Mutational profiles of primary pulmonary adenocarcinoma and paired brain metastases disclose the importance of KRAS mutations.

Vassella, Erik; Kashani, Elham; Zens, Philipp; Kündig, Alexandra; Fung, Christian; Scherz, Amina; Herrmann, Evelyn; Ermis, Ekin; Schmid, Ralph A.; Berezowska, Sabina (2021). Mutational profiles of primary pulmonary adenocarcinoma and paired brain metastases disclose the importance of KRAS mutations. European journal of cancer, 159, pp. 227-236. Elsevier 10.1016/j.ejca.2021.10.006

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BACKGROUND

Brain metastases present a significant complication in lung cancer with an unmet therapeutic need.

METHODS

In this single-centre, retrospective study, we genotyped a clinico-pathologically well-annotated cohort of consecutively resected brain metastases of lung adenocarcinomas and paired primary tumours, diagnosed from 2000 to 2015, using the Ion Torrent Oncomine Comprehensive Cancer Panel v3.

RESULTS

Among 444 consecutive brain metastases, 210 (49%) originated from lung cancer. Analysis was successful in 111 samples, including 54 pairs of brain metastasis and primary tumour. Most driver alterations were preserved in brain metastases. Private alterations exclusive to primary tumours, brain metastases or both sites (intersecting cases) were present in 22%, 26% and 26% of cases, respectively. Seven percent had no shared mutations. KRAS mutations were more frequent in primary tumours metastasised to the brain (32/55, 58%) compared to TCGA (33%, p < 0.005) and own data from routine diagnostics, independent from clinical or pathological characteristics. Fourteen cases showed alterations in the EGFR signalling pathway including additional KRAS alterations that were private to brain metastases. KRAS G12C was detected most frequently (26% of patients) and KRAS G12C and G13C variants were significantly enriched in brain metastases. Synchronous and metachronous cases had a similar mutation profile.

CONCLUSIONS

Our results suggest an important role of KRAS alterations in the pathobiology of brain metastases from lung adenocarcinomas. This has direct therapeutic implications as inhibitors selectively targeting KRAS G12C are entering the clinics.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology

Graduate School:

Graduate School for Health Sciences (GHS)

UniBE Contributor:

Vassella, Erik; Kashani, Elham; Zens, Philipp Immanuel; Kündig, Alexandra Gabriela; Scherz, Amina; Herrmann, Evelyn; Ermis, Ekin; Schmid, Ralph and Berezowska, Sabina Anna

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0959-8049

Publisher:

Elsevier

Language:

English

Submitter:

Rebeka Gerber

Date Deposited:

30 Nov 2021 12:07

Last Modified:

30 Nov 2021 12:16

Publisher DOI:

10.1016/j.ejca.2021.10.006

PubMed ID:

34781171

Uncontrolled Keywords:

Brain metastases KRAS G12C Lung cancer NSCLC Next generation sequencing

BORIS DOI:

10.48350/161350

URI:

https://boris.unibe.ch/id/eprint/161350

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