Individuals with autism spectrum disorder (ASD) exhibit an increased burden of de novo mutations (DNMs) in a broadening range of genes. While these studies have implicated hundreds of genes in ASD pathogenesis, which DNMs cause functional consequences in vivo remains unclear. We functionally test the effects of ASD missense DNMs using Drosophila through “humanization” rescue and overexpression-based strategies. We examine 79 ASD variants in 74 genes identified in the Simons Simplex Collection and find 38% of them to cause functional alterations. Moreover, we identify GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in 13 previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes points to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.

FOXM1 transcription factor network is activated in over 84% of cases in high-grade serous ovarian cancer (HGSOC), and FOXM1 upregulates the expression of genes involved in the homologous recombination (HR) DNA damage and repair (DDR) pathway. However, the role of FOXM1 in PARP inhibitor response has not yet been studied. This study demonstrates that PARP inhibitor (PARPi), olaparib, induces the expression and nuclear localization of FOXM1. On the basis of ChIP-qPCR, olaparib enhances the binding of FOXM1 to genes involved in HR repair. FOXM1 knockdown by RNAi or inhibition by thiostrepton decreases FOXM1 expression, decreases the expression of HR repair genes, such as BRCA1 and RAD51, and enhances sensitivity to olaparib. Comet and PARP trapping assays revealed increases in DNA damage and PARP trapping in FOXM1-inhibited cells treated with olaparib. Finally, thiostrepton decreases the expression of BRCA1 in rucaparib-resistant cells and enhances sensitivity to rucaparib. Collectively, these results identify that FOXM1 plays an important role in the adaptive response induced by olaparib and FOXM1 inhibition by thiostrepton induces “BRCAness” and enhances sensitivity to PARP inhibitors. Implications: FOXM1 inhibition represents an effective strategy to overcome resistance to PARPi, and targeting FOXM1-mediated adaptive pathways may produce better therapeutic effects for PARP inhibitors. Mol Cancer Res; 16(6); 961–73. ©2018 AACR.

TP53 mutations occur in more than 50% of cancers. We sought to determine the effect of the intragenic P72R single nucleotide polymorphism (SNP; rs1042522) on the oncogenic properties of mutant p53. P72R allelic selection in tumors was determined from genotype calls and a Gaussian distributed mixture model. The SNP effect on mutant p53 was determined in p53-negative cancer cell lines. RNA-sequencing, chromatin immunoprecipitation, and survival analysis were performed to describe the SNP effect. All statistical tests were 2-sided. Among 409 patients with germline heterozygous P72R SNP who harbored somatic mutations in TP53, we observed a selection bias against missense TP53 mutants encoding the P72 SNP (P = 1.64 x 10^-13). Exogenously expressed hotspot p53 mutants with the P72 SNP were negatively selected in cancer cells. Gene expression analyses showed the enrichment of p53 pathway genes and inflammatory genes in cancer cells transduced with mutants encoding P72 SNP. Immune gene signature is enriched in patients harboring missense TP53 mutations with homozygous P72 SNP. These patients have improved overall survival as compared with those with the R72 SNP (P = .04). This is the largest study demonstrating a selection against the P72 SNP. Missense p53 mutants with the P72 SNP retain partial wild-type tumor-suppressive functions, which may explain the selection bias against P72 SNP across cancer types. Ovarian cancer patients with the P72 SNP have a better prognosis than with the R72 SNP. Our study describes a previously unknown role through which the rs1042522 SNP modifies tumor suppressor activities of mutant p53 in patients.