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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
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. (Johan Botling)
Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
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2019 (Engelska)Ingår i: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 130, s. 50-58Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
2019. Vol. 130, s. 50-58
Nyckelord [en]
KRAS, Mutation patterns, Non-small cell lung cancer, STK11, TP53, Targeted resequencing
Nationell ämneskategori
Klinisk laboratoriemedicin
Forskningsämne
Patologi
Identifikatorer
URN: urn:nbn:se:uu:diva-380587DOI: 10.1016/j.lungcan.2019.01.003ISI: 000463276900008PubMedID: 30885352OAI: oai:DiVA.org:uu-380587DiVA, id: diva2:1300619
Forskningsfinansiär
Cancerfonden, 2013/711Cancerfonden, 2016/827Tillgänglig från: 2019-03-29 Skapad: 2019-03-29 Senast uppdaterad: 2020-01-03Bibliografiskt granskad
Ingår i avhandling
1. Mutation and immune profiling of non-small cell lung cancer
Öppna denna publikation i ny flik eller fönster >>Mutation and immune profiling of non-small cell lung cancer
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Several novel therapies that target molecular alterations and immune checkpoints in lung cancer have been introduced in the last decade. Still, only a minority of patients obtain long term disease control and overall survival remains poor. The aim of this thesis was to characterize the landscape of genetic alterations and immune cell infiltrates in tumor tissues from a large representative patient cohort of non-small cell lung cancer (NSCLC).

The mutational status of 82 genes related to lung cancer development were evaluated, in paper I, by a targeted re-sequencing approach adapted to work on “real-life” samples of mixed quality. We observed a remarkably high prevalence of activating KRAS mutations. Otherwise, the mutation spectrum resembled other western lung cancer populations. Poor survival was linked to subgroups of lung adenocarcinoma with mutations in TP53, STK11 and SMARCA4, independent of concomitant KRAS mutations. In lung squamous cell carcinoma, patients with mutations in CSMD3 had better survival.

The infiltration of tumor-associated immune cells was assessed by immunohistochemical analysis in paper II. Previously described immune response patterns termed “inflamed” and “desert” were confirmed in our dataset. In addition, we discovered a new immune phenotype characterized by overall sparse presence of most immune cell types except for a distinct infiltration of NK and plasma cells. This novel immune class displayed a favorable prognosis and was therefore designated “oasis”.

In paper III, infiltration of macrophage subtypes was evaluated by immunohistochemical analysis of CD68, CD163, MSR1 and MARCO. The majority of macrophages exhibited a tumor promoting phenotype and expression of MARCO, a targetable scavenger receptor, was detected in a distinct subset of NSCLC patients. Further investigation of the functional roles of MARCO in a human NSCLC setting was carried out in paper IV. Here, MARCO expression on cultured myeloid cells could be induced by NSCLC cell lines. The MARCO+ cells displayed an immunosuppressive phenotype and could effectively suppress the cytolytic effect of NK cells and CD8+ T cells. A monoclonal antibody targeting MARCO removed these inhibitory effects of the MARCO+ cells.

In summary, this thesis contributes knowledge on the genetic and immunologic underpinning of lung cancer that forms the basis for current and future treatment strategies in the evolving era of personalized oncology and pathology.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 69
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1592
Nyckelord
Non-small cell lung cancer, Tumor microenvironment, Tumor-associated macrophages, Immune infiltrates, PD-L1, Mutation patterns, Immune therapy, MARCO, TP53, STK11, KRAS
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-390321 (URN)978-91-513-0733-6 (ISBN)
Disputation
2019-10-11, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-09-19 Skapad: 2019-08-20 Senast uppdaterad: 2019-10-15

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La Fleur, LinneaFalk-Sörqvist, ElinSmeds, PatrikSundström, MagnusMattsson, Johanna Sofia MargaretaBrandén, EvaKoyi, HirshIsaksson, JohanMicke, PatrickMoens, LotteBotling, Johan

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La Fleur, LinneaFalk-Sörqvist, ElinSmeds, PatrikSundström, MagnusMattsson, Johanna Sofia MargaretaBrandén, EvaKoyi, HirshIsaksson, JohanMicke, PatrickMoens, LotteBotling, Johan
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Klinisk och experimentell patologiScience for Life Laboratory, SciLifeLabInstitutionen för immunologi, genetik och patologiCentrum för klinisk forskning, Gävleborg
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