Correspondence

Genetic and Phenotypic Correlates of Colorectal Cancer in Young Patients

N Engl J Med 2000; 342:137-138January 13, 2000

Article

To the Editor:

Colorectal cancer in young patients (age, 21 years or younger) is rare and has a well-recognized aggressive, often fatal course, but the genetic origin and developmental biology of this disease are poorly understood.1 We analyzed data from Memorial Sloan-Kettering Cancer Center on young patients with colorectal cancer to assess the hereditary basis of this disease. We used pedigree analysis and molecular assessment to identify microsatellite instability and other genetic markers. Microsatellite instability is a characteristic pattern of genetic instability seen in microsatellite DNA that occurs in most hereditary nonpolyposis colorectal cancers (more than 95 percent).2

Twenty-nine patients with adenocarcinoma of the colon who were 21 years of age or younger at diagnosis were identified over a 30-year period. The median age at diagnosis was 19 years. Pedigree analysis revealed only seven patients with a family history of colorectal cancer (one patient had hereditary nonpolyposis colorectal cancer according to the Amsterdam criteria, and six patients had family histories of the disease, some stronger than others). The majority of patients had sporadic colorectal cancer (22 of 29 patients, or 76 percent). Therefore, most patients had no clinical features suggestive of hereditary colorectal cancer other than a young age at onset. Slides and paraffin blocks were available in the case of 13 patients; microsatellite instability was found in specimens from 6 of these 13 patients (46 percent). As compared with cancers without microsatellite instability, cancers with microsatellite instability were not associated with distinct clinical, histologic, or familial features. However, they did have a significantly lower prevalence of K-ras mutations and of loss of heterozygosity at 17p or 18q (Table 1Table 1Clinical Significance of Microsatellite Instability in Young Patients with Colorectal Cancer.).

Solid tumors in young patients are extremely likely to have a genetic cause. In colorectal cancer, germ-line mutations associated with a young age at onset include mutations in the adenomatous polyposis coli (APC) gene, which are the basis of familial adenomatous polyposis, and in the DNA mismatch-repair genes (MSH2, MLH1, PMS1, and PMS2), which are the basis of hereditary nonpolyposis colorectal cancer. Because the clinical diagnosis of hereditary nonpolyposis colorectal cancer has many pitfalls, genetic testing plays an important part in diagnosis.3,4 Our data indicate that the presence of microsatellite instability in tumor specimens from young patients with colorectal cancer can be used to identify a distinct pathway of genetic development in which loss of heterozygosity at 17p or 18q and K-ras mutations are rare. Microsatellite instability is not, however, predictive of a family history of colorectal cancer or of unique phenotypic features.

Sporadic colon cancer in young patients is an aggressive disease whose morphology and natural history differ from those of familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, and adult colon cancer. The tumors appear to develop by means of either of two pathways: one involving a tumor suppressor or loss of heterozygosity and the other involving a mutation. However, it is likely that other genetic or developmental factors account for the aggressive course and poor prognosis of this disease.

Rajiv V. Datta, M.D.
Michael P. LaQuaglia, M.D.
Philip B. Paty, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021

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