Colon cancer differs by sex: women’s right-sided tumors show stronger immune evasion

The Seoul National University Bundang Hospital (SNUBH) said on Wednesday its research team has identified a phenomenon in which genes that help cancer cells evade the immune system are strongly activated in right-sided colorectal cancer in women. The findings are based on an analysis of molecular biological differences by tumor location and patient sex.

The study, published in the online issue of the Cancer Research and Treatment, was led by Professor Kim Na-young from the Department of Gastroenterology, Research Professor Song Chin-hee and Professor Choi Yong-hoon.

Colorectal cancer is a malignant tumor that develops in the appendix, colon, and rectum -- organs involved in digestion and excretion. In Korea, it is the second most common cancer, with 33,158 new cases reported annually (National Cancer Information Center, 2022), trailing only thyroid cancer. While there is a common misconception that colorectal cancer primarily affects men, partly due to a recent rise in cases among younger males, women account for about 40 percent of all patients, and it ranks as the third most common cancer among women.

Although colorectal cancer is common in both men and women, the disease exhibits distinct gender-based differences. In women, more than half of the cases occur on the right side of the colon (the ascending colon) and often develop from flat, serrated adenomas -- lesions that are difficult to detect early, according to SNUBH. 

In contrast, colorectal cancer in men more frequently arises on the left side (the descending colon), typically originating from tubular adenomas, and tends to occur five to seven years earlier on average. 

These differences suggest that sex not only influences the location of colorectal cancer but may also affect the underlying pathways through which the disease develops and progresses, the hospital noted. 

Until now, few studies have specifically examined the molecular and biological differences in colorectal cancer based on sex and tumor location. In recent years, cancer treatment has been rapidly moving away from a one-size-fits-all approach based solely on tumor type and stage, toward more precise, personalized therapies that consider the genetic traits and developmental pathways of cancer cells -- such as the use of immunotherapy. 

However, in colorectal cancer, evidence to support this shift remains limited.

In response, the research team analyzed genetic differences in tumor development and immune system interactions using colon tissue samples from 378 patients treated at SNUBH, comparing findings based on patient sex and tumor location.

The results showed that expression levels of the antioxidant-related gene NRF2 and the immune checkpoint protein PD-L1 were highest in female patients with right-sided colorectal cancer. The NRF2 gene helps regulate oxidative stress within cells, enhancing their survival, while PD-L1 suppresses immune cell attacks, allowing cancer cells to evade the immune response.

In other words, right-sided colorectal cancer in women appears to develop in an environment that supports cancer cell survival, enabling them to protect themselves and evade immune system attacks. This reliance on molecular biological mechanisms distinguishes this type of cancer from other forms of colorectal cancer, which typically begin with chromosomal instability caused by genetic mutations.

Additionally, the research team observed that the expression of the gene COX-2, which plays a role in inflammatory responses, and the inflammatory cytokine IL-1β both progressively increase as colorectal cancer advances.

These findings suggest that inflammation and the immune environment interact closely to influence the formation and progression of colorectal cancer. They also support the idea that the immune environment is significantly disrupted in female right-sided colorectal cancer, where the immune evasion function of the PD-L1 protein is activated -- potentially serving as a key pathway for cancer development.

The study holds significant implications, as its findings can serve as biological evidence for the development of cancer immunotherapies as well as for patient selection and predicting treatment responses.

“This study goes beyond the conventional approach of classifying colorectal cancer solely by tumor location or disease stage, confirming at the genetic level that cancer cell mechanisms can vary depending on sex and the site of origin,” Professor Kim said.

“In particular, in right-sided colorectal cancer, which is more prevalent in women, gene pathways related to immune evasion are more actively expressed. This could serve as important evidence for predicting responses to immunotherapy or developing personalized treatment strategies in the future.”