Prognostic Value of Germline Copy Number Variants and Environmental Exposures in Non-small Cell Lung Cancer

Our plain-English summary of Prognostic Value of Germline Copy Number Variants and Environmental Exposures in Non-small Cell Lung Cancer, by S. Chen, L. Lu, J. Xian, et al (Frontiers in Genetics, 2021).

The study

• Authors: S. Chen, L. Lu, J. Xian, C. Shi, J. Chen, B. Rao, F. Qiu, J. Lu, L. Yang
• Journal: Frontiers in Genetics
• Published: 2021;12:681857
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Germline copy number variant (gCNV) has been studied as a genetic determinant for prognosis of several types of cancer, but little is known about how it affects non-small cell lung cancer (NSCLC) prognosis. We aimed to develop a prognostic nomogram for NSCLC based on gCNVs. Promising gCNVs that are associated with overall survival (OS) of NSCLC were sorted by analyzing the TCGA data and were validated in a small Chinese population. Then the successfully verified gCNVs were determined in a training cohort (n = 570) to develop a prognostic nomogram, and in a validation cohort (n = 465) to validate the nomogram. Thirty-five OS-related gCNVs were sorted and were reduced to 15 predictors by the Lasso regression analysis. Of them, only CNVR395.1 and CNVR2239.1 were confirmed to be associated with OS of NSCLC in the Chinese population. High polygenic risk score (PRS), which was calculated by the hazard effects of CNVR395.1 and CNVR2239.1, exerted a significantly higher death rate in the training cohort (HR = 1.41, 95%CI: 1.16-1.74) and validation cohort (HR = 1.42, 95%CI: 1.13-1.77) than low PRS. The nomogram incorporating PRS and surrounding factors, achieved admissible concordance indexes of 0.678 (95%CI: 0.664-0.693) and 0.686 (95%CI: 0.670-0.702) in predicting OS in the training and validation cohorts, respectively, and had well-fitted calibration curves. Moreover, an interaction between PRS and asbestos exposure was observed on affecting OS (P interaction = 0.042). Our analysis developed a nomogram that achieved an admissible prediction of NSCLC survival, which would be beneficial to the personalized intervention of NSCLC.

Copyright © 2021 Chen, Lu, Xian, Shi, Chen, Rao, Qiu, Lu and Yang.

In plain English

The authors studied whether inherited DNA differences called germline copy number variants, along with environmental exposures, were linked to overall survival in patients with non-small cell lung cancer (NSCLC). This was a retrospective cohort study in southern China covering 2006 to 2019. The authors screened 200 cases from The Cancer Genome Atlas database and checked candidate variants in 213 Chinese patients. They then built a survival prediction tool in 570 patients from Guangzhou and tested it in 465 patients from Suzhou. A risk score combining two variants, CNVR395.1 and CNVR2239.1, was associated with a higher death rate in both groups. Patients with asbestos exposure also had shorter survival. In the combined cohorts, a high versus low risk score was linked to a higher hazard of death among asbestos-exposed patients (HR 2.04, 95% CI 1.32–3.17) than among unexposed patients (HR 1.34, 95% CI 1.14–1.58), with an interaction p-value of 0.042. The authors concluded that the two variants may affect survival through interaction with asbestos exposure. The authors noted they lacked treatment and disease-free survival data. The article gives neither the asbestos fiber type nor how exposure was defined.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective cohort study of survival, using genetic screening of public database cases followed by two Chinese patient cohorts (training and validation)
• Who was studied: Patients with pathologically confirmed primary NSCLC, all Han Chinese. The groups were 200 cases from The Cancer Genome Atlas (screening), 213 Guangzhou patients recruited 2015 to 2019 (variant checking), a training cohort of 570 Guangzhou patients, and a validation cohort of 465 Suzhou patients.
• Exposure: Germline copy number variants (mainly CNVR395.1 and CNVR2239.1, combined into a polygenic risk score) and environmental exposures recorded as yes or no. These included asbestos exposure (38 of 570 in training, 25 of 465 in validation), arsenic, paint, metallic toxicants, smoking pack-years and housing ventilation. Fiber type is not stated. Variable definitions are referred to earlier studies by the same group.
• Main results:
  • Training cohort: patients with asbestos exposure had a shorter median survival than unexposed patients (3 vs. 13 months) and a higher death rate (HR 1.61, 95% CI 1.11–2.33).
  • Validation cohort: 21 of 25 asbestos-exposed patients (84.0%) died. Their median survival was 7 months, against 14 months for unexposed patients (HR 1.94, 95% CI 1.25–3.02). The authors reported that asbestos exposure was confirmed as significantly associated with overall survival in this cohort.
  • High versus low polygenic risk score was associated with shorter median survival and a higher death rate. In the training set this was 10 vs. 15 months (HR 1.41, 95% CI 1.16–1.74). In the validation set it was 12 vs. 15 months (HR 1.42, 95% CI 1.13–1.77).
  • In the combined cohorts, there was a multiplicative interaction between the risk score and asbestos exposure on survival (interaction HR 1.61, 95% CI 1.02–2.56; P for interaction 0.042).
  • High versus low risk score carried a higher hazard of death among asbestos-exposed patients (HR 2.04, 95% CI 1.32–3.17) than among unexposed patients (HR 1.34, 95% CI 1.14–1.58). The interaction remained after adjusting for age, pre-existing tuberculosis, pack-years smoked and clinical stage.
  • The prediction tool (nomogram) combined the risk score, age, pre-existing tuberculosis, asbestos exposure, pack-years smoked and stage. Its concordance index was 0.678 (95% CI 0.664–0.693) in the training set and 0.686 (95% CI 0.670–0.702) in the validation set.
• The authors' conclusion: The authors concluded that CNVR395.1 and CNVR2239.1 may affect carriers' survival through interaction with asbestos exposure. They also concluded that the nomogram achieved an admissible prediction of NSCLC survival.
• Limitations the authors state:
  • The authors lacked data on disease-free survival.
  • The authors lacked treatment information, which they say might bias the associations between the prognostic factors and survival.

Topics

Medical terms in this study, explained in our Lexicon: Environmental Exposure, Non-Small Cell Lung Cancer, Prognosis, Overall Survival, Concordance Index, Asbestos Exposure.

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