Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC)

Epidemiology/Genetics

  • Autosomal Dominant

Physiology

Normal DNA Mismatch Repair (MMR) Process

  • DNA Mismatching Normally Occurs During DNA Synthesis: with a frequency of 1 per each 106 bases
    • DNA Mismatch Repair Process: normally corrects the mismatched bases
    • DNA Mismatches Frequently Occur in Regions of Repetitive Nucleotide Sequences (Microsatellites)
      • Microsatellite Instability: malignancies frequently demonstrate expansion/contraction of these microsatellite regions (as compared to normal tissues)

Lynch Syndrome Results from a Germline Mutation in One Allele of an MMR (or Related) Gene with the Second Allele Inactivated by Mutation, Loss of Heterozygosity, or Epigenetic Silencing by Promoter Methylation

Biallelic Inactivation of an MMR (or Related) Gene Causes a Failure of the DNA Repair Process, Resulting in an Increased Mutation Rate (Genomic Instability) and Increased Cancer-Susceptibility

  • Mutated MMR and Related Genes
    • DNA Mismatch Repair Genes
      • MutL Homolog 1(MLH1) (found in 32% of patients with identifiable mismatch repair gene mutations): chromosome 3p21
      • MutS Homolog 2 (MSH2) (found in 39% of patients with identifiable mismatch repair gene mutations): chromosome 2p16
      • MutS Homolog 6 (MSH6) (found in 15% of patients with identifiable mismatch repair gene mutations): chromosome 2p16
      • Postmeiotic Segregation 2 (PMS2) (found in 14% of patients with identifiable mismatch repair gene mutations): located on chromosome 7p22
    • Other Genes
      • EPCAM (TACSTD1): deletion in this gene may lead to loss of MSH2 expression
  • Microsatellite Instability is a Characteristic Feature of Lynch Syndrome-Associated Cancers and May Affect Genes Which Regulate Either Cell Growth, Cell Death, or the Mismatch Repair Process Itself
    • Insulin-Like Growth Factor Receptors: regulates cell growth
    • Transforming Growth Factor-Beta: regulates cell growth
    • Bax: regulates cell death
    • Caspase 5: regulates cell death
    • MSH3: mismatch repair gene
    • MSH6: mismatch repair gene

Diagnosis

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Amsterdam II Criteria for Lynch Syndrome [MEDLINE]

  • There Should Be At Least 3 Relatives with Any Lynch Syndrome-Associated Cancer
    • Colorectal Cancer (see Colorectal Cancer, [[Colorectal Cancer]])
    • Endometrial Cancer (see Uterine Cancer, [[Uterine Cancer]])
    • Small Intestinal Cancer
    • Ureteral Cancer (see Urothelial Cell Carcinoma, [[Urothelial Cell Carcinoma]])
    • Urothelial Cell Carcinoma (Transitional Cell Carcinoma) of the Renal Pelvis (see Renal Cancer, [[Renal Cancer]])
  • One Patient Should Be a First-Degree Relative of the Other Two
  • At Least Two Successive Generations Should Be Affected
  • At least One Patient Should Be Diagnosed Before Age 50
  • Familial Adenomatous Polyposis Should Be Excluded in the Colorectal Cancer Case(s) (If Present)
  • Tumors Should Be Pathologically Verified

Clinical Manifestations

Gastrointestinal Manifestations

Colorectal Cancer (see Colorectal Cancer, [[Colorectal Cancer]])

  • Epidemiology
    • Lynch syndrome accounts for 2-3% of all colorectal cancers
    • Patients with Lynch syndrome have a 70% lifetime risk of developing colorectal cancer
    • Average age of presentation: 45 y/o (while spontaneous colorectal cancer typically presents at age 64 y/o)
  • Clinical
    • Predilection for Right-Sided Colorectal Cancer: approximately 60-80% of cases are right-sided (in contrast, in usual colorectal cancer, only 20-30% are right-sided)

Small Intestinal Cancer

  • Epidemiology
  • Clinical

Renal Manifestations

  • Urothelial Cell Carcinoma (Transitional Cell Carcinoma) of the Renal Pelvis (see Renal Cancer, [[Renal Cancer]])
  • Ureteral Cancer (see Urothelial Cell Carcinoma, [[Urothelial Cell Carcinoma]])

Reproductive Manifestations

Endometrial Cancer (see Uterine Cancer, [[Uterine Cancer]])

Other Manifestations

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Treatment

Aspirin Prophylaxis (see Acetylsalicylic Acid, [[Acetylsalicylic Acid]])

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References

  • New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999 Jun;116(6):1453-6 [MEDLINE]