a rare case of SPS in a 32-year-old woman with MSH6 and SMARCA4 variants, which have not previously been reported in the literature.

Adenomatous polyposis coli in cancer and therapeutic implications

Inactivating mutations of the adenomatous polyposis coli (APC) gene and consequential upregulation of the Wnt signaling pathway are critical initiators in the development of colorectal cancer (CRC), the third most common cancer in the United States for both men and women. Emerging evidence suggests APC mutations are also found in gastric, breast and other cancers. The APC gene, located on chromosome 5q, is responsible for negatively regulating the β-catenin/Wnt pathway by creating a destruction complex with Axin/Axin2, GSK-3β, and CK1. In the event of an APC mutation, β-catenin accumulates, translocates to the cell nucleus and increases the transcription of Wnt target genes that have carcinogenic consequences in gastrointestinal epithelial stem cells. A literature review was conducted to highlight carcinogenesis related to APC mutations, as well as preclinical and clinical studies for potential therapies that target steps in inflammatory pathways, including IL-6 transduction, and Wnt pathway signaling regulation. Although a range of molecular targets have been explored in murine models, relatively few pharmacological agents have led to substantial increases in survival for patients with colorectal cancer clinically. This article reviews a range of molecular targets that may be efficacious targets for tumors with APC mutations.

Role of adenomatous polyposis coli in proliferation and differentiation of colon epithelial cells in organoid culture

Adenomatous polyposis coli (APC) is a tumor-suppressing protein whose inactivation triggers the formation of colorectal polyps. Numerous studies using cell lines or genetically engineered mice have revealed its role in suppressing Wnt/β-catenin signaling pathway and regulating cell proliferation and differentiation. Here, we performed genetic analyses of APC using a three-dimensional organoid culture of mouse colon epithelia, which enables the detailed examination of epithelial properties. Analyses of Apc-knockout colon organoids not only confirmed the importance of APC in suppressing Wnt/β-catenin signaling and regulating cell differentiation, but also revealed several novel features: a significant decrease in proliferating speed and an increase in cross-sectional area of cells. Moreover, we found a significant number of lysozyme-positive Paneth-like cells, which were never observed in wild-type colon tissues or organoids, but have been reported to emerge in colon cancers. Therefore, APC autonomously suppresses ectopic differentiation into lysozyme-positive cells, specifically in the colon epithelia. Colon organoids would be an ideal material to investigate the molecular mechanism and biological importance of the ectopic differentiation associated with cancer development.