Editorial

Telomeres and disease: An overview

Since the latest 2017 French guidelines, knowledge about idiopathic pulmonary fibrosis has evolved considerably.

Practical guidelines were drafted on the initiative of the Coordinating Reference Center for Rare Pulmonary Diseases, led by the French Language Pulmonology Society (SPLF), by a coordinating group, a writing group, and a review group, with the involvement of the entire OrphaLung network, pulmonologists practicing in various settings, radiologists, pathologists, a general practitioner, a health manager, and a patient association. The method followed the "Clinical Practice Guidelines" process of the French National Authority for Health (HAS), including an online vote using a Likert scale.

After a literature review, 54 guidelines were formulated, improved, and then validated by the working groups. These guidelines addressed multiple aspects of the disease: epidemiology, diagnostic procedures, quality criteria and interpretation of chest CT scans, lung biopsy indication and procedures, etiological workup, methods and indications for family screening and genetic testing, assessment of the functional impairment and prognosis, indication and use of antifibrotic agents, lung transplantation, management of symptoms, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis.

These evidence-based guidelines are intended to guide the diagnosis and practical management of idiopathic pulmonary fibrosis.

Depuis les précédentes recommandations françaises publiées en 2017, les connaissances concernant la fibrose pulmonaire idiopathique ont évolué sur de nombreux aspects.

Des recommandations pratiques ont été établies à l’initiative du Centre coordonnateur de référence des maladies pulmonaires rares, sous l’égide de la Société de Pneumologie de Langue Française, par un groupe de coordination, un groupe de rédaction, et un groupe de lecture, impliquant l’ensemble du réseau OrphaLung, des pneumologues de divers modes d’exercice, des radiologues, des pathologistes, un médecin généraliste, un cadre de santé, et une association de patients. La méthode a respecté les règles d’élaboration des « Bonnes pratiques cliniques » selon la méthode des « Recommandations pour la pratique clinique » de la Haute Autorité de Santé, incluant un vote en ligne selon une échelle Likert.

Après une analyse bibliographique, 54 recommandations ont été formulées, améliorées, puis validées par les groupes de travail, portant sur des aspects multiples de la maladie : épidémiologie, modalités diagnostiques, critères de qualité et interprétation du scanner thoracique, indication et réalisation de la biopsie pulmonaire, bilan étiologique, modalités et indications de l’enquête familiale et de l’analyse génétique, évaluation du retentissement fonctionnel et du pronostic, indication et emploi des médicaments antifibrosants, transplantation pulmonaire, prise en charge des symptômes, comorbidités et complications, traitement de l’insuffisance respiratoire chronique, diagnostic et prise en charge des exacerbations aiguës de fibrose.

Ces recommandations fondées sur les preuves sont destinées à guider le diagnostic et la prise en charge pratique de la fibrose pulmonaire idiopathique.

Since the previous French guidelines were published in 2017, substantial additional knowledge about idiopathic pulmonary fibrosis has accumulated.

Under the auspices of the French-speaking Learned Society of Pulmonology and at the initiative of the coordinating reference center, practical guidelines for treatment of rare pulmonary diseases have been established. They were elaborated by groups of writers, reviewers and coordinators with the help of the OrphaLung network, as well as pulmonologists with varying practice modalities, radiologists, pathologists, a general practitioner, a head nurse, and a patients’ association. The method was developed according to rules entitled “Good clinical practice” in the overall framework of the “Guidelines for clinical practice” of the official French health authority (HAS), taking into account the results of an online vote using a Likert scale.

After analysis of the literature, 54 recommendations were formulated, improved, and validated by the working groups. The recommendations covered a wide-ranging aspects of the disease and its treatment: epidemiology, diagnostic modalities, quality criteria and interpretation of chest CT, indication and modalities of lung biopsy, etiologic workup, approach to familial disease entailing indications and modalities of genetic testing, evaluation of possible functional impairments and prognosis, indications for and use of antifibrotic therapy, lung transplantation, symptom management, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis.

These evidence-based guidelines are aimed at guiding the diagnosis and the management in clinical practice of idiopathic pulmonary fibrosis.

The occurrence of pulmonary fibrosis in numerous individuals from the same family suggests a genetic cause for the disease. During the last 10 years, mutations involving proteins from the telomerase complex and from the surfactant system have been identified in association with pulmonary fibrosis. Mutations of TERT, the coding gene for the telomerase reverse transcriptase, are the most frequently identified mutations and are present in 15% of cases of familial pulmonary fibrosis. Other mutations (TERC, surfactant proteins genes) are only rarely evidenced in adults. Patients with mutations involving the telomerase complex may present with pulmonary fibrosis, hematologic, cutaneous or liver diseases. Other genetic variations associated with pulmonary fibrosis such as a polymorphism in the promoter of MUC5B or a polymorphism in TERT have been recently described, and could be considered to be part of a polygenic transmission. Evidence for mutations associated with the development of pulmonary fibrosis raises numerous clinical questions from establishing a diagnosis, providing counselling to deciding on therapy, and requires specific studies. From a pathophysiological point of view, the function of the genes highlights the central role of alveolar epithelium and aging in fibrogenesis.

Environ 10 % des patients atteints de fibrose pulmonaire idiopathique ont au moins un apparenté atteint de pneumopathie interstitielle, définissant une fibrose pulmonaire familiale. Des mutations ou des polymorphismes génétiques associés aux fibroses pulmonaires familiales ont été identifiés. Il s’agit notamment de mutations portant sur les gènes codant les protéines du complexe télomérase et les protéines du surfactant. Les mutations du gène TERT codant la transcriptase inverse de la télomérase sont les plus fréquentes (environ 15 %). Les mutations dans les autres gènes (TERC, protéines du surfactant) sont plus rarement retrouvées chez l’adulte. Les mutations affectant le complexe télomérase peuvent être associées à des fibroses pulmonaires mais aussi à des anomalies hématologiques, hépatiques ou cutanées, ce qui étend le spectre des fibroses familiales vers le complexe des téloméropathies. Dans le cadre d’une hérédité polygénique, des polymorphismes de TERT ou du promoteur de MUC5B ont été associés aux fibroses pulmonaires. La découverte de mutations associées aux fibroses pulmonaires soulève de nombreuses questions cliniques et éthiques pour lesquelles des études spécifiques sont nécessaires. Sur le plan physiopathologique, ces mutations soulignent l’importance des perturbations de l’épithélium alvéolaire et du vieillissement au cours de la fibrogenèse.

Human telomerase reverse transcriptase (TERT) encodes a rate-limiting catalytic subunit of telomerase that maintains genomic integrity. TERT expression is mostly repressed in somatic cells with exception of proliferative cells in self-renewing tissues and cancer. Immortality associated with cancer cells has been attributed to telomerase over-expression. The precise mechanism behind the TERT activation in cancers has mostly remained unknown. The newly described germline and recurrent somatic mutations in melanoma and other cancers in the TERT promoter that create de novo E-twenty six/ternary complex factors (Ets/TCF) binding sites, provide an insight into the possible cause of tumor-specific increased TERT expression. In this review we discuss the discovery and possible implications of the TERT promoter mutations in melanoma and other cancers.