December 20, 2019

Cancer snubs mutant crypts in inflammatory bowel disease

Kyoto scientists find unexpected genetic flaw in ulcerative colitis patients that is shunned by cancer cells

People living with long term inflammatory conditions face a lifetime of intermittent pain, a greater risk of dying, and a much higher risk of cancer. As we age, cells in our bodies accumulate mutations, some of which have potential to cause cancer. Chronic inflammation also forces our body to continuously replace those damaged cells, which also carries a risk of promoting mutation.

Ulcerative colitis is a particularly debilitating inflammation of the colon and rectum, which often requires lifelong treatment with dietary management and drug therapy. There are around 2.1 million patients in Europe alone. Nobody knows exactly what causes the conditions but its sufferers do have a much higher risk of colorectal cancer.

Writing in the journal Nature, a collaboration of researchers throughout Japan, led by Kyoto University, have mapped the gene mutations that occur in inflamed tissues of ulcerative colitis patients. Unexpectedly, they found one major mutation that was actually avoided by cancerous cells in the same organs. This finding may point to a possible weakness of the cancer and new direction for therapy.

Corresponding author, Seishi Ogawa from Kyoto University says, “We presumed that the increased colorectal cancer risk in ulcerative colitis patients is related to expansion of mutated clones in tissues remodeled by chronic inflammation but no one has been able to verify this explicitly.”

The researchers examined biopsy samples from more than 600 patients, including 76 who had ulcerative colitis. They applied a genetic sequencing technique called whole exome sequencing, which gives insights into all the protein-coding regions of the genome.

First, they compared the genetic profiles of small groups of cells in the colon and rectum, known as crypts. After reaching 20 years old, new crypts stop forming to enlarge colorectal mucosa in humans, which means that any damage to tissue is repaired by existing crypts splitting off to fill in the gap. Continuous cycles of inflammation and repair that happens in ulcerative colitis patients paves the way for replication of crypts carrying mutations, which then take over and “remodel” the colon and rectum.

The team confirmed that although the number of mutations increased in both healthy and ulcerative colitis patients with age, the rate of mutation was around three times as high in the crypt cells from those with ulcerative colitis compared with those from regular patients.

Next, they looked for the most common mutations among ulcerative colitis patients. One of the most frequently affected genes was NFKBIZ, which is known to produce a protein molecule that regulates inflammatory response. The mutant form of NFKBIZ loses the ability to exercise this control, resulting in down-regulation of inflammatory signaling pathways, such as IL-17. This protein is known to be the root cause of many different kinds of inflammatory responses like psoriasis of the skin.

Curiously, when the team looked at the genetic profiles of cancerous tissues from the same ulcerative colitis patients, they found something strange. The mutant NFKBIZ gene, which was overall a very common in the ulcerative colitis patients, was completely absent from almost 100 cancerous cell specimens.

In parallel, the team performed studies in mice that were given a mutant version of the NFKBIZ gene. They confirmed that the mutant version of the gene seemed to give the mice a better change of avoiding cancerous tumors.

Ogawa says, “Our insights into how chronic inflammation can remodel of tissues through positive selection of clones that acquire mutations, adds to body of knowledge on ulcerative colitis. But it was quite surprising to find that NFKBIZ is negatively selected for in the cancers of these tissues. More work is clearly needed, but this could point to novel vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.”

Paper Information

Nobuyuki Kakiuchi, Kenichi Yoshida, Motoi Uchino, Takako Kihara, Kotaro Akaki, Yoshikage Inoue, Kenji Kawada, Satoshi Nagayama, Akira Yokoyama, Shuji Yamamoto, Minoru Matsuura, Takahiro Horimatsu, Tomonori Hirano, Norihiro Goto, Yasuhide Takeuchi, Yotaro Ochi, Yusuke Shiozawa, Yasunori Kogure, Yosaku Watatani, Yoichi Fujii, Soo Ki Kim, Ayana Kon, Keisuke Kataoka, Tetsuichi Yoshizato, Masahiro M. Nakagawa, Akinori Yoda, Yasuhito Nanya, Hideki Makishima, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Masashi Sanada, Eiji Sugihara, Taka-aki Sato, Takashi Maruyama, Hiroyuki Miyoshi, Makoto Mark Taketo, Jun Oishi, Ryosaku Inagaki, Yutaka Ueda, Shinya Okamoto, Hideaki Okajima, Yoshiharu Sakai, Takaki Sakurai, Hironori Haga, Seiichi Hirota, Hiroki Ikeuchi, Hiroshi Nakase, Hiroyuki Marusawa, Tsutomu Chiba, Osamu Takeuchi, Satoru Miyano, Hiroshi Seno & Seishi Ogawa (2019). Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis, Nature, DOI: