Immunoglobulin A nephropathy

A working hypothesis is that patients with immunoglobulin A (IgA) nephropathy have inherited defects in B cells producing galactose-deficient polymeric IgA1. Additional cofactors are required to form immune complexes and their deposition in glomeruli. Molecular characterization of IgG autoantibodies that recognize abnormally underglycosylated IgA1 reveals a specific amino acid substitution in the variable region of the IgG1 heavy chain. This substitution greatly enhances IgG1 binding to the galactose-deficient IgA1. The triggering antigens may include viral or bacterial antigens, or possibly by ingested food epitopes. Antiglycan IgG1 antibodies are one of the additional risk factors, or a second/multiple hit, which predisposes to disease development.

Regional missense constraint improves variant deleteriousness prediction

Given increasing numbers of patients who are undergoing exome or genome sequencing, it is critical to establish tools and methods to interpret the impact of genetic variation. While the ability to predict deleteriousness for any given variant is limited, missense variants remain a particularly challenging class of variation to interpret, since they can have drastically different effects depending on both the precise location and specific amino acid substitution of the variant. In order to better evaluate missense variation, we leveraged the exome sequencing data of 60,706 individuals from the Exome Aggregation Consortium (ExAC) dataset to identify sub-genic regions that are depleted of missense variation. We further used this depletion as part of a novel missense deleteriousness metric named MPC. We applied MPC to de novo missense variants and identified a category of de novo missense variants with the same impact on neurodevelopmental disorders as truncating mutations in intolerant genes, supporting the value of incorporating regional missense constraint in variant interpretation.

Comparison of the characteristics and clinical course of 677 patients with metastatic lung cancers with mutations in KRAS codons 12 and 13.

8025 Background: Patients (pts) with KRAS mutant lung cancers have a shorter survival compared to pts with KRAS/EGFR wild type tumors (Johnson et al, Cancer 2012). Whether outcomes for patients with KRAS mutant metastatic lung cancers differ by smoking status or specific amino acid substitution is unknown. In order to understand the impact of KRAS mutation subtype in the metastatic setting, we analyzed a large cohort of patients with KRAS mutant metastatic lung cancer. Methods: We identified all pts with KRAS mutant metastatic or recurrent lung cancers from Feb 2005 to Aug 2011. KRAS mutation type, clinical characteristics, and outcomes from diagnosis were obtained from the medical record. A multivariate cox proportion hazard model was used to identify factors associated with overall survival. Results: KRAS mutations were identified in 677 pts (53 at codon 13, 624 at codon 12). Median age: 66 (range 31-89), women: 62%, never smokers: 7%. Pts with transition mutations (n=157) were more likely to be never-smokers (p<0.0001). There was no difference in outcome for pts with KRAS transition versus transversion mutations (p=1) or when comparing current/former smokers to never smokers (p=0.33). There was no difference in overall survival (OS) when comparing specific amino acid substitutions (G12C=366, G12V=141, G12D=114, G12A=68, G13C=27, G13D=23, G12S=19, G12F=11)(p=0.20). Pts with KRAS codon 13 mutant tumors had inferior OS compared to pts with codon 12 mutant tumors, median 13 months (mo) (95% CI 13-17 mo) and 16 mo (95% CI 9-16 mo), respectively (p=0.009). There was no difference in frequency of receiving platinum-based chemotherapy or chemotherapy of any kind between pts with codon 12 and 13 mutant tumors. In a multivariate Cox model which included age, gender and smoking status, KRAS codon 13 mutation was associated with worse overall survival than KRAS codon 12 mutation (HR 1.52 95% CI 1.11-2.08 p=0.008). Conclusions: Among pts with KRAS mutant metastatic lung cancers, smoking history, and specific amino acid substitution do not affect outcome. Patients with KRAS codon 13 mutant metastatic lung cancer have shorter survival compared to pts with KRAS codon 12 mutant lung cancer.