The Genetic Landscape of Familial Pulmonary Fibrosis

Liu, Qi; Zhou, Yuan; Cogan, Joy D.; Sheng, Quanhu; Zhao, Shilin; Bai, Youhuang; Ciombor, Kristen K.; Markin, Cheryl; Douglas, Keith; Ding, Guixiao; Malabanan, M. Merced; Banovich, Nicholas E.; Nickerson, Deborah A.; Blue, Elizabeth; Bamshad, Michael J.; Brown, Kevin K.; Schwartz, David; Phillips, John A.; Martı́nez-Barricarte, Rubén; Salisbury, M.L.; Shyr, Yu; Loyd, James E.; Kropski, Jonathan A.; Blackwell, Timothy S.

doi:10.1164/rccm.202204-0781oc

Cited by 20 publications

(9 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rather than an initial influx of inflammatory cells or fibroblast activation, these results suggest that disruption of the alveolar epithelium and adjacent capillary network are observed before other structural remodeling is detected. This concept is supported by additional evidence that suggests PF risk is mediated primarily through the lung epithelium 10,47 . Other recognized disease-associated features including emergence of abundant activated fibroblasts and accumulation of macrophages appear to be later events in remodeling.…”

Section: Discussionmentioning

confidence: 83%

Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis

Vannan,

Lyu,

Williams

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

The human lung is structurally complex, with a diversity of specialized epithelial, stromal and immune cells playing specific functional roles in anatomically distinct locations, and large-scale changes in the structure and cellular makeup of this distal lung is a hallmark of pulmonary fibrosis (PF) and other progressive chronic lung diseases. Single-cell transcriptomic studies have revealed numerous disease-emergent/enriched cell types/states in PF lungs, but the spatial contexts wherein these cells contribute to disease pathogenesis has remained uncertain. Using sub-cellular resolution image-based spatial transcriptomics, we analyzed the gene expression of more than 1 million cells from 19 unique lungs. Through complementary cell-based and innovative cell-agnostic analyses, we characterized the localization of PF-emergent cell-types, established the cellular and molecular basis of classical PF histopathologic disease features, and identified a diversity of distinct molecularly-defined spatial niches in control and PF lungs. Using machine-learning and trajectory analysis methods to segment and rank airspaces on a gradient from normal to most severely remodeled, we identified a sequence of compositional and molecular changes that associate with progressive distal lung pathology, beginning with alveolar epithelial dysregulation and culminating with changes in macrophage polarization. Together, these results provide a unique, spatially-resolved characterization of the cellular and molecular programs of PF and control lungs, provide new insights into the heterogeneous pathobiology of PF, and establish analytical approaches which should be broadly applicable to other imaging-based spatial transcriptomic studies.

show abstract

Section: Discussionmentioning

confidence: 83%

Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis

Vannan,

Lyu,

Williams

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Since the first report of SFTPA2 variants in two families with both fILD and lung cancer, the involvement of SFTPA1 and SFTPA2 variants in ILD has been repeatedly confirmed, although the exact mechanism has yet to be understood [ 43 ]. However, the increased risk of lung cancer in SRG variant carriers remains hypothetical.…”

Section: Discussionmentioning

confidence: 99%

High risk of lung cancer in surfactant-related gene variant carriers

Brudon,

Legendre,

Mageau

et al. 2024

Eur Respir J

View full text Add to dashboard Cite

RationaleSeveral rare surfactant-related genes variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing.ObjectivesWe aimed to study the epidemiology and phenotype of lung cancer in an international cohort of surfactant-related gene (SRG) variant carriers.MethodsWe conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomerase-related gene (TRG) variant carriers.ResultsWe identified 99 SRG adult variant carriers (SFTPA1[n=18],SFTPA2[n=31],SFTPC[n=24],ABCA3[n=14] andNKX2–1[n=12]),including 20 (20.2%) with lung cancer (SFTPA1[n=7]; SFTPA2[n=8],SFTPC[n=3],NKX2–1[n=2] andABCA3[n=0]). Among SRG variant carriers, the odds of lung cancer was associated with age (odds ratio [OR] 1.04 [95% CI 1.01–1.08]), smoking (OR 20.7 [6.60–76.2]) andSFTPA1/SFTPA2variants (OR 3.97 [1.39–13.2]). Adenocarcinoma was the only histological type reported, with PDL1 expression≥1% of tumor cells in 3 cases. Cancer staging was localized (I/II) in 8 (40%) individuals, locally advanced (III) in 2 (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 3 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 patientsversusTRG patients was 18.1 [7.1–44.7].ConclusionThe high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular CT scan follow-up should be evaluated.

show abstract

“…1 ) [ 20 – 22 ]. Liu et al [ 23 ▪▪ ] performed a comprehensive evaluation for rare genetic variants by WES and/or candidate gene sequencing in a large cohort of FPF kindreds ( n = 569). They found that rare variants, mainly in TRG, account for 14.9–23.4% of FPF genetic risk, with pathways enriched for rare variant-containing genes, including focal adhesion and mitochondrial complex I assembly.…”

Section: Genetic Susceptibility To Idiopathic Pulmonary Fibrosismentioning

confidence: 99%

Recent advances in the genetics of idiopathic pulmonary fibrosis

Spagnolo

Lee

2023

Current Opinion in Pulmonary Medicine

View full text Add to dashboard Cite

Purpose of review Genetics contributes substantially to the susceptibility to idiopathic pulmonary fibrosis (IPF). Genetic studies in sporadic and familial disease have identified several IPF-associated variants, mainly in telomere-related and surfactant protein genes. Here, we review the most recent literature on genetics of IPF and discuss how it may contribute to disease pathogenesis. Recent findings Recent studies implicate genes involved in telomere maintenance, host defence, cell growth, mammalian target of rapamycin signalling, cell–cell adhesion, regulation of TGF-β signalling and spindle assembly as biological processes involved in the pathogenesis of IPF. Both common and rare genetic variants contribute to the overall risk of IPF; however, while common variants (i.e. polymorphisms) account for most of the heritability of sporadic disease, rare variants (i.e. mutations), mainly in telomere-related genes, are the main contributors to the heritability of familial disease. Genetic factors are likely to also influence disease behaviour and prognosis. Finally, recent data suggest that IPF shares genetic associations – and probably some pathogenetic mechanisms – with other fibrotic lung diseases. Summary Common and rare genetic variants are associated with susceptibility and prognosis of IPF. However, many of the reported variants fall in noncoding regions of the genome and their relevance to disease pathobiology remains to be elucidated.

show abstract

The Genetic Landscape of Familial Pulmonary Fibrosis

Cited by 20 publications

References 43 publications

Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis

Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis

High risk of lung cancer in surfactant-related gene variant carriers

Recent advances in the genetics of idiopathic pulmonary fibrosis

Contact Info

Product

Resources

About