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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.

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