Lynch Syndrome (non-polyposis syndrome)

related genes and inheritance

• autosomal dominant

• MLH1

• MSH2

• MSH6

• PMS2

• EPCAM

LS associated cancers

most to least common:

• colorectal

• endometrial

• ovarian

• gastric/small bowel

• pancreatic cancer

• prostate

• brain

• skin

mechanism for LS

tumors with signs of mismatch repair deficiency and high microsatellite instability

LS details

• >90% lifetime risk to develop colorectal or other Lynch associated

• diagnosed 10-15 yrs younger

• polyps develop at younger age with each having a greater chance to transform

• CRC in transverse and ascending colon

NCCN testing criteria (w/ personal history)

• diagnosed <50 y/o

OR

• two primary cancers

OR

• one 1st/2nd degree relative diagnosed <50 y/o

OR

• 2 or greater 1st/2nd degree relatives diagnosed with LS cancer at any age

OR

• tumor with MMR deficiency

NCCN testing criteria (w/ family history)

• 1+ 1st degree with CRC or EC <50 y/o

OR

• 1+ 1st degree with CRC or EC and seconday primary cancer at any age

OR

• 2+ 1st/2nd degree with LS related cancers with at least 1 <50y/o

OR

• 3+ 1st/2nd degree with LS related cancers at any age

MLH1

• 15-40% of all LS cases

• forms complex with PMS2 protein to repair DNA mismatches

• most LOF, 10-20% deletions

• colonoscopy starting 20-25 yrs

MSH2

• 20-40% all LS cases

• forms heterodimer with MSH6 or MSH3 to identify mismatches

• most LOF, 20-40% deletion of 1+ exon

EPCAM

• <10% LS cases

• mutations result in hypermethylation and silencing of downstream MSH2

MSH6

• 12-35% of all LS

• forms heterodimer with MSH2 to identify mismatches

• lower risk of CRC and later age of onset compared to MLH1 and MSH2

• colonoscopy starting 30-35 y/o

PMS2

• 5-25% of LS cases

• forms complex with MLH1 to repair DNA mismatches

• lower risk of CRC compared to MLH1 and MSH2

• lowest risk for any LS cancer, but earlier age of onset

variant phenotypes

• Muir-Torre:

  • sebaceous neoplasms and 1+ internal cancer (MSH2 typically)

• Turcot syndrome:

  • CRC or adenoma with CNS tumor

Constitutional MMR deficiency

• individuals with biallelic pathogenic variants in MLH1, MSH2, MSH6, and PMS2

• colon or small bowel cancer at <20 yrs

• hematologic cancer, brain cancer, and cafe au lait