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Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11

La Fleur, Linnéa ; Falk-Sörqvist, Elin ; Smeds, Patrik ; Berglund, Anders ; Sundström, Magnus ; Mattsson, Johanna SM ; Brandén, Eva ; Koyi, Hirsh ; Isaksson, Johan and Brunnström, Hans LU , et al. (2019) In Lung Cancer 130. p.50-58
Abstract

Objectives: Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort. Materials and methods: Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and... (More)

Objectives: Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort. Materials and methods: Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples. Results: We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinoma KRAS-mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis. Conclusion: Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS-positive adenocarcinoma subgroup.

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publication status
published
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keywords
KRAS, Mutation patterns, Non-small cell lung cancer, STK11, Targeted resequencing, TP53
in
Lung Cancer
volume
130
pages
9 pages
publisher
Elsevier
external identifiers
  • pmid:30885352
  • scopus:85061397269
ISSN
0169-5002
DOI
10.1016/j.lungcan.2019.01.003
language
English
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yes
id
b6f78d0a-74ab-4af1-a7f9-5057650e1a4a
date added to LUP
2019-02-18 14:01:01
date last changed
2020-05-26 05:11:06
@article{b6f78d0a-74ab-4af1-a7f9-5057650e1a4a,
  abstract     = {<p>Objectives: Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort. Materials and methods: Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples. Results: We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinoma KRAS-mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis. Conclusion: Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS-positive adenocarcinoma subgroup.</p>},
  author       = {La Fleur, Linnéa and Falk-Sörqvist, Elin and Smeds, Patrik and Berglund, Anders and Sundström, Magnus and Mattsson, Johanna SM and Brandén, Eva and Koyi, Hirsh and Isaksson, Johan and Brunnström, Hans and Nilsson, Mats and Micke, Patrick and Moens, Lotte and Botling, Johan},
  issn         = {0169-5002},
  language     = {eng},
  pages        = {50--58},
  publisher    = {Elsevier},
  series       = {Lung Cancer},
  title        = {Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11},
  url          = {http://dx.doi.org/10.1016/j.lungcan.2019.01.003},
  doi          = {10.1016/j.lungcan.2019.01.003},
  volume       = {130},
  year         = {2019},
}