Genomic alterations as independent prognostic factors to predict the type of lung cancer recurrence

A Valter; L Luhari; H Pisarev; B Truumees; A Planken; O P Smolander; K Oselin

doi:10.1016/j.gene.2023.147690

Genomic alterations as independent prognostic factors to predict the type of lung cancer recurrence

Gene. 2023 Nov 15:885:147690. doi: 10.1016/j.gene.2023.147690. Epub 2023 Aug 5.

Authors

A Valter¹, L Luhari², H Pisarev³, B Truumees⁴, A Planken⁵, O P Smolander², K Oselin⁵

Affiliations

¹ Department of Chemotherapy, Clinic of Oncology and Hematology, North Estonia Medical Centre, Tallinn, Estonia. Electronic address: ann.valter@regionaalhaigla.ee.
² Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia.
³ Institute of Family Medicine and Public Health, University of Tartu, Tartu, Estonia.
⁴ Department of Pathology, Clinic of Diagnostics, North Estonia Medical Centre, Tallinn, Estonia.
⁵ Department of Chemotherapy, Clinic of Oncology and Hematology, North Estonia Medical Centre, Tallinn, Estonia.

PMID: 37544338
DOI: 10.1016/j.gene.2023.147690

Abstract

Introduction: 33-70% of lung cancer (LC) patients develop recurrence after radical treatment. Previous studies have shown the importance of clinical-pathological characteristics for the risk of recurrence. The role of molecular mechanisms remains unclear. The aim was analyzing genomic features in LC patients with local (LR) versus distant recurrence (DR) to predict the risk and type of recurrence.

Materials and methods: Patients previously curatively treated with LC recurrences from 2015 to 2017 were retrospectively enrolled. Histological specimens collected at the time of LC diagnosis were sent for whole exome sequencing (WES). Genomic data was analyzed for single nucleotide polymorphisms (SNPs) and insertion-deletion mutations (INDELs).

Results: 191 patients were included. 33% of patients had LR and 67% DR, with median recurrence-free survival (RFS) 15.4 versus 11.2 months (p = 0.20) and overall survival (OS) after recurrence 12.9 versus 8.5 months (p = 0.007), respectively. Of various laboratory parameters studied, lymphocytes were significantly decreased at recurrence (p < 0.0001) in the DR group. In genetic analysis, significantly enriched INDEL mutations were found in 38 and 98 genes and SNP mutations in 63 and 179 genes in DR and LR groups, respectively. DMXL2 and ABCC9 gene mutations caused by INDELs appeared exclusively in the DR group. Enrichment analysis detected genes, like KNTC1, CLASP1, CLASP2 and CENPE, responsible of microtubule disturbance in the DR group. Furthermore, genes related to cytosolic Ca2+ such as STIM1, ITPR3 and RYR3, were significantly enriched in DR group whereas in LR group enrichment of pathways related to endoplasmic/sarcoplasmic reticulum Ca2+ was observed.

Conclusion: Our findings indicate distinct genomic signatures in the LR and DR cohorts, with microtubule disturbance and calcium regulation playing a crucial role in invasiveness in DR of LC. Understanding molecular mechanisms of LC recurrence may lead to the discovery of novel drug targets that could potentially stop spread of cancer cells.

Keywords: Calcium regulation; Lung cancer; Microtubule disturbance; Prognostic genetic markers; Recurrence type; Whole exome sequencing.

MeSH terms

Calcium*
Genomics
Humans
Lung Neoplasms* / genetics
Neoplasm Recurrence, Local / diagnosis
Neoplasm Recurrence, Local / genetics
Prognosis
Recurrence
Retrospective Studies

Substances

Calcium