Colorectal Cancer in Young Individuals: Opportunities for Prevention
Authors: Elena M. Stoffel
Journal: Journal of Clinical Oncology (2015)

Colorectal cancer (CRC) is the third most common cancer in the United States, yet it is also one of the most preventable. Implementation of routine screening among individuals aged 50 years and older has resulted in impressive declines in CRC-related morbidity and mortality overall. However, the incidence of CRC in young individuals continues to rise, with approximately one in 10 new cases affecting individuals younger than 50 years of age. The reason for the increase in young-onset CRC is unclear, and the relative contributions of genetic versus environmental factors remain relatively unexplored. In this issue, Mork et al present outcomes from genetic evaluations performed in individuals with young-onset CRC in whom tumors were diagnosed when they were younger than 35 years of age. Of 205 such individuals who were referred for clinical genetic evaluations at a single academic institution, approximately one third of their cases were associated with hereditary cancer syndromes. Germline mutations confirmed the diagnoses of Lynch syndrome in 12% and familial adenomatous polyposis (FAP) in 9%. Of note, approximately 20% of those with hereditary cancer syndromes had no family history of the disease. An estimated 2% to 5% of all CRC diagnoses are associated with hereditary cancer syndromes, and the prevalence of germline mutations is assumed to be likely higher among individuals in whom cancer is diagnosed at a young age. In previous studies, investigators screened individuals in whom CRC was diagnosed before the age of 50 years for Lynch syndrome and identified mutations in DNA mismatch-repair (MMR) genes in 5% to 10%. In this cohort of individuals in whom CRC was diagnosed before the age of 35 years, the proportion of cases attributable to genetic syndromes was even higher. Yet, it is important to recognize that the diagnosis of hereditary cancer syndromes in one in three individuals with young-onset CRC may not accurately capture the true prevalence of genetic syndromes in this patient population. First, the study cohort reflects a selected population of patients with CRC who were referred to a tertiary academic center for clinical genetic evaluation. Second, the genetic evaluations for these patients were performed as part of their clinical care in accordance with established clinical diagnostic algorithms; therefore, only patients who met clinical criteria for genetic testing for specific hereditary cancer syndromes underwent sequencing of germline DNA. As a consequence, many individuals who did not have polyposis phenotypes or MMRdeficient tumors, which was 44% of this cohort, did not ultimately undergo any germline genetic testing. And, even those patients who did eventually receive DNA sequencing did not undergo comprehensive genetic testing because, in most cases, testing was limited to the specific gene or genes most likely to have been altered based on the clinicians’ review of each patient’s personal and family histories. Because only a subset of young patients with CRC underwent any germline genetic testing, it is likely that individuals who did not meet clinical diagnostic criteria for a given syndrome or those who carried germline mutations in genes other than APC, MUTYH, P53, and the DNA MMR genes would have been missed. Advances in next-generation sequencing (NGS) technologies continue to make clinical genetic testing more accessible and less costly than before. NGS facilitates simultaneous sequencing of multiple genes, and a number of commercial genetic testing laboratories now offer cancer gene panels, which include multiple genes associated with different cancer risks in a variety of mix-and-match combinations. As a result, a patient referred for genetic testing because of a predisposition to CRC might undergo DNA sequencing not only for genes associated with Lynch syndrome and FAP but also for TP53 (associated with Li-Fraumeni syndrome), BMPR1A and SMAD4 (associated with juvenile polyposis syndrome), STK11 (Peutz-Jeghers syndrome), and PTEN (Cowden syndrome), as well as literally dozens of additional genes associated with high or moderate risk for different types of cancer. As use of multiplex genetic testing in clinical care increases, we are learning that the classical clinical criteria that were originally developed to define each specific hereditary cancer syndrome may be too narrow. Differences in disease penetrance and expressivity can result in variability in family history and clinical presentation. Furthermore, clinical phenotypes of carriers of gene mutations associated with different hereditary syndromes can overlap. In recent studies in which NGS multigene panels were used for germline sequencing in patients with various cancer histories, nearly one third of mutation carriers did not meet the clinical criteria for the syndrome that corresponded to the gene mutation identified. Therefore, our current strategies for clinical genetic testing may capture only a small subset of patients with a genetic predisposition for cancer. Because of the variability in clinical phenotypes associated with hereditary cancer syndromes and the relatively high diagnostic yield of genetic testing in young patients with cancer, Mork et al conclude that every patient with young-onset CRC should be referred for genetic evaluation. Nearly two decades have passed since screening CRC tumors for MMR deficiency associated with Lynch syndrome was initially recommended for specific subgroups of patients, and universal JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 31 NOVEMBER 1 2015