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

Abstract

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.

Mutation analysis in individual circulating tumor cells depicts intratumor heterogeneity in melanoma

“…For CTCs, the stochasticity related to the low volume of blood sampled in case of a low number of cells together with the difference in sensitivity level between a single cell analysis and a bulk sequencing approach is to be considered for the interpretation of concordance with the tumor tissue. Second, our results also demonstrate that CTC analysis brings complementary information to ctDNA in almost 70% of the cases with some CTC ‘private’ mutations in genes implicated in immune evasion or tumor dissemination mechanisms like CTNNB1 (Karachaliou et al, 2022 ; Damsky et al, 2011 ; Spranger et al, 2015 ; Massi et al, 2017 ; Lin et al, 2020 ) and CDKN2A (Zeng et al, 2018 ). These findings appear particularly relevant in this context since CTCs are intact viable cells that reflect an active process of tumor dissemination and a more aggressive phenotype, as corroborated by their almost significant association with worse overall survival in this cohort and by other previous reports including our own in melanoma (Gorges et al, 2019 ; Lucci et al, 2020 ; Gray et al, 2015 ; Khoja et al, 2012 ).…”

Network Analysis of Effect of Light-Dark Time Ratio on the Gene Expression Profile of Mouse Skin

“…Catenin beta 1 (Ctnnb1) which is characterized by a degree value of about 60 for all assessments is involved in melanoma and early brain metastases. 25 The role of Ctnnb1 in cell development and differentiation is highlighted in the report by Ma et al 26…”