Genomic profiles of lung cancer associated with idiopathic pulmonary fibrosis

Abstract

Little is known about the pathogenesis or molecular profiles of idiopathic pulmonary fibrosis-associated lung cancer (IPF-LC). This study was performed to investigate the genomic profiles of IPF-LC and to explore the possibility of defining potential therapeutic targets in IPF-LC. We assessed genomic profiles of IPF-LC by using targeted exome sequencing (OncoPanel version 2) in 35 matched tumour/normal pairs surgically resected between 2004 and 2014. Germline and somatic variant calling was performed with GATK HaplotypeCaller and MuTect with GATK SomaticIndelocator, respectively. Copy number analysis was conducted with CNVkit, with focal events determined by Genomic Identification of Significant Targets in Cancer 2.0, and pathway analysis (KEGG) with DAVID. Germline mutations in TERT (rs2736100, n = 33) and CDKN1A (rs2395655, n = 27) associated with idiopathic pulmonary fibrosis risk were detected in most samples. A total of 410 somatic mutations were identified, with an average of 11.7 per tumour, including 69 synonymous, 177 missense, 17 nonsense, 1 nonstop and 11 splice-site mutations, and 135 small coding indels. Spectra of the somatic mutations revealed predominant C > T transitions despite an extensive smoking history in most patients, suggesting a potential association between APOBEC-related mutagenesis and the development of IPF-LC. TP53 (22/35, 62.9%) and BRAF (6/35, 17.1%) were found to be significantly mutated in IPF-LC. Recurrent focal amplifications in three chromosomal loci (3q26.33, 7q31.2, and 12q14.3) and 9p21.3 deletion were identified, and genes associated with the JAK-STAT signalling pathway were significantly amplified in IPF-LC (P = 0.012). This study demonstrates that IPF-LC is genetically characterized by the presence of somatic mutations reflecting a variety of environmental exposures on the background of specific germline mutations, and is associated with potentially targetable alterations such as BRAF mutations.

Role of copy number variants in sudden cardiac death and related diseases: genetic analysis and translation into clinical practice

“…The corresponding positive predicting value was 64% and, therefore, the false discovery rate was 36%. In order to compare our algorithm with other CNV detection softwares, the same validation cohort was analyzed with CONTRA v.2.0.8 [20] and CNVKIT v.0.8.6 [21], for which effectiveness and reliability have been previously widely proved [22]. The best results were those achieved with our algorithm and CNVKIT, both in terms of accuracy (99.9%, whereas for CONTRA it was 99.6%) and sensitivity (100%, whereas for CONTRA it was 87.3%).…”

A low DNA methylation epigenotype in lung squamous cell carcinoma and its association with idiopathic pulmonary fibrosis and poorer prognosis

“…In our cohort, >80% of SCC cases with IPF also harbored activating p53 mutations, as assessed by immunohistochemistry, implying that these mutations are crucial to the development of carcinomas with IPF, although there was no significant difference in incidence of p53 mutations compared to SCC without IPF. Recently, Hwang et al 10 found that lung cancer with IPF showed frequent BRAF mutations (17.1%) APOBEC3-related mutational signatures. Of note, APOBEC3 is known to be induced by exogenous factors such as viral infection, while Folcik et al 48 reported that lungs with IPF are frequently infected by herpesvirus saimiri.…”

“…IPF is a persistent and chronic inflammatory disease that can be triggered by complex interactions between genetic and environmental factors such as cigarette use, although cancer development in fibrotic lungs occurs independently of cigarette smoking . Recently, exome sequencing revealed APOBEC‐related mutagenesis in lung cancers with IPF, suggesting viral and/or immune‐related mutagenic processes . Squamous cell metaplasia was also reported to frequently occur in peripheral honeycombed tissues of cancerous lungs with IPF .…”

“…1,9 Recently, exome sequencing revealed APOBEC-related mutagenesis in lung cancers with IPF, suggesting viral and/or immune-related mutagenic processes. 10 Squamous cell metaplasia was also reported to frequently occur in peripheral honeycombed tissues of cancerous lungs with IPF. 11 Furthermore, such metaplasia was linked to TP53 mutations 12 and loss of heterozygosity at the FHIT gene locus.…”

Somatic driver mutations in endometriosis as possible regulators of fibrogenesis (Review)

“…vi) CDKN2A, p16 INK4a : Cellular senescence markers, including p16 INK4a , induce interstitial remodeling, ECM deposit and pulmonary fibrosis (42). vii) BRAF: BRAF has been shown to be overexpressed and mutated in IPF samples (43). The high incidence of BRAF mutations has been observed in pulmonary fibrosis, most notably the BRAF V600E mutation profile (43).…”