As expected from the important role that DNA replication and repair enzymes play in mutation surveillance and prevention, inherited defects that alter the function of DNA repair enzymes can lead to a dramatic increase in the frequency of mutations of all types, including those that lead to cancer.
Pathogenic variants in the LS MMR genes are frequent enough in the population for there to be rare individuals with two (biallelic) germline mutations in one of the LS genes. Although much rarer than autosomal dominant forms of LS just discussed, this condition, known as constitutional MMR deficiency (CMMRD), results in a markedly elevated risk for many cancers during childhood, including colorectal and small bowel cancer, as well as some cancers not associated with LS, such as leukemia and lymphoma and various types of brain tumors. The absence of effective MMR in these tumors leads to high tumor mutational burden and expression of neoantigens, which have been shown to be effective targets for immune checkpoint inhibition (immunotherapy) yielding dramatic tumor responses in some cases. This represents one of the first approaches to targeted therapy for cancers based on underlying germline pathogenic variants.
Several other well- known autosomal recessive dis orders, including xeroderma pigmentosum, ataxia- telangiectasia, Fanconi anemia, and Bloom syndrome, are also due to loss of function of proteins required for normal DNA repair or replication. Patients with these rare conditions have a high frequency of somatic chromosome and gene mutations and, as a result, a markedly increased risk for various types of cancer, particularly leukemia or, in the case of xeroderma pigmentosum, skin cancers in sun- exposed areas. Clinically, radiography must be used with extreme caution, if at all, in patients with ataxia- telangiectasia, Fanconi anemia, and Bloom syndrome, and exposure to sunlight must be avoided in patients with xeroderma pigmentosum.
Although these are rare autosomal recessive disorders, heterozygote carriers are common, and some appear to be at increased risk for malignant neoplasia. For example, Fanconi anemia, in which individuals are at risk for congenital anomalies, bone marrow failure, leukemia, and squamous cell carcinoma of the head and neck, is a chromosome instability syndrome resulting from biallelic pathogenic variants in one of at least 22 different genes involved in DNA and chromosome repair. In the aggregate, Fanconi anemia has a population frequency of approximately one to five per million, which trans lates to a carrier frequency of approximately one to two per 500. One of these Fanconi anemia genes turns out to be the known hereditary cancer gene BRCA2. Others include BRIP1, PALB2, and RAD51C (discussed in the next section), which increase susceptibility to breast cancer in carriers of heterozygote pathogenic variants. Similarly, female heterozygotes for pathogenic variants in ATM (the gene responsible for ataxia- telangiectasia) have a twofold increased lifetime risk for breast cancer compared with controls and a fivefold higher risk for breast cancer before the age of 50 years. Thus heterozygotes for germline pathogenic variants in genes related to chromosome instability syndromes constitute a sizable pool of individuals at increased risk for cancer.
