Familial Colorectal Cancer, Beyond Lynch Syndrome

Elena M. Stoffel; Fay Kastrinos‡


Clin Gastroenterol Hepatol. 2014;12(7):1059-1068. 

In This Article

Abstract and Introduction


Although 30% of individuals diagnosed with colorectal cancer (CRC) report a family history of the disease, only 5% to 6% carry germline mutations in genes associated with known hereditary cancer syndromes. The evaluation and management of families affected with CRC can be complicated by variability in disease phenotypes and limited sensitivity of genetic tests. In this review, we examine what is currently known about familial CRC and what we have yet to learn, and explore how novel genomic approaches might be used to identify additional genetic and epigenetic factors implicated in heritable risk for cancer.


The average American's lifetime risk for developing colorectal cancer (CRC) is estimated to be 5% to 6%. The implementation of routine screening for CRC among individuals age 50 and older has been associated with significant reductions in morbidity and mortality from the disease in the United States.[1] Family history of CRC remains a key factor in algorithms used to risk-stratify individuals for screening and surveillance. Approximately 30% of individuals with CRC report having one or more relatives also diagnosed with the disease. A history of CRC in a first-degree relative has been associated with a 2-fold increase in an individual's risk; in the case of numerous affected relatives and/or diagnoses at young ages the risk for CRC is even higher.[2] In the setting of specific hereditary cancer syndromes, lifetime risk of CRC may approach 70% to 90% in the absence of any medical or surgical interventions.[3] Given the effectiveness of colonoscopy with polypectomy and surgical resection, identifying individuals who are high risk for CRC at presymptomatic stages provides the opportunity for cancer prevention.

Germline mutations in known cancer-causing genes have been implicated in up to 5% to 6% of all CRC cases. Making the diagnosis of a hereditary cancer syndrome has significant implications for the medical management of CRC patients and their families. Genetic testing can be useful for confirming the diagnosis and provides at-risk relatives the opportunity to pursue predictive testing. Lynch syndrome is the most common of the hereditary CRC syndromes and discovery of the genetic basis of the disease has resulted in the implementation of population-based screening for individuals diagnosed with CRC. However, as awareness of familial CRC continues to grow and as more patients are referred for genetic evaluation, we are discovering that for many of these families with striking family histories a genetic cause cannot be identified.

Historically, our approaches to evaluating families with cancer have focused on searching for mutations in single genes associated with highly penetrant disease phenotypes. This strategy has resulted in the identification of the genetic basis of a number of hereditary cancer syndromes (Table 1), but the majority of familial CRC cases are not associated with known germline mutations, which suggests that other mechanisms may be involved in the pathogenesis. As more information related to the chromosomal instability, microsatellite instability, and serrated pathways of colorectal neoplasia becomes available, our understanding of the genetic and epigenetic events involved in carcinogenesis continues to evolve. The potential roles of low-penetrance loci, gene–gene interactions, epigenetic modification, environmental exposures, and/or a combination of these factors are being investigated. This review summarizes what we currently know and explores what we have yet to learn about familial CRC.