Colorectal cancer

• 1. Introduction

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  Colorectal cancer ranked fifth among cancer killers in Americans under 50 in the early 1990s. By 2026, it had climbed to first place. That shift, measured across decades of data and confirmed in the Journal of the American Medical Association, tells the story of a disease that most people think of as belonging to the old. It does not. Around the world in 2022 alone, colorectal cancer struck 1.93 million people and killed more than 900,000. It is now the third most common cancer on the planet, making up roughly 10% of all cases globally. Yet despite those numbers, about half of all cases are preventable. The questions this documentary will answer are ones every listener deserves to know: where does this cancer come from, how do doctors find it before it becomes lethal, what happens when treatment begins, and why are younger people now its fastest-growing victims?

• 2. From Polyp to Cancer

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  A colorectal cancer almost always begins not as a cancer at all, but as a benign polyp growing along the inner lining of the colon or rectum. The transformation from that innocent growth into something dangerous follows what scientists call the adenoma-carcinoma sequence, a process driven by progressive genetic mutation. At the center of that process sits the APC gene, the most commonly mutated gene across all colorectal cancers. Normally, the protein the APC gene produces keeps a molecule called beta-catenin in check. When APC is mutated, beta-catenin builds up, moves into the cell's nucleus, and switches on genes that drive uncontrolled growth. That is the first domino. Further mutations must then follow before a cell becomes fully cancerous. A protein called p53, produced by the TP53 gene, normally acts as a watchdog: it detects Wnt pathway defects and triggers programmed cell death. When the TP53 gene itself mutates, that safeguard is gone. Other protective proteins, including TGF-beta and DCC (Deleted in Colorectal Cancer), are deactivated in a large share of colorectal cancers as well. TGF-beta carries a deactivating mutation in at least half of all cases. The picture that emerges is not one catastrophic event but an accumulation: an average colorectal cancer carries only one or two oncogene mutations and one to five tumor suppressor mutations, with roughly 60 additional passenger mutations riding along. Epigenetic changes compound the genetic ones. Unlike mutations, epigenetic alterations do not rewrite the DNA sequence; they change how genes are expressed. Researchers have found 164 microRNAs significantly altered in colorectal cancers. One of those, miRNA-143, is downregulated in 88% of colorectal cancer cases, an absence that allows the oncogene KRAS to become overactive. As a person ages, the probability that these genetic and epigenetic changes will accumulate rises steadily, which helps explain why older age is one of the strongest risk factors for the disease.

• 3. Risk Factors and Lifestyle

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  Between 75% and 95% of colorectal cancer cases occur in people with little or no elevated genetic risk. Diet is described as the largest environmental risk factor, and of all dietary variables, alcohol carries the strongest evidence: consuming more than one drink per day raises the risk. Processed meat is classified by the International Agency for Research on Cancer as a group I carcinogen because the evidence that it causes colorectal cancer in humans is sufficient. Red meat is also consistently linked to higher risk. On the protective side, whole grain intake is inversely related to risk. Drinking five glasses of water a day may be linked to a decrease in risk of both colorectal cancer and adenomatous polyps. Calcium, as found in dairy products, appears protective. Approximately 10% of cases are linked to insufficient physical activity. High levels of physical activity reduce colon cancer risk by about 21%, though exercise does not eliminate risk entirely. Sitting for prolonged periods regularly is associated with higher mortality from colon cancer. The gut microbiome adds another layer. Studies find that tumors are consistently associated with reduced microbial diversity and enrichment of specific bacteria. Fusobacterium nucleatum is enriched in colorectal cancer tissue compared with adjacent normal mucosa. Populations characterized by high levels of pathogenic bacteria like Escherichia coli and Fusobacterium nucleatum, alongside depletion of beneficial genera such as Bifidobacterium and Lactobacillus, carry an increased risk. These findings suggest that disturbances in the gut's microbial community can influence cancer development through multiple mechanisms, including inflammation and altered immune response.

• 4. Inherited Risk

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  Roughly 20% of all colorectal cancer cases involve a family history of two or more first-degree relatives with the disease, a pattern that confers a two- to threefold greater risk. Specific inherited syndromes carry far heavier odds. Hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome, is present in about 3% of all colorectal cancer patients. Gardner syndrome and familial adenomatous polyposis (FAP) together account for about 1% of cases, but for individuals who carry these syndromes, cancer almost always occurs. Because the risk of malignancy in FAP is so high, a total proctocolectomy, removal of both the colon and rectum, may be recommended as a preventive measure. Removing only the colon is often not enough: the risk of rectal cancer remains high if the rectum is left in place. The most common polyposis syndrome affecting the colon is serrated polyposis syndrome, associated with a 25%-40% risk of colorectal cancer. Ashkenazi Jews carry a 6% higher risk of developing adenomas and then colon cancer, traceable to mutations in the APC gene being more prevalent in that population. A gene known as MACC1, metastasis-associated in colon cancer 1, has been isolated as a contributor to the risk of metastatic disease specifically: it influences the expression of hepatocyte growth factor and is associated with the proliferation, invasion, and spread of cancer cells in cell culture as well as tumor growth and metastasis in mice. Clinical studies are still needed to confirm whether MACC1 could serve as a target for intervention.

• 5. Screening and Detection

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  More than 80% of colorectal cancers arise from adenomatous polyps, and that fact makes screening powerful: polyps can be found and removed before they become cancer. Screening has the potential to reduce colorectal cancer deaths by 60%. Diagnosis through screening typically occurs two to three years earlier than diagnosis driven by symptoms. The three main tools are colonoscopy, fecal occult blood testing, and flexible sigmoidoscopy. Flexible sigmoidoscopy has the best evidence for decreasing the risk of death from any cause, but it cannot reach the right side of the colon, where 42% of cancers are found. Colonoscopy covers the full colon and can remove small polyps at the time of the procedure. Fecal occult blood testing, recommended every two years, reduces colorectal cancer deaths by 16% when screening is offered, and by up to 25% when people actually participate. In the United States, the American Cancer Society moved its recommended starting age from 50 down to 45 in 2018, responding directly to the rising number of cases in younger adults. Canada's provinces of Prince Edward Island and Ontario are set to match that change beginning in 2026. Among younger populations, those aged 20 to 29 experienced the sharpest increase in cases: incidence rose by 7.9% per year between 2004 and 2016. The men and women aged 30 to 39 saw an increase of 3.4% per year over the same period. Despite these trends, researchers note that mortality rates for colorectal cancer in younger populations have not risen at the same pace, suggesting that earlier detection is making some difference. A rectal cancer was diagnosed in an ancient Egyptian mummy from the Dakhleh Oasis, dating to the Ptolemaic period, evidence that this disease is not new to the human experience, but the scale and demographic shift happening now is.

• 6. Treatment Landscape

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  Surgery is the cornerstone of curative treatment for colorectal cancer caught at an early stage. When the cancer is confined to the colon wall, complete surgical removal with adequate margins gives a realistic chance of cure. The standard procedure is a partial colectomy, or a proctocolectomy for rectal tumors, removing the affected segment along with the surrounding lymph nodes. That can be done as open surgery or laparoscopically. If only a few metastases are present in the liver or lungs, those too may be removed surgically. Chemotherapy enters the picture from Stage III onward, and for Stage IV patients, agents including fluorouracil, capecitabine, oxaliplatin, and irinotecan are used in combination. Specific regimens carry names such as FOLFOX and FOLFIRI. Antiangiogenic drugs like bevacizumab are often added in first-line therapy. For rectal cancer, radiation is frequently combined with chemotherapy before surgery to shrink the tumor and reduce the need for a permanent colostomy. A notable development in immunotherapy involves the subgroup of tumors with mismatch repair deficiency. In a prospective phase 2 study published in June 2022 in The New England Journal of Medicine, 12 patients with deficient mismatch repair stage II or III rectal adenocarcinoma received the drug dostarlimab every three weeks for six months. After a median follow-up of 12 months, all 12 patients had a complete clinical response: no evidence of tumor on MRI, on positron-emission tomography, or on biopsy. No patient in the trial required chemoradiotherapy or surgery, and no patient reported grade 3 or higher adverse events. The study is small and long-term outcomes remain uncertain, but the result drew wide attention. For advanced disease where cure is not possible, palliative care, including procedures to relieve obstruction, bleeding, and pain, focuses on preserving quality of life.

• 7. Survival and Living Beyond Diagnosis

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  The five-year survival rate in the United States was around 65% in 2014, and survival varies dramatically by stage. People whose tumor has not breached the muscularis mucosa have a five-year survival rate of 100%. Those with invasive cancer in the earliest layers carry an average five-year survival rate of approximately 90%. A more invasive tumor without lymph node involvement drops that figure to approximately 70%. Positive lymph nodes bring it to approximately 40%. Distant metastases carry a five-year survival ranging from under 5% to 31%. In Europe, the five-year survival rate is less than 60%, and in the developed world about a third of people who get the disease die from it. Survival rates for colorectal cancers detected early are about five times higher than for late-stage cancers. Beyond survival statistics, the experience of living after a colorectal cancer diagnosis involves a set of physical and psychological challenges that statistics alone do not capture. Postoperative life may include stomas, bowel issues, incontinence, odor, and changes to sexual functioning. Colorectal cancer patients have a 51% higher risk of experiencing depression than individuals without the disease. Stigma is a documented part of the illness: the disease is associated with bodily functions that carry social taboo, and patients with stomas face particular vulnerability to social judgment. Researchers identify three factors as most influential in adaptation after treatment: support mechanisms, the severity of late treatment effects, and psychosocial adjustment. Face-to-face interventions, including talk therapy, body-mind-spirit practices, and support groups, have been identified as most effective in reducing anxiety and depression. A phase 3 randomized trial found that a structured three-year exercise program after adjuvant chemotherapy improved disease-free survival and was associated with lower all-cause mortality at a median follow-up of 7.9 years.