Hot spot mutations in Finnish non-small cell lung cancers

Our plain-English summary of Hot spot mutations in Finnish non-small cell lung cancers, by S. Mäki-Nevala, V.K. Sarhadi, M. Rönty, et al (Lung Cancer, 2016).

The study

• Authors: S. Mäki-Nevala, V.K. Sarhadi, M. Rönty, E. Kettunen, K. Husgafvel-Pursiainen, H. Wolff, A. Knuuttila, S. Knuutila
• Journal: Lung Cancer
• Published: 2016;99:102-10
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Non-small cell lung cancer (NSCLC) is a common cancer with a poor prognosis. The aim of this study was to screen Finnish NSCLC tumor samples for common cancer-related mutations by targeted next generation sequencing and to determine their concurrences and associations with clinical features.

Materials And Methods: Sequencing libraries were prepared from DNA isolated from formalin-fixed, paraffin-embedded tumor material of 425 patients using the AmpliSeq Colon and Lung panel covering mutational hot spot regions of 22 cancer genes. Sequencing was performed with the Ion Torrent Personal Genome Machine (PGM).

Results: Data analysis of the hot spot mutations revealed mutations in 77% of the patients, with 7% having 3 or more mutations reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Two of the most frequently mutated genes were TP53 (46%) and KRAS (25%). KRAS codon 12 mutations were the most recurrently occurring mutations. EGFR mutations were significantly associated with adenocarcinoma, female gender and never/light-smoking history; CTNNB1 mutations with light ex-smokers, PIK3CA and TP53 mutations with squamous cell carcinoma, and KRAS with adenocarcinoma. TP53 mutations were most prevalent in current smokers and ERBB2, ERBB4, PIK3CA, NRAS, NOTCH1, FBWX7, PTEN and STK11 mutations occurred exclusively in a group of ever-smokers, however the association was not statistically significant. No mutation was found that associated with asbestos exposure.

Conclusion: Finnish NSCLC patients have a similar mutation profile as other Western patients, however with a higher frequency of BRAF mutations but a lower frequency of STK11 and ERBB2 mutations. Moreover, TP53 mutations occurred frequently with other gene mutations, most commonly with KRAS, MET, EGFR and PIK3CA mutations.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In plain English

This study used targeted gene sequencing on tumor samples from 425 Finnish patients with non-small cell lung cancer. Samples were collected in the Hospital District of Helsinki and Uusimaa during 2006–2014, and most tumors were adenocarcinomas. The study looked for mutations in hot spot regions of 22 cancer genes. Asbestos exposure was assessed by occupational interview and/or fiber counts in normal lung tissue. Of the patients, 29 were classed as exposed, 234 as non-exposed and 162 as unknown or uncertain. Overall, 77% of tumors had at least one known mutation, and TP53 (46% of patients) and KRAS were the most commonly mutated genes. EGFR mutations were statistically significantly associated with adenocarcinoma, women and never or light ex-smokers. No mutation was significantly associated with asbestos exposure. EGFR mutations appeared in 9% of non-exposed and 0% of exposed patients (p = 0.146), and TP53 mutations in 62% of exposed and 46% of non-exposed patients (p = 0.118). The authors attributed this to the small number of exposed patients and uncertain or partial exposure information.

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: Laboratory study of archived lung tumor samples using targeted next-generation sequencing of mutation hot spots in 22 genes, with comparison of mutation status against clinical features (histology, smoking, asbestos exposure, gender)
• Who was studied: 425 Finnish patients with non-small cell lung cancer whose samples were sequenced successfully, out of 442 collected. Samples came mainly from lung cancer surgery in the Hospital District of Helsinki and Uusimaa, Finland, 2006–2014. The group was 66.6% adenocarcinoma and 20.9% squamous cell carcinoma, 239 (56.2%) male, with a median age of 66.0.
• Exposure: Asbestos exposure was assessed by interview about occupational history and/or fiber count by SEM on normal lung tissue; fiber types were not specified. More than 2.0 million asbestos fibers per gram of dried lung tissue counted as exposed, and less than 1.0 million as non-exposed. Results: 29 (6.8%) exposed (26 by interview only, 3 by fiber count only), 234 (55.1%) non-exposed, 162 (38.1%) not known or uncertain. Smoking history was also studied.
• Main results:
  • 77% of the 425 tumor samples had one or more mutations listed in the COSMIC database.
  • TP53 was the most frequently mutated gene, with mutations in 46% of patients.
  • KRAS mutations were the second most common, with codon 12 and 13 mutations the most recurrent (25%).
  • EGFR mutations were statistically significantly associated with adenocarcinoma (p = 0.037). They were also associated with never and light ex-smokers (p less than 0.001) and with female patients (p less than 0.001).
  • PIK3CA mutations (p = 0.016) and TP53 mutations (p less than 0.001) were most prevalent in squamous cell carcinoma, and KRAS mutations in adenocarcinoma (p less than 0.001).
  • CTNNB1 mutations were associated with light ex-smokers (p = 0.011).
  • Asbestos exposure: EGFR mutations were more frequent in the non-exposed group than the exposed group (9% vs 0%, p = 0.146). TP53 mutations were more frequent in the asbestos-exposed group than the non-exposed group (62% vs 46%, p = 0.118). Neither difference was statistically significant.
  • MET mutations (17% non-exposed vs 10% exposed) and KRAS mutations (25% non-exposed vs 21% exposed) occurred at similar frequencies in the two asbestos groups.
  • BRAF mutations were found in 5.6% of patients.
• The authors' conclusion: The authors concluded that the mutation profiles of Finnish non-small cell lung cancer patients did not differ essentially from those of other Western patients. However, BRAF mutations were seen more often, and STK11 and ERBB2 mutations less often. TP53 mutations were the most frequent and tended to occur alongside EGFR and KRAS mutations. As a novel finding, CTNNB1 mutations were significantly associated with ex-light smokers.
• Limitations the authors state:
  • The authors could not find any mutation significantly associated with asbestos exposure, because few patients were asbestos-exposed and exposure information was often uncertain or only partial.
  • No normal tissue was available to confirm that mutations arose in the tumor, so some reported mutations might be inherited (germline).
  • Some mutations may have been missed in 8 samples with tumor content below 10%.
  • The sequencing panel covered only the mutation hot spot regions of the genes, which may partly explain lower frequencies of some mutations such as STK11.
  • Most patients had early, operable disease and follow-up was short, so the authors drew no clear conclusions about mutations and survival.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Non-Small Cell Lung Cancer, Prognosis, Somatic Mutation, EGFR, Adenocarcinoma, Squamous Cell Carcinoma, Asbestos Exposure.

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