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Genes play a role in colorectal cancer

Inherited colorectal cancer usually occurs at an earlier age and clusters in families across generations.

The last segment dealt with colorectal cancer in a general and introductory manner. Today, inherited colorectal cancer syndromes and sporadic cancers will be dealt with.

Inherited CRC usually occurs at an earlier age, tends to cluster in families across generations and the cancers appear in multiple sites concomitantly, or sequentially, over a lifetime. There are two well-described CRC syndromes that I will deal with separately and succinctly.

FAP (familial adinomatous polyposis): In this condition, polyps start forming in the first two decades of life and, if left untreated, will develop CRC by the fourth and fifth decades of life. This is a consequence of inheriting one mutated copy of a tumor suppressor gene, APC (adenomatous polyposis coli). Tumor suppressor genes are supposed to recognize mutated signals promoting tumor formation and arresting further growth until appropriate remedial steps can occur. If the mutation is beyond repair, the mutated cell will be killed by a process called apoptosis (programmed cell death).

In normal health, two wild type (normal) copies of the APC gene are inherited: one from each parent. Even if one copy is mutated or dysfunctional, the remaining normal copy will ensure tumor suppression. For both copies of the same gene to be randomly mutated will be a rare event and takes several decades. That is why sporadic cancers occur in the later years of life.

However, if a person is born with one mutated copy, for a second mutation to occur takes less time, hence the early occurrence of CRC in APC syndromes. Since inheritance in the gene line is in the sperm or egg, and since the rest of the body is made up of cells derived from the union of sperm and egg, every cell in the body will carry one mutated copy of the APC gene. Therefore many organs besides the colon and rectum are at risk for early occurrence of cancer.

Cancer of the stomach, small bowel, bone and brain are susceptible for cancer at an early age. There are rare conditions of DeNovo mutation in the sperm or egg that confer the same risk described above without any family history. The inherited CRC syndrome is HNPCC (hereditary non-polyposis colorectal cancer). Here CRC susceptibility begins at an early age, owing to the inheritance of a mutated copy of one of the genes responsible for repair of mutations.

The principles of early occurrence of second and final mutation and the consequent early cancer occurrence and in multiple sites described in APC apply here as well. Some of the other organs at risk are small bowel, ureters and the endometrium. Some familial CRC do not fit the above two entities. These may be due to yet-to-be-discovered gene mutations.

We at the Cancer and Blood Disease Center are involved in studies looking at these additional mutations. It is already apparent that such knowledge can enable us to decrease both incidence and death due to CRC. Further research at the cellular and molecular level will only add to these gains.

In the next and the final segment on CRC I will describe the recommendations for screening and explain the rationale for the same.

_ V. Upender Rao, MD, FACP, Cancer and Blood Disease Center, Lecanto.