Lynch Syndrome: Genomics Update and Imaging Review

Abstract

Lynch syndrome is the most common hereditary cancer syndrome, the most common cause of heritable colorectal cancer, and the only known heritable cause of endometrial cancer. Other cancers associated with Lynch syndrome include cancers of the ovary, stomach, urothelial tract, and small bowel, and less frequently, cancers of the brain, biliary tract, pancreas, and prostate. The oncogenic tendency of Lynch syndrome stems from a set of genomic alterations of mismatch repair proteins. Defunct mismatch repair proteins cause unusually high instability of regions of the genome called microsatellites. Over time, the accumulation of mutations in microsatellites and elsewhere in the genome can affect the production of important cellular proteins, spurring tumorigenesis. Universal testing of colorectal tumors for microsatellite instability (MSI) is now recommended to (a) prevent cases of Lynch syndrome being missed owing to the use of clinical criteria alone, (b) reduce morbidity and mortality among the relatives of affected individuals, and (c) guide management decisions. Organ-specific cancer risks and associated screening paradigms vary according to the sex of the affected individual and the type of germline DNA alteration causing the MSI. Furthermore, Lynch syndrome-associated cancers have different pathologic, radiologic, and clinical features compared with their sporadic counterparts. Most notably, Lynch syndrome-associated tumors tend to be more indolent than non-Lynch syndrome-associated neoplasms and thus may respond differently to traditional chemotherapy regimens. The high MSI in cases of colorectal cancer reflects a difference in the biologic features of the tumor, possibly with a unique susceptibility to immunotherapy. RSNA, 2018.

Hereditary Gastrointestinal Cancer Syndromes: Role of Imaging in Screening, Diagnosis, and Management

“…Previously known as hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, Lynch syndrome is the most common cancer syndrome, affecting one in 400 people, and is the most common cause of inherited colorectal cancer (14,20). Individuals with Lynch syndrome have an increased risk of many malignancies, notably colorectal and endometrial carcinomas (14,20). Cancers of the ovary, stomach, urinary tract, raise concern for a hereditary cancer syndrome (2).…”

“…In patients with hereditary GI cancer syndromes, MRI is recommended for surveillance of breast cancer, pancreatic cancer, and intraabdominal desmoids; diagnosis and staging of ovarian cancer; and local staging of rectal and endometrial cancers (1,14). US is recommended for surveillance of ovarian, breast, and thyroid cancers and is useful in diagnosis of testicular malignancies (1,15).…”

Constitutional mismatch repair-deficiency: current problems and emerging therapeutic strategies

“…However, the limited number of CMMRD patients means the identification of commonly mutated microsatellites is challenging. In addition, CMMRD vaccinations must be approached with caution since all cells of a CMMRD patient are MMR deficient [ 17 – 19 ] leading to a risk of autoimmune disease. It is likely that the combination of check-point inhibitors and neoantigen vaccination will hold the most promise for CMMRD.…”

“…Heterozygous (monoallelic) mutations in MMR genes can impair MMR functionality resulting in a cancer condition termed Lynch Syndrome (LS), previously known as hereditary non-polyposis colorectal cancer (HNPCC) syndrome [ 9 , 11 , 16 – 19 ]. LS is characterized by gastrointestinal and genitourinary cancers during adulthood and represents 1–7% of all cases of colorectal cancer (CRC) [ 9 , 11 , 18 ].…”

Repurposing Non-invasive prenatal testing data; population study of single nucleotide variants associated with colorectal cancer and Lynch syndrome

“…From a clinical point of view, 10-82 % (Yurgelun and Hampel 2018) of LS cases are associated with a lifetime risk of developing CRC, unless the risk is signi cantly lower in other types of cancer (Møller et al 2017(Møller et al , 2018. LS is caused by pathogenic germline mutations in a class of genes called DNA mismatch repair (MMR) genes, mainly MLH1, located in 3p22.2 chromosome, and MSH2, located in 2p21 chromosome (Soares et al 2018), which represent 70-85% of cases of LS (Cox et al 2018). Mutations found in MSH6 (2p16.3), PMS2 (7p22.1) (Le et al 2017) and MLH3 genes have lower incidence (Peltomäki 2016).…”