Background: Data are scarce about tumor mutational burden (TMB) as a biomarker in never smokers with non-small-cell lung cancer (NSCLC). Methods: TMB was assessed by whole-genome sequencing (WGS) and compared with in-silico reduced whole-exome sequencing (WES) and targeted commercial NGS gene panels in 92 paired tumor-normal samples from never smokers who underwent NSCLC resection with curative intent. Analyses were performed to test for association with survival after surgery and to identify the optimal prognostic TMB cutoff. Results: Tumors of never smokers with NSCLC had low TMB scores (median 1.57 mutations/megabase, range 0.13-17.94). A TMB cutoff of 1.70 mutations/megabase was associated with a 5-year overall survival of 58% in the high-TMB (42% of cases) compared to 86% in low-TMB patients (Wald p = 0.0029). TMB scores from WGS and WES were highly correlated (Spearman ρ = 0.93, p <2.2e-16). TMB scores from NGS panels demonstrated high intra-individual fluctuations and identified high-TMB patients with 65% concordance in average compared to WGS. Conclusions: In resected NSCLC of never smokers, high TMB was associated with worse prognosis. WES provided a good estimate of TMB while targeted NGS panels seem to lack adequate depth and resolution in the setting of low mutation burden. Impact: TMB is a prognostic indicator of survival in resected NSCLC from individuals who never smoked. In this setting of low mutation counts, TMB can be accurately measured by WGS or WES, but not NGS panels.
Variants of filamin C (FLNC) have been identified as rare genetic substrate for hypertrophic cardiomyopathy (HCM). Data on the clinical course of FLNC‐related HCM are conflicting with some studies suggesting mild phenotypes whereas other studies have reported more severe outcomes. In this study, we present a novel FLNC variant (Ile1937Asn) that was identified in a large family of French‐Canadian descent with excellent segregation data. FLNC‐Ile1937Asn is a novel missense variant characterized by full penetrance and poor clinical outcomes. End stage heart failure requiring transplantation occurred in 43% and sudden cardiac death in 29% of affected family members. Other particular features of FLNC‐Ile1937Asn include an early disease onset (mean age of 19 years) and the development of a marked atrial myopathy (severe biatrial dilatation with remodeling and multiple complex atrial arrhythmias) that was present in all gene carriers. The FLNC‐Ile1937Asn variant is a novel, pathogenic mutation resulting in a severe form of HCM with full disease penetrance. The variant is associated with a high proportion of end‐stage heart failure, heart transplantation, and disease‐related mortality. Close follow‐up and appropriate risk stratification of affected individuals at specialized heart centers is recommended.
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