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Background: Several rare surfactant-related gene (SRG) variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing. We aimed to study the epidemiology and phenotype of lung cancer in an international cohort of SRG variant carriers., Methods: We conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomere-related gene (TRG) variant carriers., Results: We identified 99 SRG adult variant carriers ( SFTPA1 (n=18), SFTPA2 (n=31), SFTPC (n=24), ABCA3 (n=14) and NKX2-1 (n=12)), including 20 (20.2%) with lung cancer ( SFTPA1 (n=7), SFTPA2 (n=8), SFTPC (n=3), NKX2-1 (n=2) and ABCA3 (n=0)). Among SRG variant carriers, the odds of lung cancer was associated with age (OR 1.04, 95% CI 1.01-1.08), smoking (OR 20.7, 95% CI 6.60-76.2) and SFTPA1 / SFTPA2 variants (OR 3.97, 95% CI 1.39-13.2). Adenocarcinoma was the only histological type reported, with programmed death ligand-1 expression ≥1% in tumour cells in three samples. Cancer staging was localised (I/II) in eight (40%) individuals, locally advanced (III) in two (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and three received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patients versus TRG patients was 18.1 (95% CI 7.1-44.7)., Conclusions: The high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular computed tomography scan follow-up should be evaluated., Competing Interests: Conflict of interest: P. Bonniaud reports grants from AstraZeneca, lecture honoraria from Sanofi and AstraZeneca, travel support from AstraZeneca, Novartis, Sanofi, Boehringer and Stallergenes, and advisory board membership with AstraZeneca, Novartis, Sanofi, GSK and Boehringer. J. Cadranel had a patent planned, received consulting fees and participated on a data safety monitoring board or advisory board for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Daichi, Lilly, Pfizer, Novartis, MSD, Roche and Takeda. A. Cazes reports lecture honoraria and travel support from Boehringer Ingelheim. B. Crestani reports grants from Boehringer Ingelheim, consulting fees from Apellis, BMS, Boehringer Ingelheim and Sanofi, lecture honoraria from Apellis, AstraZeneca, BMS, Boehringer Ingelheim, Novartis and Sanofi, support for attending meetings or travel from AstraZeneca, BMS, Boehringer Ingelheim and Sanofi, participated on a data safety monitoring board or advisory board for Apellis, BMS, Boehringer Ingelheim and Sanofi, and had a leadership role as President of the Board of Trustees of the Fondation du Souffle. R. Epaud reports consulting fees from AstraZeneca, lecture honoraria from GSK, AstraZeneca and Menarini, travel support from GSK and AstraZeneca, and advisory board membership with AstraZeneca and Novartis. M-P. Debray reports lecture honoraria and travel support from Boehringer Ingelheim. E. Manali reports lecture honoraria from Boehringer Ingelheim, CLS Behring and Hoffman-La Roche, support for attending meetings or travel from Boehringer Ingelheim, CLS Behring, Hoffman-La Roche and Elpen, and had a leadership role as a Chair in the ERS Task Force for transition of chILD to adult care. S. Papiris reports lecture honoraria from Boehringer Ingelheim and Hoffmann-La Roche, and travel support from Boehringer Ingelheim and Elpen. N. Nathan reports grants from Legs poix de la Chancellerie des Universités 2022 (number 2022000594). C. Andréjak participated on a data safety monitoring board or advisory board for the EVER-ILD2 study (rituximab in diffuse interstitial pneumonia) and received funding via a grant from the French Research Ministry. S. Jouneau reports grants from AIRB, Boehringer Ingelheim and Roche, lecture honoraria from AIRB, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Chiesi, Genzyme, GSK, LVL, Novartis, Pfizer, Roche and Sanofi, travel support from Boehringer Ingelheim, Roche and AIRB, and advisory board participation for Boehringer Ingelheim, GSK and Sanofi. G. Beltramo reports lecture honoraria from Bristol Myers Squibb, and support for attending meetings or travel from Sanofi Aventis France and Boehringer Ingelheim France. S. Hirschi reports research grants from Agence de la Biomedécine, CSL Behring and Adiral medical assistance, lecture honoraria from Boehringer Ingelheim, travel support from CSL Behring, Boehringer Ingelheim and ISIS Medical, and received medical equipment from ISIS Medical. C. Picard reports lecture honoraria and consulting fees from Boehringer Ingelheim. G. Prévot reports honoraria for presentations and educational event from Boehringer Ingelheim, Sanofi, Jansen and MSD. G. Zalcman reports consulting fees from AstraZeneca, BMS, Pfizer and Sanofi, lecture honoraria from BMS, AstraZeneca and Sanofi, support for attending meetings or travel from AstraZeneca and BMS, and participated on a data safety monitoring board or advisory board for AstraZeneca and BMS. V. Cottin reports grants from Boehringer Ingelheim, consulting fees from AstraZeneca, Boehringer Ingelheim, Celgene/BMS, CSL Behring, Ferrer/United Therapeutics, GSK, Pliant, Pure Tech, RedX, Roche, Sanofi and Shionogi, lecture honoraria from Boehringer Ingelheim, Ferrer/United Therapeutics and Roche, support for attending meetings or travel from Boehringer Ingelheim and Roche, participated on a data safety monitoring board or advisory board for Galapagos, Galecto and GSK, and had a leadership role in an adjudication committee for Fibrogen. R. Borie reports consulting fees from Boehringer Ingelheim, Ferrer and Sanofi, lecture honoraria from Boehringer Ingelheim and Roche, travel support from Boehringer Ingelheim, Roche and Chiesi, and advisory board participation for Savara. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Introduction: Interstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex SP-A. Only 11 SFTPA1 or SFTPA2 mutations have so far been reported worldwide, of which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives., Methods: The consequences of the 11 SFTPA1 or SFTPA2 mutations were analysed both in vitro , by studying the production and secretion of the corresponding mutated proteins and ex vivo , by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented., Results: For the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6-65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic., Discussion: This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic SFTPA1 or SFTPA2 mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance., Competing Interests: Conflict of interest: M. Legendre has nothing to disclose. Conflict of interest: A. Butt has nothing to disclose. Conflict of interest: R. Borie reports grants and personal fees from Boehringer Ingelheim and Roche, and personal fees from Savapharma, outside the submitted work. Conflict of interest: M-P. Debray has nothing to disclose. Conflict of interest: D. Bouvry has nothing to disclose. Conflict of interest: E. Filhol-Blin has nothing to disclose. Conflict of interest: T. Desroziers has nothing to disclose. Conflict of interest: V. Nau has nothing to disclose. Conflict of interest: B. Copin has nothing to disclose. Conflict of interest: F. Dastot Le Moal has nothing to disclose. Conflict of interest: M. Héry has nothing to disclose. Conflict of interest: P. Duquesnoy has nothing to disclose. Conflict of interest: N. Allou has nothing to disclose. Conflict of interest: A. Bergeron has nothing to disclose. Conflict of interest: J. Bermudez has nothing to disclose. Conflict of interest: A. Cazes has been invited to national and international meetings, and/or has received grants and/or personal fees for various activities from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: A-L. Chene has nothing to disclose. Conflict of interest: V. Cottin reports personal fees for lectures and advisory board work and non-financial support for meeting attendance from Actelion; grants, personal fees for lectures and advisory board work, and non-financial support for meeting attendance from Boehringer Ingelheim; personal fees for advisory board and data monitoring committee work from Bayer/MSD and Galapagos; personal fees for lectures and advisory board work from Novartis; personal fees for lectures, consultancy, data monitoring committee and steering committee work, and non-financial support for meeting attendance from Roche/Promedior; personal fees for lectures from Sanofi and AstraZeneca; personal fees for data monitoring committee work from Celgene and Galecto; and personal fees for advisory board work from Shionogi, outside the submitted work. Conflict of interest: B. Crestani has nothing to disclose. Conflict of interest: J-C. Dalphin has nothing to disclose. Conflict of interest: C. Dombret has nothing to disclose. Conflict of interest: B. Doray has nothing to disclose. Conflict of interest: C. Dupin reports personal fees for lectures and advisory board work, and non-financial support and meeting invitations from AstraZeneca; personal fees for lectures, non-financial support and meeting invitations from Boehringer and Novartis; personal fees for research and lectures, and non-financial support and meeting invitations from GSK; personal fees for lectures and meeting invitations from Chiesi; personal fees for lectures and advisory board work, and non-financial support from Sanofi; and personal fees, non-financial support and meeting invitations from Roche, outside the submitted work. Conflict of interest: V. Giraud has nothing to disclose. Conflict of interest: A. Gondouin has nothing to disclose. Conflict of interest: L. Gouya has nothing to disclose. Conflict of interest: D. Israël-Biet has nothing to disclose. Conflict of interest: C. Kannengiesser has nothing to disclose. Conflict of interest: A. Le Borgne has nothing to disclose. Conflict of interest: S. Leroy has nothing to disclose. Conflict of interest: E. Longchampt has nothing to disclose. Conflict of interest: G. Lorillon has nothing to disclose. Conflict of interest: H. Nunes has nothing to disclose. Conflict of interest: C. Picard has nothing to disclose. Conflict of interest: M. Reynaud-Gaubert has nothing to disclose. Conflict of interest: J. Traclet has nothing to disclose. Conflict of interest: P. de Vuyst has nothing to disclose. Conflict of interest: A. Coulomb L'Hermine has nothing to disclose. Conflict of interest: A. Clement has nothing to disclose. Conflict of interest: S. Amselem has nothing to disclose. Conflict of interest: N. Nathan reports a 2018 AstraZeneca Mobility Grant from Société de pneumologie pédiatrique et d'allergologie (France), outside the submitted work., (Copyright ©ERS 2020.)

Children with ABCA3 mutations may survive beyond infancy and reach adulthood. Genetic mechanisms should always be examined in adult patients with childhood onset ILD and molecular analysis should be performed accordingly in specialised referral centres. http://bit.ly/2LzMNOE., Competing Interests: Conflict of interest: E.D. Manali has nothing to disclose. Conflict of interest: M. Legendre has nothing to disclose. Conflict of interest: N. Nathan has nothing to disclose. Conflict of interest: C. Kannengiesser has nothing to disclose. Conflict of interest: A. Coulomb L'Hermine has nothing to disclose. Conflict of interest: T. Tsiligiannis has nothing to disclose. Conflict of interest: P. Tomos has nothing to disclose. Conflict of interest: M. Griese reports grants from EU, during the conduct of the study; and personal fees from Boehringer and Vertex, outside the submitted work. Conflict of interest: R. Borie reports grants and personal fees from Roche and Boerhinger Ingelheim, and personal fees from Savapharma, outside the submitted work. Conflict of interest: A. Clement has nothing to disclose. Conflict of interest: S. Amselem has nothing to disclose. Conflict of interest: B. Crestani has nothing to disclose. Conflict of interest: S.A. Papiris has nothing to disclose.

Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT , RTEL1 , PARN or SFTPC coding regions . The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT , RTEL1 , PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53-6.12; p=9.45×10 -4 ). Telomeres were shorter in RA-ILD patients with a TERT , RTEL1 or PARN mutation than in controls (p=2.87×10 -2 ).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Transmission electron microscopy (TEM) analysis of ciliary ultrastructure is classically used for the diagnosis of primary ciliary dyskinesia (PCD). We report our extensive experience of TEM analysis in a large series of patients in order to evaluate its feasibility and results. TEM analysis performed in 1,149 patients with suspected PCD was retrospectively reviewed. Biopsies (1,450) were obtained from nasal (44%) or bronchial (56%) mucosa in children (66.5%) and adults (33.5%). TEM analysis was feasible in 71.4% of patients and showed a main defect suggestive of PCD in 29.9%. TEM was more feasible in adults than in children, regardless of the biopsy site. Main defects suggestive of PCD were found in 76.9% of patients with sinopulmonary symptoms and in only 0.4% of patients with isolated upper and 0.4% with isolated lower respiratory tract infections. The defect pattern was similar in children and adults, involving dynein arms (81.2%) or central complex (CC) (18.8%). Situs inversus was never observed in PCD patients with CC defect. Kartagener syndrome with normal ciliary ultrastructure was not an exceptional condition (10.2% of PCD). In conclusion, TEM analysis is feasible in most patients and is particularly useful for PCD diagnosis in cases of sinopulmonary syndrome of unknown origin.