Because tobacco is a potent carcinogen, secondary causes of lung cancer are often diminished in perceived importance. To assess the extent of inherited susceptibility to small cell lung cancer (SCLC), the most lethal type of lung cancer, we sequenced germline exomes of 87 patients (77 SCLC and 10 extrapulmonary small cell) and considered 607 genes, discovering 42 deleterious variants in 35 cancer-predisposition genes among 43.7% of patients. These findings were validated in an independent cohort of 79 patients with SCLC. Loss of heterozygosity was observed in 3 of 14 (21.4%) tumors. Identification of variants influenced medical management and family member testing in nine (10.3%) patients. Unselected patients with SCLC were more likely to carry germline RAD51 paralog D (RAD51D), checkpoint kinase 1 (CHEK1), breast cancer 2 (BRCA2), and mutY DNA glycosylase (MUTYH) pathogenic variants than healthy controls. Germline genotype was significantly associated with the likelihood of a first-degree relative with cancer or lung cancer (odds ratio: 1.82, P = 0.008; and 2.60, P = 0.028), and longer recurrence-free survival after platinum-based chemotherapy (P = 0.002), independent of known prognostic factors. Treatment of a patient with relapsed SCLC and germline pathogenic mutation of BRCA1 interacting protein C-terminal helicase 1 (BRIP1), a homologous recombination–related gene, using agents synthetically lethal with homologous recombination deficiency, resulted in a notable disease response. This work demonstrates that SCLC, currently thought to result almost exclusively from tobacco exposure, may have an inherited predisposition and lays the groundwork for targeted therapies based on the genes involved.

Introduction Defects in immunological self-tolerance result in an increased risk for development of autoimmune paraneoplastic diseases (AD) and immune-mediated toxicity in response to immune stimulation in individuals with thymic epithelial tumors (TETs). We conducted a survey to evaluate the tolerability of Covid-19 messenger RNA (mRNA) vaccines in patients with TETs, including individuals with pre-existing AD. Methods After reviewing published data on adverse events (AEs) associated with the BNT162b2 (Pfizer, Inc., and BioNTech) and mRNA-1273 (ModernaTX, Inc.) mRNA vaccines, we designed and administered a questionnaire to participants at three timepoints: after each dose of vaccination and one month following the final dose. Questions related to AD and use of immunosuppressive drugs were included. Descriptive statistics were used to analyze data and results were compared with previously described results related to the BNT162b2 and mRNA-1273 vaccines. Results From February 26 th and June 1 st , 2021, we administered the survey to 54 participants (median age: 58 years; thymoma: 33; pre-existing AD: 19). Common AEs included injection-site pain, fatigue, and headaches. There were no vaccination-related hospitalizations or deaths. Autoimmune flares occurred in three (16%) patients after the first dose and three (17%) patients after the second dose. The majority of AD flares were mild and self-limited. One patient (2%) was diagnosed with a new AD following vaccination. Conclusions Tolerability of COVID-19 mRNA vaccines in patients with TETs is comparable to the general population. Most patients with pre-existing AD did not experience disease flares and the development of new AD was rare. Patients with TETs should be encouraged to get vaccinated against COVID-19 due to the documented benefits of vaccination and manageable risk profile.

ObjectivesInflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICIs) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis.MethodsBulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (seven ICI-myositis, four DM, three AS, six IMNM and two IBM).ResultsUnsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1 and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed coexisting myocarditis. ICI-MYO2 was composed of patients with predominant necrotising pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway.ConclusionsWe identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICI-DM and ICI-MYO1 and only ICI-MYO1 patients developed myocarditis.