Schizophrenia is a serious psychiatric disorder with a broadly undiscovered genetic etiology. Recent studies of de novo mutations (DNMs) in schizophrenia and autism have reinforced the hypothesis ...that rare genetic variation contributes to risk. We carried out exome sequencing on 57 trios with sporadic or familial schizophrenia. In sporadic trios, we observed a ~3.5-fold increase in the proportion of nonsense DNMs (0.101 vs 0.031, empirical P=0.01, Benjamini-Hochberg-corrected P=0.044). These mutations were significantly more likely to occur in genes with highly ranked probabilities of haploinsufficiency (P=0.0029, corrected P=0.006). DNMs of potential functional consequence were also found to occur in genes predicted to be less tolerant to rare variation (P=2.01 × 10(-)(5), corrected P=2.1 × 10(-)(3)). Genes with DNMs overlapped with genes implicated in autism (for example, AUTS2, CHD8 and MECP2) and intellectual disability (for example, HUWE1 and TRAPPC9), supporting a shared genetic etiology between these disorders. Functionally CHD8, MECP2 and HUWE1 converge on epigenetic regulation of transcription suggesting that this may be an important risk mechanism. Our results were consistent in an analysis of additional exome-based sequencing studies of other neurodevelopmental disorders. These findings suggest that perturbations in genes, which function in the epigenetic regulation of brain development and cognition, could have a central role in the susceptibility to, pathogenesis and treatment of mental disorders.
Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of ...genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWER
), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWER
P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWER
P=0.0043). These results identify altered regulation of schizophrenia candidate genes by DISC1 and its core Interactome as an alternate pathway for schizophrenia risk, consistent with the emerging effects of rare copy number variants associated with intellectual disability.
Clinical patterns and the associated optimal management of acquired resistance to PD-(L)1 blockade are poorly understood.
All cases of metastatic lung cancer treated with PD-(L)1 blockade at Memorial ...Sloan Kettering were reviewed. In acquired resistance (complete/partial response per RECIST, followed by progression), clinical patterns were distinguished as oligo (OligoAR ≤ 3 lesions of disease progression) or systemic (sAR). We analyzed the relationships between patient characteristics, burden/location of disease, outcomes, and efficacy of therapeutic interventions.
Of 1,536 patients, 312 (20%) had an initial response and 143 developed AR (9% overall, 46% of responders). OligoAR was the most common pattern (80/143, 56%). Baseline tumor mutational burden, depth of response, and duration of response were significantly increased in oligoAR compared with sAR (P < 0.001, P = 0.03, P = 0.04, respectively), whereas baseline PD-L1 and tumor burden were similar. Post-progression, oligoAR was associated with improved overall survival (median 28 months vs. 10 months, P < 0.001) compared with sAR. Within oligoAR, post-progression survival was greater among patients treated with locally-directed therapy (e.g., radiation, surgery; HR, 0.41; P = 0.039). Fifty-eight percent of patients with oligoAR treated with locally-directed therapy alone are progression-free at last follow-up (median 16 months), including 13 patients who are progression-free more than 2 years after local therapy.
OligoAR is a common and distinct pattern of acquired resistance to PD-(L)1 blockade compared with sAR. OligoAR is associated with improved post-progression survival and some cases can be effectively managed with local therapies with durable benefit.
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Background: Combination therapy with I/N can achieve long-term benefit in a sizable proportion of RCC pts, but broad application has been challenged by a high incidence of irAEs. Host features ...affecting antigen presentation are candidate determinants of irAE pathogenesis, and isolated reports have linked Human Leukocyte Antigen (HLA) variations to organ- specific irAEs. We analyzed data for pts treated on a phase 3 trial to investigate association of class 1 HLA variants with development of irAEs from I/N and develop a tool to predict risk for toxicity. Methods: We analyzed germline HLA + clinical data for 472 pts receiving I/N vs sunitinib (SUT). Based on allelic variants for HLA-A and B pts were categorized into 12 established HLA "Super-Types" (ST), sets of HLA variants with largely overlapping peptide binding specificity. We conducted uni- and multivariate (UV; MV) Cox proportional hazards regression to correlate HLA-ST variables with time to treatment-related AEs (TTrAE, grade 2+) in I/N pts using the Kaplan Meier method. Several MV HLA-ST models were developed on a discovery set (DISC; 2/3 random sample of I/N pts without replacement ) and compared using model concordance (c-index) on a validation set (VAL; remaining 1/3). Model coefficients were used to create a “HLA-ST score” that could be computed for individual pts. Results: 235 pts and 237 pts received I/N vs SUT and had available HLA data, respectively. On UV analysis for I/N, HLA-B07 ST had protective association TTrAE (HR= 0.65, 95% CI: 0.46,0.90; p= 0.010), while B62 associated adversely (HR=1.64, 95% CI: 1.12, 2.40; p=0.014). Relevant to the development of our model we identified interactions between several pairs of HLA ST. The HLA ST model with best performance in DISC (c-index= 0.606) and VAL (c-index=0.595) integrates B07, B62, A01, B08, and two interactions: B07-B08 and B07-A01. The model-generated HLA-ST score was significantly associated with TTrAE after adjusting for race, BMI, region, PDL1 status, and MSKCC risk score (DISC p<0.001; VAL p=0.028). No association with TTrAE was seen in SUT treated pts (p=0.655), neither in UV nor MV model. I/N-treated patients with HLA-ST score dichotomized >= vs < median had significantly different TTrAE both in DISC (p=0.004) and VAL (p=0.009); again, no difference was observed in the SUT arm (p=0.5). The weighted HLA-ST score had no association with PFS or OS for I/N pts. Conclusions: In this large sample of I/N-treated patients, class I HLA variants were associated with the risk of developing irAEs. We developed a HLA ST based score that correlated with treatment toxicity independent of relevant clinical and demographic features. No association with TTrAE was seen in SUT-treated pts. These results highlight the potential of characterizing germline features to predict immune related toxicity upfront and deserves further study. Clinical trial information: NCT02231749 .
Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 ...blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFNγ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance may inform therapeutic strategies to effectively reprogram and reverse acquired resistance.
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•>60% of initial responders to ICBs with stage IV NSCLC acquire resistance (AR)•AR tumors had upregulated or stable expression of IFNγ response genes•An AR inflammatory phenotype can be recapitulated in multiple murine models•Altered, persistent inflammation informs strategies to overcome AR to ICB in NSCLC
Memon et al. demonstrate the relationship between persistent and upregulated interferon signaling and acquired resistance in tumors from patients with NSCLC who have developed acquired resistance to PD-(L)1 blockade. These findings inform approaches for overcoming acquired resistance, which occurs in >60% of patients with NSCLC who initially respond to PD-(L)1 blockade.
Psychiatric disorders are a group of genetically related diseases with highly polygenic architectures. Genome-wide association analyses have made substantial progress towards understanding the ...genetic architecture of these disorders. More recently, exome- and whole-genome sequencing of cases and families have identified rare, high penetrant variants that provide direct functional insight. There remains, however, a gap in the heritability explained by these complementary approaches. To understand how multiple genetic variants combine to modify both severity and penetrance of a highly penetrant variant, we sequenced 48 whole genomes from a family with a high loading of psychiatric disorder linked to a balanced chromosomal translocation. The (1;11)(q42;q14.3) translocation directly disrupts three genes: DISC1, DISC2, DISC1FP and has been linked to multiple brain imaging and neurocognitive outcomes in the family. Using DNA sequence-level linkage analysis, functional annotation and population-based association, we identified common and rare variants in GRM5 (minor allele frequency (MAF) > 0.05), PDE4D (MAF > 0.2) and CNTN5 (MAF < 0.01) that may help explain the individual differences in phenotypic expression in the family. We suggest that whole-genome sequencing in large families will improve the understanding of the combined effects of the rare and common sequence variation underlying psychiatric phenotypes.
Psychiatric illnesses are a group of genetically-related disorders with highly polygenic architecture and a significant environmental component. Even within families, these conditions show the ...attributes of many complex traits: reduced penetrance and phenotypic heterogeneity. An extended pedigree design has several advantages: it avoids population stratification and reduces genetic heterogeneity, narrowing the search for rare and functional variants that segregate with a phenotype. We have analysed a multigenerational pedigree where major mental illness segregates with a balanced translocation between chromosomes 1 and 11.
Whole genome sequencing was performed on 49 family members (20 carriers, 29 non-carriers of the translocation). Polygenic risk scores were calculated using summary statistics from the PGC MDD 2011 and used to predict diagnosis. Multipoint linkage analyses were performed using the variance components method implemented in SOLAR. Multiple phenotypic classes were used constructed to reflect the multiple phenotypes within the family. Fine-mapping was performed using two-point linkage analyses across the linked regions and association analyses performed in a Scottish cohort with measures of mental health, cognitive and personality traits (N= 6,555; 2,060 cases and 4,495 controls).
Two genome-wide significant peaks with LOD > 5.5 were detected on the translocated chromosomes 1 and 11 with maximum linkage to schizophrenia, bipolar disorder, recurrent major depression and cyclothymia; as previously noted for the translocation itself. In addition, two further peaks, a second on chromosome 1 and a peak on chromosome 5, showed genome-wide significant linkage to affective disorder (bipolar disorder, and major depressive disorder). Polygenic risk scores of schizophrenia and bipolar disorder, but not major depressive disorder significantly predict mental illness in the family. Functional annotation of the whole genome sequence, and case-control association for affective disorder in the Scottish population, support a role for GRM5, CNTN5 and PDE4D in the phenotypic heterogeneity seen in the family.
These results suggest that the high density of psychiatric illness in the t(1;11) family may be a combination of: direct effects of the translocation on the genes located at the breakpoint (DISC1, DISC2, DISC1FP), “locking together” of additional familial risk factors and the accumulation of common risk variants. We have identified additional modifying loci that may explain the variance in disease expression. Our findings suggest that pleiotropy may play a significant role and that this is now tractable by whole genome sequencing in families.
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