Study reveals new clues to why colorectal cancer in young people is so deadly

Colorectal cancer rates have been rising in people under 50 since the mid-1990s. These early-onset cancers tend to be more aggressive and resistant to treatment than cancers in older adults — and now, scientists may be learning why.

A new study published Thursday (Oct. 29) in the journal Nature Medicine compared colorectal tumors from people between 29 and over 90 years old, and it revealed key differences between young and old patients.

The new findings might, in turn, help scientists uncover new ways to fight colorectal cancer in young people, said study co-author Ana Anderson, a professor of neurology at Harvard Medical School and a core faculty member of the Gene Lay Institute of Immunology and Inflammation at Brigham and Women's Hospital.

"I believe that our study is essentially a turning point now in the field," Anderson told Live Science. "Because up until now, we've had more questions than answers."

Many questions surround early-onset colorectal cancer, as the disease is rising in people under 50 even as it falls in older populations. It's now the leading cause of cancer death in the U.S. for people under 50, and its numbers are even on the rise among children and adolescents.

Beyond questions about what's driving this uptick in cases, another mystery has been why this disease is so deadly in young people.

"The clinical data suggests that the disease in the younger patients is more aggressive overall," Anderson said. "The patients, being very healthy otherwise, do not do well with treatment."

To investigate that mystery, Anderson collaborated with Dr. Kimmie Ng, an oncologist at the Dana-Farber Cancer Institute, and Dr. Ramnik Xavier, a gastroenterologist at the Broad Institute and Mass General Brigham. They used a method of analyzing RNA in cells that allowed them to work with frozen and banked tumor tissue. RNA, a cousin of DNA, reflects the genes that are active in cells. In all, the team analyzed 189 tumors: 54 from patients under 50 and 135 from patients over 50.

With that many samples, the researchers could look at gradual differences tied to each age group, instead of just comparing tumors between the younger and older groups overall. That enabled them to pinpoint subtle differences, Anderson said.

For starters, younger people had a higher proportion of connective tissue cells in their tumors than they did of malignant cancer cells. That pattern was flipped in patients of older ages. Having a smaller proportion of malignant cells might sound good, but connective tissue in tumors can secrete compounds that suppress the immune system, Anderson said. That helps protect the tumor from immune cells that might otherwise target its cells for destruction.

These connective tissue cells can also physically block chemotherapy drugs from getting to the cancerous cells. This could be one reason younger patients' cancers resist treatment, the researchers suggested.

Based on patterns of gene activity in the tumors, the researchers suspect that younger patients' cancer cells also show distinct activity related to cell-to-cell communication. That may help the cells migrate through the body more easily than cancer cells in older patients do. In other cancers, this kind of gene activity has been linked to more aggressive tumors and a greater chance that the disease will spread, or metastasize, Anderson said.

The study's results also turned up an intriguing mystery: the presence of lots of long noncoding RNA. These strands of RNA contain more than 200 building blocks, called nucleotides, that don't provide instructions for building proteins. Coding RNA, in contrast, is ferried to protein-building factories in cells to be used as blueprints.

Scientists don't know what much of this long noncoding RNA does in the body, nor do they understand what it is doing in the tumors specifically. However, they hope to find out.

Anderson and her team are already working on manipulating the RNA they found inside cancer cells in petri dishes. In time, this line of research could supply another piece of the puzzle, helping scientists understand why colorectal cancer is so aggressive in young people.

"It's a new avenue for research into this disease that we previously had no idea about," Anderson said.