Are Italians at risk for Lynch syndrome?

Lynch Syndrome Risk in Italians

Italians are at risk for Lynch syndrome, with genetic testing showing a unique MSH2 exon 8 deletion that accounts for a major portion of all mismatch repair gene mutations in Lynch syndrome families of Sardinian origin. 1

Genetic Basis of Lynch Syndrome in Italians

• Lynch syndrome is an autosomal dominant genetic disorder caused by germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or deletions in the EPCAM gene, which significantly increases cancer risk 2
• In Italian populations, particularly those of Sardinian origin, a unique MSH2 exon 8 deletion (c.1277-1180_1386+2226del3516insCATTCTCTTTGAAAA) has been identified as a founder mutation 1
• This specific deletion shows typical features of a founder effect and appears restricted to the population of South-West Sardinia 1
• Studies have identified that this single mutation may represent up to 50% of the overall mutational spectrum of the four MMR genes causing Lynch syndrome in families of Sardinian origin 1

Cancer Risk Profile in Lynch Syndrome

• Colorectal cancer: 22-80% lifetime risk (varies by specific gene mutation) 2
• Endometrial cancer: 40-60% lifetime risk in women 2, 3
• Other associated cancers include: stomach, ovary, urinary tract, hepatobiliary tract, brain, small intestine, and sebaceous gland tumors 2, 4
• Gastric cancer risk shows marked variation between populations, with higher risks in populations that have higher gastric cancer risks in the general population 5

Diagnostic Approach for Italians

• Family history assessment is crucial, with attention to the "3-2-1 rule": 3 affected relatives, across 2 generations, with 1 diagnosed before age 50 2
• For Italians of Sardinian origin, specific testing for the MSH2 exon 8 deletion should be considered as a first-line approach given its high prevalence 1
• Tumor tissue testing includes immunohistochemistry (IHC) to detect loss of MMR protein expression and microsatellite instability (MSI) testing 2
• Amsterdam II criteria and Revised Bethesda guidelines can be used for clinical screening, but may miss many cases 5
• Current practice of Lynch syndrome diagnosis in Italy shows noncompliance with latest guidelines, with no systematic tumor screening performed on colorectal cancer cases 6

Surveillance Recommendations

• Colonoscopy every 1-2 years beginning at age 20-25 or 2-5 years younger than the youngest diagnosis in the family, whichever comes first 2, 7
• This colonoscopic surveillance reduces colorectal cancer risk by 77% 2
• For women, annual gynecologic examination with endometrial sampling and transvaginal ultrasound starting at age 30-35 years 7
• Daily aspirin (600mg) may decrease odds of getting colorectal cancer by 44%, though optimal dosage is not known 5

Management Considerations Specific to Italians

• The lack of structured multidisciplinary teams who manage colorectal cancer patients from risk assessment to diagnosis and follow-up has been reported in Italian hospitals 6
• Cascade testing of at-risk relatives is not systematically performed in Italian hospitals 6
• Availability of professionals and laboratory technologies differ widely between Italian hospitals 6
• Development of quick tests for the identified Sardinian founder deletion can improve genetic testing efficiency 1

Clinical Implications

• Lynch syndrome colorectal cancers have more rapid adenoma-to-carcinoma progression (approximately 35 months vs. 10-15 years in sporadic cases) 2
• Lynch syndrome colorectal cancers have better stage-for-stage survival compared to sporadic colorectal cancer 2
• For women who have completed childbearing, total abdominal hysterectomy and bilateral salpingo-oophorectomy is an effective option for risk reduction 7
• Prophylactic colectomy is not routinely recommended for unaffected Lynch syndrome carriers, but subtotal colectomy may be a reasonable option for those who develop colorectal cancer 7