Published: 08-06-2015 17:10 | Updated: 09-06-2015 09:27

New mutational patterns in gastrointestinal tract cancers

Researchers at Karolinska Institutet and the University of Helsinki have discovered previously uncharacterized mutational patterns in the human regulatory genome, in gastrointestinal tract and other cancers. The study is published in the journal Nature Genetics.

Mutations that lead to cancer are not only occurring in the 2 percent of the DNA that encodes for proteins, but also in the non-coding regions. These regions are determining when and where the genes are expressed. In the largest cancer genome study performed in the Nordic countries, researchers lead by Professors Lauri Aaltonen and Jussi Taipale, studied more than two hundred whole genomes from colorectal cancer samples.

The scientists detected a distinct accumulation of mutations at sites where the proteins CTCF and cohesin bind to the DNA. Both CTCF and cohesin are transcription factors carrying out essential functions in the genome, including regulation of gene expression and chromatin structure.

Hypermutated tumors

According to the findings, in hypermutated tumors CTCF/cohesin sites appear to be protected from mutations. In contrast, in another group of tumors these sites are mutated with a higher frequency than protein coding cancer genes. Tumors with high CTCF site mutation load tend to have a greater frequency of certain types of mutations, distributed throughout their genome. The process producing these mutations is not fully understood and needs further investigation.

“Until now the complete mutational pattern of colorectal cancer genomes has been poorly characterized”, says Jussi Taipale, Professor of medical systems biology at Karolinska Institutet’s Department of Biosciences and Nutrition. “Unraveling the underlying mechanisms of regulatory mutations in cancer remains a great challenge. These novel findings are significant and an important step towards understanding the cause and consequences of cancer-associated mutations.”

This project was supported by the Academy of Finland Centre of Excellence for Cancer Genetics, the EU FP7 project SYSCOL, the Jane and Aatos Erkko Foundation, the Finnish Cancer Society, ERC, the Sigrid Juselius Foundation, NIASC, NordForsk and State research funding of Kuopio University Hospital.


CTCF/cohesin-binding sites are frequently mutated in cancer
Riku Katainen*, Kashyap Dave*, Esa Pitkänen*, Kimmo Palin*, Teemu Kivioja, Niko Välimäki, Alexandra E Gylfe, Heikki Ristolainen, Ulrika A Hänninen, Tatiana Cajuso, Johanna Kondelin, Tomas Tanskanen, Jukka-Pekka Mecklin, Heikki Järvinen, Laura Renkonen-Sinisalo, Anna Lepistö, Eevi Kaasinen, Outi Kilpivaara, Sari Tuupanen, Martin Enge, Jussi Taipale & Lauri A Aaltonen ​
Nature Genetics, published online 08 June 2015, doi:

*These authors contributed equally to the work