More and more young adults are suffering from colorectal cancer. What makes their tumors different?

These differences may provide clues as to why the disease can sometimes behave more aggressively at younger ages. Researchers from Massachusetts General Hospital, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, and the Broad Institute of MIT and Harvard mapped gene activity in more than 850,000 cells from 189 tumors.

According to the American Cancer Society, the incidence of colorectal cancer among Americans under the age of 50 increased by 2.9% each year between 2013 and 2022. The disease is now the leading cause of cancer death in this age group in the United States. At the same time, overall incidence and mortality have declined in recent decades, in part due to screening and improved treatments. The decline between 2013 and 2022 is mainly explained by falling rates among people aged 65 and over, while incidence increased slightly among people aged 50 to 64. Amid an increase in cases among young adults, the recommended starting age for routine screening among average-risk Americans was lowered from 50 to 45.

Younger people also tend to be diagnosed at a later stage. According to the American Cancer Society, about three in four cases of colorectal cancer in Americans under age 50 are detected after the disease has spread locally or to distant organs. Distant metastases are discovered at diagnosis in approximately 27% of younger patients, compared to 21-23% in older groups.

“We’re seeing a lot more young people with cancer than before,” said Dr. Yaron Rudnitzky, director of the colorectal surgery and proctology unit and deputy director of the surgical division at Meir Medical Center, part of Clalit Health Services. Most of the younger patients he sees are around 40, he said, although some are even younger.

“People in their 40s don’t think they can have cancer,” he said. “Very often, they’ve been walking around for a year with abdominal pain, bloody stools or weight loss. By the time they’re diagnosed, they often come in with more advanced disease.”

Rudnitzky highlighted two factors that can contribute to late diagnosis. “We don’t have a systematic screening protocol for young people,” he said. And even after symptoms appear, cancer is not always immediately suspected.

The question is whether the later stage of diagnosis also reflects the biology of the tumors themselves.

“The big question on the ground has been, ‘Why is this increasing?’ and the second question is: “Is it a different disease?” ” said Professor Ana Anderson, director of the Cancer Program at the Gene Lay Institute of Immunology and Inflammation at Brigham and Women’s Hospital and one of the study’s principal investigators.

The study, the largest of its kind, analyzed tumor samples collected during surgery at Brigham and Women’s Hospital and stored frozen in the Dana-Farber tissue bank. The samples came from patients aged 29 to over 90 years old. Fifty-four were diagnosed before age 50, while 135 were diagnosed at age 50 or older.

The researchers used a technique known as mononuclear RNA sequencing, which allows scientists to determine which genes are active in individual cells. Since the method can be used on frozen tissue, the team was able to analyze archived samples accompanied by extensive medical information. In total, they mapped gene activity in more than 850,000 cells, including cancer cells and other cell types found in tumors.

In some statistical analyses, researchers treated age as a continuum rather than simply comparing patients under 50 and those over 50, looking for biological characteristics that gradually changed with age. They also took into account the location of the tumor, the stage of the disease, gender and the treatment received before surgery. This allowed them to identify trends that a simple two-group comparison might have missed.

“When we looked beyond conventional age limits, we discovered biological patterns that previous studies might have missed,” Anderson said.

The most striking finding concerned the cellular composition of the tumors. In microsatellite-stable colorectal cancer, or MSS, the most common subtype of the disease, tumors from younger patients had a higher proportion of stromal cells compared to cancer cells.

Stromal cells are connective and supporting cells that form a kind of structure around and between cancer cells. They can influence tumor growth and, under certain conditions, make it more difficult for immune cells and drugs to access and attack cancer cells. In several types of solid tumors, a high proportion of stromal tissue has been associated with resistance to chemotherapy.

The same pattern appeared in two additional groups analyzed by the researchers. One included genetic activity data from hundreds of tumors, while another used machine learning to analyze images of stained tissue from 712 tumors.

“This could explain why younger patients may respond less well to treatment,” said Professor Kimmie Ng, director of the Young-Onset Colorectal Cancer Center at Dana-Farber and one of the study’s principal investigators.

In cancer cells from MSS tumors, researchers identified 215 genes whose expression was higher in younger patients and 44 that were more active in older patients.

A substantial portion of the most active genes in younger patients produce long noncoding RNA molecules. Unlike conventional RNA which contains instructions for making proteins, these molecules do not code for proteins, although some can regulate the activity of other genes. In the three major cancer cell types analyzed, long noncoding RNAs accounted for about 30% to 45% of the genes showing increased expression in younger tumors, with some appearing in more than one cancer cell type.

About half of the long noncoding RNA molecules identified in this analysis belong to a poorly understood group, sometimes described as “dark RNA.” Researchers still know relatively little about what they are doing.

According to the researchers, approximately 60 to 70% of long non-coding RNAs are located inside the cell nucleus. Since the study specifically analyzed nuclei, the method might have been particularly well suited to detect differences missed by previous studies of colorectal cancer.

Much of the increase in colorectal cancer among young adults is linked to tumors on the distal or left side of the colon and rectum. In a computerized analysis looking at left-sided MSS tumors, researchers identified 29 signaling pathways in which predicted communication between cells was stronger in tumors from younger patients, compared to seven pathways that were stronger in older patients.

Some of these pathways are associated with the ability of cancer cells to change their characteristics and invade surrounding tissues, while others are involved in the formation of blood vessels that feed the tumor.

To determine whether the differences might simply reflect natural aging of the intestine, the researchers compared their results with data from normal intestinal tissue. Only five genes overlapped. They say this limited overlap supports the idea that the gene expression patterns they identified are linked to tumor biology rather than normal aging.

“The study doesn’t tell us why this happens in young people,” Rudnitzky said.

When a person develops colorectal cancer at a young age, one of the possibilities doctors look at is hereditary predisposition. But in many of the younger patients he treats, genetic testing does not identify any known hereditary cause.

“We’ve been constantly looking for the holy grail, what characterizes these tumors in young people,” he said, adding that the results reinforce his impression that the biology of tumors in younger patients can sometimes be more aggressive.

In his clinic, he sees young patients who already have metastatic disease at diagnosis or complications such as intestinal obstruction. For him, the newly identified molecular features offer another direction for determining whether tumor biology itself contributes to these findings.

The researchers emphasized that their results generate hypotheses about disease progression and response to treatment, but do not yet prove them. The sequencing method also recovered relatively few immune cells, leaving open the question of whether immune responses inside tumors also vary by age.

Professor Heinz-Josef Lenz, a colorectal cancer researcher at the University of Southern California who was not involved in the study, called the results promising but cautioned that researchers still don’t know whether the differences identified actually make the tumors more aggressive or more resistant to treatment.

“That’s the missing question,” he said.

Professor Ramnik Xavier, a gastroenterologist at Massachusetts General Hospital and the study’s other principal investigator, said the research creates a basis for examining how cellular patterns interact with substances derived from diet and the gut microbiome, and whether these interactions contribute to the development of colorectal cancer at younger ages.

Ng said younger patients are currently generally treated the same as older patients. Previous research in other cancers has looked at therapies targeting stromal cells.

“We hope that with further research, these findings could eventually become targets for personalized treatment for our young patients,” she said. “There is still…