Lynch syndrome

Most common form of hereditary colon cancer

Previously also called hereditary non-polyposis colorectal cancer (HNPCC) - however this is a misnomer, because patients can develop many non-CRC cancers

• Some say HNPCC can be applied to patients who have not yet had a specific germline mutation identified

Genetics

• Autosomal dominant
• Mutation in one of the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EpCAM)
  • Lynch syndrome CRCs are characterised by microsatellite instability - ubiquitous mutations at simple repetitive sequences (microsatellites) are found in the tumour DNA
  • Also, they demonstrate loss of expression of MMR protein
  • MLH1 chromosome 3, MSH 2 chromosome 2, MSH6 chromosome 2, PMS2 chromosome 7, epCAM chromosome 2
• These MSI regions can be tested for, since >90% of cancers in Lynch syndrome patients have them, and diagnose Lynch syndrome that way
• If BRAF mutations are present, probably not Lynch syndrome

When to suspect

• Amsterdam II criteria below, or:
• Synchronous or metachronous CRC
• CRC or endometrial cancer <50yo
• Multiple Lynch-associated cancers
• Familial clustering of Lynch-associated cancers
• dMMR CRC

Diagnosis

• Either germline sequencing of MMR genes, or identified to be high-risk via prediction tools
• MMRpredict tool (https://webapps.igc.ed.ac.uk/world/research/hnpccpredict/) performs better than either of the below tools (sp 91%; se 94%)
• Amsterdam II criteria (to identify individuals at risk of carrying the mutation)
  • THREE or more relatives on the same side of the family with HNPCC-associated cancers (CRC, endometrial, small bowel, ureter, renal pelvis)
    • Plus all of the following
  • TWO or more generations involved with HNPCC-associated cancers
  • ONE or more cancers diagnosed before age 50
  • FAP must be excluded and invasive cancer must be confirmed in the patient too.
• Revised Bethesda criteria for identifying which tumours should be tested for MSI
  • Specificity 77%; sensitivity 82%
  • Relevance declined significantly since universal IHC screening for dMMR was implemented
  • betHESDA
    • H istopathological characteristics of an MSI-unstable cancer
    • E xtra HNPCC cancers - metachronous or synchronous
    • S ingle person in the family with CRC or uterine cancer diagnosed <50yo
    • D ouble (two or more) first-degree relatives with an HNPCC-associated cancer
    • A ge - diagnosed CRC <50yo in this patient

Risks

• CRC
  • Accounts for 3-5% of all CRC, and 10-19% of CRC diagnosed before age 50
  • Lifetime CRC risk 70% for men and 40% for women
  • Mean age of diagnosis 44-61yo
  • Predilection for right-sided cancers, but other sites are also common
  • If first cancer treated by segmentectomy, 16% risk of a second cancer at 10 years, 41% at 20 years, and 62% at 30 years
  • Don't develop as many adenomas as FAP (usually <3 by 50yo), but these adenomas do tend to progress to cancer faster than normal
  • Single-agent 5-FU is less beneficial for Lynch cancers, so FOLFOX should be used instead.
    • As of 2025 immunotherapy and FOLFOX/FOLFIRINOX have not been directly compared, but the NEJM trial in 2024 showed pathological major response of 95% when used as neoadjuvant therapy
  • Immunotherapy with an immune checkpoint inhibitor targeting PD-1 pathway is effective (and also true for many other Lynch cancers). Often use nivolumab/ipilimumab.
• Gastric cancer
• Endometrial adenocarcinoma
  • Lifetime risk 32-45%
• Ovarian
• Small bowel
• Urinary tract
• Brain
• Pancreas - 8x increased risk
• Prostate cancer risk could be up to 30%, although lack of evidence
• Sebaceous adenomas/carcinomas of skin
  • Seen in Muir-Torre variant of Lynch syndrome
• Muir-Torre Syndrome - Lynch-associated colon, genitourinary and skin cancers

Screening

• Colonoscopy every 1-2 years, beginning at 25yo for MLH1/MSH2 or 35yo for MSH6/PMS2 (or earlier if there is earlier family history of CRC)
  • Persons at risk: first-degree relatives of known MMR gene mutation carriers who have not had genetic testing
  • Known Lynch syndrome - in this case, annual colonoscopy is preferred
• No gynae screening, but early referral if symptoms develop
• Gastroscopy with biopsy of antrum at 30yo, with subsequent surveillance every 2 years considered based on individual patient risk factors
• No annual urinalysis
• No prostate cancer surveillance

Medical

• Recommend 100mg aspirin daily after starting colonoscopy screening to reduce risk of CRC

Surgery

• If no previous cancer and endoscopically normal, no need for prophylactic colectomy
  • However, patients who have a segmental colectomy for cancer have a 22% chance of having another cancer, and so it may be reasonable to opt for a subtotal colectomy and ileorectal anastomosis
  • If having rectal cancer treated, it should be treated based on standard principles, with consideration of completion colectomy
• Hysterectomy and bilateral salpingo-oophorectomy at 40yo or after child-bearing complete (at 50yo in PMS2)