Lynch syndrome

• Also known as hereditary nonpolyposis colorectal carcinoma (HNPCC)

• Lynch syndrome preferred term since most patients will develop one or several adenomatous polyps
• Caused by inactivation of one of several DNA mismatch repair genes

• Genetics
• MMR genes: MLH1, MSH2, MSH6, PMS2
• Mutations in MLH1 and MSH2 account for up to 90% of LS cases
• Autosomal dominant
  • NCI definition: autosomal dominant inheritance is a way a genetic trait or condition can be passed down from parent to child. One copy of a mutated (changed) gene from one parent can cause the genetic condition. A child who has a parent with the mutated gene has a 50% chance of inheriting that mutated gene.[1]
• Increased risk of cancer
• LS cancers form only after a second hit (by one of several genetic damage mechanisms) occurs within somatic tissue, which causes loss of function to the normal (wild-type) allele inherited from the unaffected parent
• This results in total loss of DNA MMR activity in that cell and subsequent microsatellite instability.
• Associated malignancies:
• Colon (most common)
• Endometrial (second most common)
• Urologic (3): Prostate, Urothelial, Adrenal
• Other: Stomach, Hepatobiliary, Small bowel, Ovarian, Brain (glioblastoma), Sebaceous, carcinomas
• Inconsistent: Pancreas, Breast

References

Giardiello, Francis M., et al. "Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer." Gastroenterology 147.2 (2014): 502-526.