The adenoma to carcinoma sequence describes how most colorectal cancers develop. This process illustrates how normal colon lining cells gradually transform into benign growths called adenomas, which can then progress into malignant tumors. Understanding this progression is central to colorectal cancer development and informs early detection and prevention strategies.
The Classic Progression
The classic adenoma to carcinoma sequence begins with normal cells lining the colon. These cells can undergo changes leading to uncontrolled growth. The initial stage involves a hyperproliferative epithelium, where cells multiply at an increased rate but appear normal under a microscope.
This heightened cellular activity leads to an early adenoma, a benign polyp with disorganized cell growth and slight changes in cell appearance. As it grows, it can become an intermediate adenoma, showing more significant cellular abnormalities. The progression continues to an advanced adenoma, also known as adenocarcinoma in situ. Here, abnormal cells exhibit high-grade dysplasia, meaning they are highly disorganized and distinctly different from normal cells. At this stage, the lesion is still confined to the inner lining of the colon but has a high potential to become cancerous.
Finally, the advanced adenoma can transform into an invasive adenocarcinoma. This occurs when the abnormal cells break through the basement membrane, the boundary separating the inner lining from deeper tissues, and invade the underlying layers of the colon wall. Once invasive, the cancer can spread to nearby lymph nodes and distant organs, marking a more advanced stage of the disease. The entire process from a benign adenoma to an invasive carcinoma can take over a decade to unfold.
Key Genetic Alterations
The classic adenoma to carcinoma sequence is driven by accumulating genetic mutations. An initiating event often involves a mutation in the Adenomatous Polyposis Coli (APC) gene, a tumor suppressor gene responsible for regulating cell growth and adhesion. Loss of APC function leads to increased cell proliferation and decreased cellular adhesion, setting the stage for polyp formation.
Following the APC mutation, a mutation in the KRAS gene occurs. KRAS is an oncogene involved in cell signaling pathways that promote cell growth and division. A mutated KRAS gene leads to unregulated intracellular signaling, contributing to adenoma growth.
Later in the progression, mutations in tumor suppressor genes such as p53 and Deleted in Colorectal Carcinoma (DCC) are observed. The p53 gene acts as a guardian of the genome, initiating cell cycle arrest or programmed cell death upon DNA damage. A mutation in p53 impairs this protective mechanism, allowing damaged cells to divide uncontrollably, promoting the transition from adenoma to carcinoma. Similarly, the DCC gene is involved in cell-cell and cell-substrate interactions, and its alteration can interfere with these controls, contributing to tumor growth. The accumulation of these and other genetic changes ultimately determines the tumor’s biological properties and its progression to malignancy.
Other Routes to Cancer
While the classic adenoma to carcinoma sequence accounts for most colorectal cancers, other pathways can lead to the disease. One notable alternative is the “serrated pathway,” which is estimated to be responsible for 15% to 30% of all colorectal cancer cases. This pathway often involves distinct precursor lesions known as serrated polyps, including hyperplastic polyps, sessile serrated adenomas/polyps, and traditional serrated adenomas/polyps.
Serrated pathway tumors are characterized by mutations in the BRAF gene, an oncogene involved in cell growth and proliferation. These tumors are associated with the CpG island methylator phenotype (CIMP), an epigenetic mechanism involving the abnormal methylation of CpG islands in gene promoter regions. This methylation can silence tumor suppressor genes, contributing to uncontrolled cell growth. The BRAF mutation and CIMP are considered early events in the serrated pathway, leading to a different molecular evolution of colorectal cancer compared to the classic sequence.
Implications for Detection and Prevention
Understanding the adenoma to carcinoma sequence has impacted colorectal cancer detection and prevention strategies. The knowledge that most colorectal cancers arise from pre-cancerous polyps underpins current screening guidelines, emphasizing the detection and removal of these lesions before they become malignant. Colonoscopy is a primary screening tool, allowing for direct visualization and removal of polyps, thereby interrupting the progression to cancer.
Guidelines for surveillance colonoscopies are based on the characteristics of detected polyps, with factors like size, number, and histological features influencing the recommended follow-up interval. For example, individuals with one or two small tubular adenomas may have a repeat colonoscopy in five to ten years, while those with three or more adenomas or advanced adenomas might require repeat screening in three years. Lifestyle factors also influence this progression. Obesity, smoking, and heavy alcohol consumption have been associated with an increased risk of high-risk adenomas and colorectal cancer. Therefore, adopting a healthy lifestyle complements screening efforts in preventing colorectal cancer.