Linnéa La Fleur1, Elin Falk-Sörqvist1, Patrik Smeds1, Anders Berglund2, Magnus Sundström1, Johanna Sm Mattsson1, Eva Brandén3, Hirsh Koyi3, Johan Isaksson4, Hans Brunnström5, Mats Nilsson6, Patrick Micke1, Lotte Moens1, Johan Botling7. 1. Dept. of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden. 2. Epistat, Uppsala, Sweden. 3. Dept. of Respiratory Medicine, Gävle Hospital, Gävle, Centre for Research and Development, Uppsala university/County Council of Gävleborg, Gävle, Sweden. 4. Dept. of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden; Dept. of Respiratory Medicine, Gävle Hospital, Gävle, Centre for Research and Development, Uppsala university/County Council of Gävleborg, Gävle, Sweden. 5. Dept. of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden. 6. Dept. of Biochemistry and Biophysics, Stockholm University, Sweden. 7. Dept. of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden. Electronic address: johan.botling@igp.uu.se.
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 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.
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 adenocarcinomapatients. Worse overall survival was observed for adenocarcinomapatients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinomaKRAS-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.
Authors: Anand Khadse; Vilde D Haakensen; Laxmi Silwal-Pandit; Julian Hamfjord; Patrick Micke; Johan Botling; Odd Terje Brustugun; Ole Christian Lingjærde; Åslaug Helland; Elin H Kure Journal: Front Oncol Date: 2022-04-29 Impact factor: 5.738
Authors: Ferdinandos Skoulidis; Bob T Li; Grace K Dy; Timothy J Price; Gerald S Falchook; Jürgen Wolf; Antoine Italiano; Martin Schuler; Hossein Borghaei; Fabrice Barlesi; Terufumi Kato; Alessandra Curioni-Fontecedro; Adrian Sacher; Alexander Spira; Suresh S Ramalingam; Toshiaki Takahashi; Benjamin Besse; Abraham Anderson; Agnes Ang; Qui Tran; Omar Mather; Haby Henary; Gataree Ngarmchamnanrith; Gregory Friberg; Vamsidhar Velcheti; Ramaswamy Govindan Journal: N Engl J Med Date: 2021-06-04 Impact factor: 176.079