Before our current understanding of the genetics involved in the polyp-to-cancer sequence, it was observed that many right sided colon cancers, those lesions proximal to the splenic flexure, behaved differently than tumors in the more distal colon or rectum. As always, our observations preceded our understanding. And then, with the development of gene sequencing techniques, followed our understanding. It is now believed that the development of colorectal cancer results from the interplay between environmental insults and genetic factors. The resulting mutations initiate a mutant genetic cascade that culminates in colorectal cancer formation and possible metastatic disease.
The Scope of the Problem
Colorectal carcinoma, whether inherited or sporadic, is known to be a disease controlled by our genes. Approximately 75% of the newly diagnosed 150,000 colorectal cancers per year are sporadic in origin and occur in patients with no known familial or hereditary predisposition. They are caused by genetic mutations brought about by some type of environmental insult. An additional 20% of new cancers seem to be clustered in familial groups and may be based on inherited germline genetic mutations which have yet to be identified. Most likely, there is an interaction between a pre-existing, undiscovered genetic mutation, and an environmental carcinogen, combining to cause the malignancy in this group.
Finally, up to 5% of colorectal cancers can be traced to specific gene mutations which are carried through successive generations. Environmental toxins seem to play only a small role in carcinogenesis, with the inherited mutation being the primary cause of the cancer development. It is in this cohort of patients that the clinician has a chance to make an early diagnosis and disrupt a costly pattern of morbidity and mortality. With knowledge, the clinician can spot a problem before the mutant phenotype becomes manifest.
The Pathways to Cancer
As presently understood, most, if not all, colorectal cancers begin as benign abnormalities. Environmental toxins interact with genetic factors and lead to mutations. Our foods, our activity, our pesticides and other chemicals, interact with our genes, and lead to an initial mutation. As the mutation reproduces, other mutations develop as a result. At this point, a cancer has not yet developed. The reproduction of faulty cells continues until a branch point is reached and then a cancer develops through one of two malignancy pathways (FIGURE 1).
Whether sporadic, familial or hereditary, the final genetic pathways controlling colorectal cancer formation are similar. The final genes controlling colorectal cancer development are members of one of three
different categories: oncogenes, tumor suppressor genes or mismatch repair genes (MMR).
At this branch point, the build up of mutations in dysplastic cells causes the mutation of either the APC gene, or one of the MMR genes. These final mutations ultimately lead to the growth of a malignant clone.
The Branch Point
It is believed that 70% of colorectal cancers are the result of a mutation in the APC gene located on chromosome 5. Tumors with an APC defect develop through a pathway termed LOH, or Loss of heterozygosity. These tumors are predominantly left sided lesions (FIGURE 2).
The remainder of colorectal tumors are the result of a defect in one of the mismatch repair genes in the replication error pathway, or RER for short. These tumors commonly present as right sided lesions (FIGURE 3).
While most discovered tumors give no advance warning of their intentions to develop in other family members, tumors with certain characteristic gross and histopathologic features allow the clinician to explore the gene pool of related family members and possibly head off the beginnings of colorectal cancer through a prophylactic plan of polyp discovery or early surgical intervention.
In certain patients, the first clues that there may be a chance to effect an intervention in related family members are: cancers located in the right side of the colon, (proximal to the splenic flexure) many polyps in a single patient, many polyps in other family members, a patient or other family members with certain extra-colonic tumors or cancers developing at a young age.
The “Easy” Interventions
In families with known genetic colorectal cancer syndromes, evaluating family members is relatively straight forward.
Family members of patients with Familial Adenomatous Polyposis (FAP) or Hereditary Nonpolyposis Colorectal Cancer (HNPCC or Lynch Syndrome), can easily be tested for these inherited diseases using serologic gene sequencing techniques.
But, these are the relatively easy cases to unearth. What about those patients with no known family history? How can the clinician intervene early?
Right and Left. The “Thoughtful” Clinician.
In patients with lesions located proximal to the splenic flexure, an observant, educated clinician can save lives and shine as a true beacon of help. The astute clinician, aware that right sided colonic tumors may represent a marker for inherited genetic disease, may initiate a search for disease in relatives. There are benefits to understanding the difference between right and left.
Right Sided Tumors:
- Develop along the RER pathway.
- Develop in as fast as one to five years following a normal colorectal screening exam, and at an
earlier age (mean age 44 years).
- Have a higher incidence of associated synchronous and metachronous tumors.
- Are often found in other family members, especially first degree relatives.
- Have normal cytogenetics.
- Demonstrate diploid DNA (a normal number of chromosomes).
- Have a higher incidence of poorly differentiated, mucin-producing tumors and Crohn’s-like
lymphocytes located around the tumor.
- Have slower growth.
- Have a better prognosis.
- Have fewer metastases.
- Have a higher frequency of associated extra-colonic tumors (endometrial, gastric and duodenal,
biliopancreatic, uroepithelial and brain).
- Have a higher frequency of extra-colonic tumors in first degree relatives.
- Are more resistant to chemotherapeutic interventions.
Left sided tumors:
- Develop along the LOH pathway.
- Develop over seven to ten years and at an older age (mean age 63 years).
- Are more likely to be sporadic or, seemingly spontaneous.
- Are less commonly found in other family members.
- Demonstrate aneuploidy (an abnormal number of chromosomes).
- Have a worse prognosis compared with right sided lesions.
- Demonstrate a higher metastatic rate.
With the simple knowledge that a cancer is a right sided lesion, the clinician has an advantage in the battle against the disease in both the patient and his or her relatives.
The astute, educated clinician has a real opportunity to intervene early in the prevention of colorectal cancer. Knowing right from left is a good place to start.