Lynch Syndrome

(based on Dutch Guideline 2017)

Diagnostic criteria:

  • Detection of a mutation in one of the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2)
  • Detection of deactivation of MSH2 due to deletion 3′ exons of the EPCAM gene
  • Lynch syndrome is likely in patients with a tumor (colorectal carcinoma (CRC), endometrial carcinoma (EC)) showing molecular genetic features of mismatch repair (MMR) deficiency *, but without a detectable germline mutation in one of the MMR genes

* Microsatellite instability (MSI) and absence of immunohistochemical (IHC) expression of one or more MMR proteins, wherein hypermethylation of the MLH1 promoter and biallelic somatic mutations in the MMR genes are excluded.

Inheritance:

  • Autosomal dominant


Prevalence:

  • 1-5% of all CRC cases


Clinical features:

  • Lifetime risk of CRC at the age of 70 years:
    1. MLH1, MSH2, MSH6: 25-70%
    2. PMS2: 5-35%
  • The risk of CRC may be higher for men than for women
  • Average age at diagnosis CRC is approximately 45 years; higher mean age at diagnosis for MSH6 mutation carriers and PMS2-mutation carriers (around 50-55 years)
  • 60% of the colorectal tumors are located in the proximal part of the colon
  • In 18% of cases, multiple primary colon tumors; risk of 2nd colon tumor: 10-15%/10 years
  • Lifetime risk of EC at the age of 70 years: MLH1, MSH2, MSH6: 15-55%; PMS2: 5-35%
  • Carcinoma of stomach, small intestine, pyelum, ureter, bladder, ovarian, biliary tract and sebaceous carcinoma: slightly increased risk (1-15%)

Genetic basis:

  • DNA mismatch repair (MMR) genes: MSH2, MLH1, MSH6 and PMS2
  • Deactivation MSH2 gene by deletion in 3′ exons of the EPCAM gene
  • Due to failure of the mismatch repair function, mutations accumulate in microsatellites of the tumor DNA (i.e., microsatellite Instability (MSI))


Indication for a referral to the clinical genetics clinic for counseling and DNA diagnostics:
Persons with CRC or EC diagnosed under 70 years of age:

  1. With IHC / MSI-analysis of CRC or EC available
    • <70 years with abnormal IHC / MSI (unless MLH1-hypermethylation)

2. Without IHC / MSI-analysis of CRC or EC available:

  • <50 years
  • <70 years and 2nd primary CRC or Lynch syndrome-associated cancer * <70 years
  • <70 years and first-degree family member with CRC or Lynch syndrome-associated carcinom <70 years, one of the cancers diagnosed <50 years
  • <70 years and at least two (first or second degree) family members with CRC or Lynch syndrome-associated carcinoma, all <70 years

* Lynch syndrome-associated malignancies are colorectal, endometrium, stomach, small intestine, pyelum, ureter, bladder, ovaries, biliary tract and sebaceous carcinoma.

 

DNA Diagnostics:

  • Depending on family history and results of IHC and/or MSI, mutation analysis of MMR genes
  • If mutation is known: pre-symptomatic mutation analysis from age 18-21 years
  • Mutation detection rate is approximately 3% in people with CRC before the age of 70 years

Periodic examination:
In mutation carriers and in first-degree relatives of mutation carriers

  • Colorectal cancer: from 25 years 1x per 2-year colonoscopy
  • Endometrial cancer: from 40 to 60 years 1x per year: gynecological examination, transvaginal ultrasound and microcurettage
  • Gastric cancer: one-time testing for Helicobacter pylori infection and depending on the outcome: eradication
  • Other tumors: Surveillance is not recommended; Except in patients with sebaceous carcinomas: refer to dermatologist for surveillance

Risk-reducing operations:

  • Consider in patients (<60 years) with screen-detected CRC the option of (sub) total colectomy and ileorectal anastomosis due to Increased risk of a second primary colon tumor; discuss the pros and cons; post-operative follow-up of residual colorectum: 1x per 2 years
  • Discuss the option of prophylactic hysterectomy and Risk Reduction Salpingo Ophorectomy (RRSO) in female mutation carriers > 40 years without children’s wishes

Literature:

  1. www.oncoline.nl
  2. Vasen HFA, Moslein G, Alonso A et al. Revised guidelines for the clinical management of Lynch syndrome. Gut 2013; 62: 812-23
  3. Van Lier MG, Leenen CH, Wagner A, et al. Yield of routine Molecular analyzes in colorectal cancer patients ≤70 years to detect underlying Lynch syndrome. J Pathol 2012; 226: 764-74
  4. Mensenkamp AR, Vogelaar IP, van Zelst-Stams WA et al. Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology 2014; 146: 643-646.e8
  5. Baglietto L, Lindor NM, Dowty JG et al. Risk of Lynch syndrome cancer for MSH6 mutation carriers. J Natl Cancer Inst 2010; 102: 193-201
  6. Kempers MJ, Kuiper RP, Ockeloen CW et al. Risk of colorectal and endometrial cancer in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol 2011; 12: 49-55
  7. Engel JC, Loeffler M, Steinke V et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. J Clin Oncol 2012; 30: 4409-1
  8. Ten Broeke SW, Brohet RM, Tops CM et al. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J Clin Oncol 2015; 33: 319-25