Siok F. Leong

Supplementary Table S4 shows the estimated effects of SNPs on gene expression in human skin samples.

Supplementary Table S1 shows SNP information and their associations with MPM relative to SPM in the GEM study.

Background:Recent genome-wide association studies (GWAS) have identified new susceptibility loci for melanoma, but their associations with multiple primary melanoma (MPM) are unclear.Methods:We investigated the associations of 69 SNPs in 39 GWAS-identified loci with odds of MPM relative to single primary melanoma in the international, population-based Genes, Environment, and Melanoma study. Per-minor-allele ORs and 95% confidence intervals (CI) for individuals with MPM “cases” (n = 1,205) relative to single primary melanoma “controls” (n = 2,458) were estimated using multivariable logistic regression, and polygenic risk scores (PRS) were calculated and weighted based on a 2020 GWAS meta-analysis (57 of the 68 independent GWAS SNPs available).Results:Thirteen SNPs in 11 gene regions (PARP1, CYP1B1/RMDN3, TERT, RAPGEF5, TYRP1, MTAP, CDKN2A/CDKN2B, KLF4, TYR, SOX6, and ASIP) were statistically significantly associated (P < 0.05) with MPM adjusting for age, sex, age-by-sex interaction, and study center. The highest versus lowest PRS quintile was associated with a 2.81-fold higher odds of MPM (95% CI, 2.10–3.78; P = 7.5 × 10−13); this association was attenuated but remained statistically significant after excluding SNPs individually associated with MPM (OR = 1.75, 95% CI, 1.32–2.31).Conclusions:Inherited genetic variants spanning 11 gene regions were independently associated with MPM. Nonsignificant SNPs were associated with MPM when aggregated into a PRS, indicating that their cumulative effect may influence MPM risk despite lacking individual statistical significance in our study population.Impact:Our findings provide additional evidence that these loci are associated with melanoma risk and estimate the magnitude of their genetic effect on subsequent (multiple) primary melanoma risk.

Supplementary Table S3 shows the genotype associations with multiple primary melanoma stratified by phenotypic index and back nevi in the GEM study.

Supplementary Table S2 shows detailed information of 68 independent SNPs identified in the Landi et al. 2020 GWAS.

Background: Recent genome-wide association studies (GWAS) have identified new susceptibility loci for melanoma, but their associations with multiple primary melanoma (MPM) are unclear. Methods: We investigated the associations of 69 SNPs in 39 GWAS-identified loci with odds of MPM relative to single primary melanoma in the international, population-based Genes, Environment, and Melanoma study. Per-minor-allele ORs and 95% confidence intervals (CI) for individuals with MPM “cases” (n = 1,205) relative to single primary melanoma “controls” (n = 2,458) were estimated using multivariable logistic regression, and polygenic risk scores (PRS) were calculated and weighted based on a 2020 GWAS meta-analysis (57 of the 68 independent GWAS SNPs available). Results: Thirteen SNPs in 11 gene regions (PARP1, CYP1B1/RMDN3, TERT, RAPGEF5, TYRP1, MTAP, CDKN2A/CDKN2B, KLF4, TYR, SOX6, and ASIP) were statistically significantly associated (P < 0.05) with MPM adjusting for age, sex, age-by-sex interaction, and study center. The highest versus lowest PRS quintile was associated with a 2.81-fold higher odds of MPM (95% CI, 2.10–3.78; P = 7.5 × 10−13); this association was attenuated but remained statistically significant after excluding SNPs individually associated with MPM (OR = 1.75, 95% CI, 1.32–2.31). Conclusions: Inherited genetic variants spanning 11 gene regions were independently associated with MPM. Nonsignificant SNPs were associated with MPM when aggregated into a PRS, indicating that their cumulative effect may influence MPM risk despite lacking individual statistical significance in our study population. Impact: Our findings provide additional evidence that these loci are associated with melanoma risk and estimate the magnitude of their genetic effect on subsequent (multiple) primary melanoma risk.

CCAAT/enhancer binding protein β (C/EBPβ) is a basic leucine zipper (bZIP) family transcription factor, which is upregulated or overactivated in many cancers, resulting in a gene expression profile that drives oncogenesis. C/EBPβ dimerization regulates binding to DNA at the canonical TTGCGCAA motif and subsequent transcriptional activity, suggesting that disruption of dimerization represents a powerful approach to inhibit this previously “undruggable” oncogenic target. Here we describe the mechanism of action and antitumor activity of ST101, a novel and selective peptide antagonist of C/EBPβ that is currently in clinical evaluation in patients with advanced solid tumors. ST101 binds the leucine zipper domain of C/EBPβ, preventing its dimerization and enhancing ubiquitin-proteasome dependent C/EBPβ degradation. ST101 exposure attenuates transcription of C/EBPβ target genes, including a significant decrease in expression of survival, transcription factors, and cell-cycle-related proteins. The result of ST101 exposure is potent, tumor-specific in vitro cytotoxic activity in cancer cell lines including glioblastoma, breast, melanoma, prostate, and lung cancer, whereas normal human immune and epithelial cells are not impacted. Further, in mouse xenograft models ST101 exposure results in potent tumor growth inhibition or regression, both as a single agent and in combination studies. These data provide the First Disclosure of ST101, and support continued clinical development of ST101 as a novel strategy for targeting C/EBPβ-dependent cancers.

CCAAT/enhancer binding protein β (C/EBPβ) is a basic leucine zipper (bZIP) family transcription factor, which is upregulated or overactivated in many cancers, resulting in a gene expression profile that drives oncogenesis. C/EBPβ dimerization regulates binding to DNA at the canonical TTGCGCAA motif and subsequent transcriptional activity, suggesting that disruption of dimerization represents a powerful approach to inhibit this previously “undruggable” oncogenic target. Here we describe the mechanism of action and antitumor activity of ST101, a novel and selective peptide antagonist of C/EBPβ that is currently in clinical evaluation in patients with advanced solid tumors. ST101 binds the leucine zipper domain of C/EBPβ, preventing its dimerization and enhancing ubiquitin-proteasome dependent C/EBPβ degradation. ST101 exposure attenuates transcription of C/EBPβ target genes, including a significant decrease in expression of survival, transcription factors, and cell-cycle-related proteins. The result of ST101 exposure is potent, tumor-specific in vitro cytotoxic activity in cancer cell lines including glioblastoma, breast, melanoma, prostate, and lung cancer, whereas normal human immune and epithelial cells are not impacted. Further, in mouse xenograft models ST101 exposure results in potent tumor growth inhibition or regression, both as a single agent and in combination studies. These data provide the First Disclosure of ST101, and support continued clinical development of ST101 as a novel strategy for targeting C/EBPβ-dependent cancers.

Supplementary Data from Anticancer Activity of ST101, A Novel Antagonist of CCAAT/Enhancer Binding Protein β