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Background: Deleterious alterations in tumor suppressor genes (TSGs) TP53, RB1, and PTEN are potential markers of small cell neuroendocrine prostate cancer (SCNP), and androgen receptor pathway inhibitor (ARPI) resistance. We examined the outcomes and clinical features of mCRPC patients (pts) harboring biallelic loss in 0, 1, 2 or all 3 TSGs. Method(s): We identified 210 consecutive mCRPC pts providing >=1 plasma cell-free DNA sample with >=20% circulating tumor DNA fraction (ctDNA%) during their mCRPC disease course. ctDNA% >=20% enabled sensitive characterization of biallelic TSG loss (including by homozygous deletions and mutation plus somatic loss-of-heterozygosity; LOH). Patient records were reviewed for baseline characteristics, SCNP histology, and presence of liver metastases. We investigated associations between TSG loss and the following clinical outcomes: PSA response (PSA decline >=50% (PSA50 RR)), progression free survival (PFS) on 1L therapy, and overall survival (OS) from 1L therapy. Result(s): Median follow-up was 16.5 months (range: 0.4-112.4) and OS event rate was 95%. Median age at 1L mCRPC was 71 years (range: 48-98). Most pts were ECOG PS 0-1 (79%) and 13% had liver metastases. 91% received ARPI for 1L mCRPC and 7% received ARPI for castration-sensitive disease. TP53 was primarily inactivated by somatic mutation plus LOH (90%), whereas RB1 (71%) and PTEN (86%) were more commonly inactivated by homozygous deletions. Compared to pts without evidence of biallelic TSG loss, pts with loss of 3 TSGs were significantly enriched for de-novo M1 disease (86 vs. 60%, p=0.05) and liver metastases (28.5 vs. 6.8%, p<0.05). Ten pts (4.7%) had histologically confirmed SCNP and provided ctDNA at time of SCNP diagnosis. Of these, 7 (70%) had biallelic loss of >=2 TSGs. For all pts receiving 1L therapy, loss of >=1 TSG(s) was associated with decreased OS (HR: 1.86, 95% CI: 1.40-2.48, p<0.01) and PFS (HR:1.74, 95% CI 1.29-2.34, p<0.01) compared to pts with no bialle

Background: Deleterious alterations in tumor suppressor genes (TSGs) TP53, RB1, and PTEN are potential markers of small cell neuroendocrine prostate cancer (SCNP), and androgen receptor pathway inhibitor (ARPI) resistance. We examined the outcomes and clinical features of mCRPC patients (pts) harboring biallelic loss in 0, 1, 2 or all 3 TSGs. Method(s): We identified 210 consecutive mCRPC pts providing >=1 plasma cell-free DNA sample with >=20% circulating tumor DNA fraction (ctDNA%) during their mCRPC disease course. ctDNA% >=20% enabled sensitive characterization of biallelic TSG loss (including by homozygous deletions and mutation plus somatic loss-of-heterozygosity; LOH). Patient records were reviewed for baseline characteristics, SCNP histology, and presence of liver metastases. We investigated associations between TSG loss and the following clinical outcomes: PSA response (PSA decline >=50% (PSA50 RR)), progression free survival (PFS) on 1L therapy, and overall survival (OS) from 1L therapy. Result(s): Median follow-up was 16.5 months (range: 0.4-112.4) and OS event rate was 95%. Median age at 1L mCRPC was 71 years (range: 48-98). Most pts were ECOG PS 0-1 (79%) and 13% had liver metastases. 91% received ARPI for 1L mCRPC and 7% received ARPI for castration-sensitive disease. TP53 was primarily inactivated by somatic mutation plus LOH (90%), whereas RB1 (71%) and PTEN (86%) were more commonly inactivated by homozygous deletions. Compared to pts without evidence of biallelic TSG loss, pts with loss of 3 TSGs were significantly enriched for de-novo M1 disease (86 vs. 60%, p=0.05) and liver metastases (28.5 vs. 6.8%, p<0.05). Ten pts (4.7%) had histologically confirmed SCNP and provided ctDNA at time of SCNP diagnosis. Of these, 7 (70%) had biallelic loss of >=2 TSGs. For all pts receiving 1L therapy, loss of >=1 TSG(s) was associated with decreased OS (HR: 1.86, 95% CI: 1.40-2.48, p<0.01) and PFS (HR:1.74, 95% CI 1.29-2.34, p<0.01) compared to pts with no bialle

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.