Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC is synonymous with Lynch syndrome, an autosomal dominant genetic condition that is most commonly associated with a high risk of colon cancer and secondarily most associated with endometrial cancer, as well as ovarian, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin cancers. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch-like syndrome, polymerase proofreading-associated polyposis, and familial colorectal cancer type X.
Terminology Henry T. Lynch, Professor of Medicine at Creighton University Medical Center, characterized the syndrome in 1966. In his earlier work, he described the disease entity as "cancer family syndrome." The term "Lynch syndrome" was coined in 1984 by other authors; Lynch named the condition HNPCC in 1985. Since then, the two terms have been used interchangeably until later advances in the understanding of the genetics of the disease led to the term HNPCC falling out of favor. Other sources reserve the term "Lynch syndrome" when there is a known DNA mismatch repair defect and the term "familial colorectal cancer type X" when the Amsterdam criteria are met but there is no known DNA mismatch repair defect. The putative "type X" families appear to have a lower overall incidence of cancer and lower risk for non-colorectal cancers than families with documented DNA mismatch repair deficiency. About 35% of people who meet Amsterdam criteria do not have a DNA-mismatch-repair gene mutation. Complicating matters is the presence of an alternative set of criteria, known as the "Bethesda Guidelines."
Signs and symptoms
Risk of cancer Lifetime risk and mean age at diagnosis for Lynch syndrome–associated cancers
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. Increased risk of prostate cancer and breast cancer has also been associated with Lynch syndrome, although this relationship is not entirely understood. Cancer types, including prostate cancer and breast cancer, along with other cancer types such as sarcomas and adrenocortical carcinoma, have also been associated with Lynch syndrome. There is not enough information to firmly establish that Lynch syndrome increases the risk of development of such cancers, however. Two-thirds of colon cancers occur in the proximal colon and common signs and symptoms include blood in the stool, diarrhea or constipation, and unintended weight loss. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 60 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age, with intestinal-type adenocarcinoma being the most commonly reported pathology. HNPCC-associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. While MLH1, MSH2, and MSH6 are the most commonly associated genes with Lynch syndrome, relying solely on pathogenic variants in these well-known genes as a diagnostic approach may not be effective. This is because there are patients who do not have any identifiable pathogenic variants but still show a high susceptibility to Lynch syndrome. This situation suggests that other genes may also play a role in the development of Lynch syndrome and colorectal cancer. .
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI-H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA...). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single-stranded-DNA binding-protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
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