Mutations targeting the coagulation pathway are enriched in brain metastases

Cristina Richichi,Monica Patanè,Paola Brescia,Dana A M Mustafa,Bianca Pollo,Massimiliano Del Bene,Elisabetta Munzone,Giancarlo Pruneri,Giuliana Pelicci,Pier Giuseppe Pelicci,Lorenzo Fornasari,Giorgio E M Melloni,Francesco Dimeco,Laura Riva,Angela Sciandivasci,Johan M Kros

doi:10.1038/s41598-017-06811-x

Abstract

Brain metastases (BMs) are the most common malignancy of the central nervous system. Recently it has been demonstrated that plasminogen activator inhibitor serpins promote brain metastatic colonization, suggesting that mutations in serpins or other members of the coagulation cascade can provide critical advantages during BM formation. We performed whole-exome sequencing on matched samples of breast cancer and BMs and found mutations in the coagulation pathway genes in 5 out of 10 BM samples. We then investigated the mutational status of 33 genes belonging to the coagulation cascade in a panel of 29 BMs and we identified 56 Single Nucleotide Variants (SNVs). The frequency of gene mutations of the pathway was significantly higher in BMs than in primary tumours, and SERPINI1 was the most frequently mutated gene in BMs. These findings provide direction in the development of new strategies for the treatment of BMs.

Highlights

Brain metastases (BMs) are the most common malignancy of the central nervous system
We identified somatic mutations, including single nucleotide variants (SNVs, using MuTect17) and small insertions and deletions, present in each primary Breast cancer (BC) and in the corresponding metastasis
Since we analysed somatic mutations in multiple samples for the same patient, to increase sensitivity in mutation-calling we merged the mutations identified in each sample (i.e. Single Nucleotide Variants (SNVs) and indels called in the metastasis sample and tumour sample compared to the matched normal sample), and we counted the number of alternative and reference reads supporting the mutations in all the samples

Summary

Results and Discussion

Recent studies have shown that plasmin from the reactive brain stroma, which is lethal to cancer cells passing through the blood-brain-barrier, acts as a natural defence against metastatic invasion, and plasminogen activator (PA)-inhibitor serpins in cancer cells sustain the mechanism for the metastatic colonization of the brain[18] These findings suggest that mutations in serpins and possibly other members of the coagulation cascade are critical to the formation of BMs. Interestingly, loss of function of one of these genes, FGA, is described as driving metastasis in vivo[19]. We analysed public gene mutation profiles of primary tumours coming from the cBioPortal[20, 21] from distinct organs, and we found that the frequency of samples with at least one of the complement and coagulation pathway genes mutated was significantly lower than in BMs (12% in breast cBioPortal samples against 58% in our breast samples, 12% in kidney against 43% and 40% in lung cancer against 70%; Table 1 and in Supplementary Table S5). Molecules targeting proteins of the serpin family may be applied to the management of patients with brain metastases

Methods

Author Contributions

Additional Information