One and the same MMR gene mutation can be found in families with a range of family histories of CRC from very strong to relatively weak. One reason for this range of family histories is that penetrance is variable (penetrance is defined as the probability of developing the disease given the presence of the mutation). On average, penetrance of MMR mutations is less than 50 %. The reasons for variable penetrance are not well understood. Probabilistic events (family size, ascertainment bias, etc.) may explain some of the variation in family history. Deterministic factors also probably play an important role, including genetic factors that modify the risk conferred by the cancer-causing mutation (these genetic factors are called modifiers), exposure to environmental factors, or both.

Up to 30 % of APC mutations are new mutations that are not associated with previous family history of CRC, but which are every bit as dangerous to the present and subsequent generations. Clearly, in these cases, there is no family history to help predict disease occurrence.

Late-onset Mendelian syndromes associated with increased susceptibility that are caused by recessive genes are difficult to identify and characterize because family sizes are generally small and penetrance is dependent on age. Neither parent is likely to have been diagnosed with CRC and the probability for each son or daughter of having both disease alleles is 25 %. A perfect example of this scenario is the recently described CRC syndrome MYH-associated polyposis (MAP) , which is associated with biallelic recessively inherited mutations in MUTYH (also referred to as MYH). Many more recessive CRC syndromes may explain CRC incidence in persons with no previous family history or in familial CRC.

Strong family histories of CRC may not be associated with classical single-gene, Mendelian mutations, but rather with the presence of multiple genetic risk factors that combine to create high risk. This scenario can resemble recessive inheritance in that each parent may be at low risk of CRC because he or she carries one or two low-risk or moderate-risk genetic factors. Segregation of genetic factors to a son or daughter from both parents is thus a relatively low-frequency event.

For the purposes of this chapter, we define hereditary CRC as a syndrome caused by one or more genetic risk factors that are associated with a strong family history of CRC, which can be established statistically through tests of genetic segregation in families. Consequently, the main focus here is on the syndromes defined by disease-causing mutations in single-gene Mendelian disorders. There is a general consensus now that the known single-gene disorders do not account for all the genetic variation that influences CRC susceptibility and that many low-risk or moderate-risk genetic variants need to be identified in order to explain the remaining heritability of CRC. We note that numerous reports describing low-risk CRC susceptibility factors have recently been published and elucidation of the role and impact of the major low-penetrance risk alleles is an active area of current genetic investigation [12]. These low-risk genetic factors explain but a small fraction of the yet-to-be-determined CRC susceptibility factors. Consequently, the search goes on to identify genetic risk factors that explain the heritability of CRC with the hope that these factors will some day allow a more precise and reliable prediction of CRC risk.

The non-polyposis disorders are so called to distinguish them from those syndromes that lead to the formation of numerous polyps of the lower gastrointestinal tract. Foremost among the non-polyposis disorders is Lynch syndrome (hereditary non-polyposis colorectal cancer). This syndrome arises from mutations in the MMR pathway and results, to varying degrees, in a phenotype of early-onset CRC and extracolonic malignancies. The MMR genes function in a specific type of DNA repair that ensures high fidelity of DNA replication. When MMR function is deficient in a cell, it is associated with a high mutation rate, which drives carcinogenesis. The high mutation rate can be detected using a simple polymerase chain reaction (PCR) assay that tests for microsatellite instability (MSI) . Tumors that exhibit MSI have the hypermutation phenotype that is associated with loss of MMR gene function.

Historically, the earliest descriptions of Lynch syndrome came from the pathologist Aldred S. Warthin at the University of Michigan who, in 1913, published a review of several cancer-prone families [13]. Approximately 50 years later, Henry T. Lynch and colleagues collected data from these same families and recognized that CRC was the most prominent cancer in this syndrome. Initially, this familial syndrome was given the name hereditary non-polyposis colorectal cancer (HNPCC) to distinguish it from hereditary conditions in which cancers arise in a milieu of carpeting colonic polyps. In 1984, the name Lynch syndrome was proposed in honor of Dr. H.T. Lynch’s seminal observations. Moreover, HNPCC was thought to be a misleading name because polyps are still encountered albeit not to the degree seen in polyposis conditions. Arguably, the definition of polyposis is somewhat arbitrary. In 1993, the field of Lynch syndrome genetics was energized by the identification of MSH2 and, shortly thereafter, MLH1 as genes the mutation of which results in Lynch syndrome. In the 1990s, clinical criteria and guidelines were established including the Amsterdam criteria and Bethesda guidelines that are used to guide molecular genetic testing in individuals who might be affected by the syndrome (Table 25.2). The Amsterdam criteria were devised to enrich for families with mutations to help in the identification of the culprit genes; the Bethesda guidelines were an attempt to devise a more inclusive set of rules to identify mutation carriers. These guidelines nonetheless cannot be used to identify all persons with disease-causing mutations or families in which MMR gene mutations are segregating, because age of disease onset is variable, penetrance is variable, and family sizes are often small. Universal screening—MSI testing, immunohistochemistry (IHC) for MLH1, MSH2, MSH6, and PMS2, or both—on all CRCs has been recommended, which obviates the need for guidelines, and it has slowly gained widespread acceptance. As whole-genome DNA sequencing becomes more efficient and lower cost, we can foresee a day in which genetic screening using whole-genome sequencing would help overcome the limitations of clinical guidelines.

The MMR system recognizes and corrects incorporation errors that occur during DNA replication , some chemically induced or spontaneous DNA lesions, and mismatches produced during homologous recombination. Components of the system are also utilized during somatic hypermutation in the maturation of B-cells. MMR repairs both base-base mismatches and insertion/deletion loops (IDLs). Base-base mismatches can be generated by DNA polymerase incorporation errors that escape the proofreading activity of the DNA polymerases. IDLs occur when primer and template strands dissociate and re-anneal incorrectly. Slipped strand mispairings, as these are called, occur preferentially in repetitive DNA sequences of one-nucleotide to five-nucleotide repeats, referred to as microsatellites. Slipped strand mispairings in microsatellite regions can be of varying lengths depending on where loops form in the double helix. The high frequency of unrepaired IDLs plays an important role in development of MSI. MSI is one part of the mutator phenotype associated with MMR gene mutations, in which somatic mutations accumulate at a higher rate as a result of loss of MMR function.

MMR pathways are conserved across all domains of life. Initially, investigation of prokaryotic MMR provided major insights into the existence and functions of genes involved in MMR. The genes mutH, mutL, and mutS were identified in E. coli, and subsequently homologues for mutL and mutS were found in yeasts, mammals, and other species. In Fig. 25.3, we depict MMR mechanisms in eukaryotes schematically. MMR involves four stages: (1) mismatch recognition, (2) incision of the strand that contains the erroneous base(s), (3) strand excision to remove the base(s), and (4) restoration of the correct base by DNA replication using the undamaged DNA template. While MMR mechanisms have been more precisely defined in prokaryotes, the focus in this chapter is on eukaryotic MMR mechanisms. Recent review articles provide in-depth discussions of MMR biochemistry in both prokaryotes and eukaryotes [54–56].