Is a PMS2 (Postmeiotic Segregation 2) gene mutation indicative of Lynch syndrome?

PMS2 Gene Mutation and Lynch Syndrome

Yes, a PMS2 gene mutation is definitively indicative of Lynch syndrome, as PMS2 is one of the four mismatch repair (MMR) genes associated with this hereditary cancer syndrome. 1, 2

Understanding Lynch Syndrome and PMS2

Lynch syndrome (previously known as hereditary non-polyposis colorectal cancer or HNPCC) is an autosomal dominant condition caused by germline mutations in one of the mismatch repair genes:

• MLH1
• MSH2
• MSH6
• PMS2

These mutations lead to microsatellite instability (MSI) in tumor DNA and predispose carriers to various cancers 1.

PMS2 Mutation Characteristics

PMS2 mutations have some distinct features compared to other MMR gene mutations:

• Prevalence: PMS2 mutations account for approximately 2-3% of all Lynch syndrome cases, making them the rarest among the four MMR genes 1, 3
• Penetrance: PMS2 mutations have lower penetrance compared to other MMR gene mutations 3, 4
• Cancer risk profile: Different from MLH1/MSH2 mutations 1, 4

Cancer Risks Associated with PMS2 Mutations

According to recent research, PMS2 mutation carriers have the following cumulative lifetime risks to age 70-80:

• Colorectal cancer: 15-20% for both males and females (compared to 6.6% and 4.7% in the general population) 1, 3, 4
• Endometrial cancer: 15% for females (compared to 2.4% in the general population) 1, 3, 4
• Overall risk for any Lynch syndrome-associated cancer: 25-32% 3

Importantly, unlike other MMR gene mutations, PMS2 mutations do not appear to significantly increase the risk for other Lynch syndrome-associated cancers such as ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancers 4.

Diagnostic Challenges with PMS2

Identifying PMS2 mutations presents unique challenges:

1. Pseudogene interference: The presence of multiple PMS2 pseudogenes complicates genetic testing 3, 5
2. Screening criteria limitations: PMS2 mutation carriers may be missed by traditional screening criteria due to:
   • Later age of cancer onset
   • Lower penetrance of colorectal cancer
   • Possible mismatch repair-stable phenotype in some tumors 2
3. Isolated loss of PMS2 expression: Can be caused by:
   • PMS2 germline mutation
   • MLH1 germline mutation
   • MLH1 promoter hypermethylation (a non-hereditary cause) 6

Screening and Management Recommendations

For individuals with confirmed PMS2 mutations:

1. Colonoscopy:

   • Begin at age 20-25 years
   • Repeat every 1-2 years 1

2. Endometrial cancer screening (for females):

   • Begin at age 30-35 years
   • Annual gynecological examination
   • Pelvic ultrasound
   • CA-125 analysis
   • Aspiration biopsy 1

3. Other cancer screening:

   • Unlike other Lynch syndrome mutations, PMS2-specific screening protocols could potentially be restricted to colonoscopies due to the limited cancer spectrum 4
   • The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy requires further evaluation 4

Clinical Implications

The identification of a PMS2 mutation has important implications for:

• The individual (cancer surveillance)
• Family members (genetic counseling and testing)
• Cancer prevention strategies

However, it's crucial to note that PMS2 mutation carriers have a lower cancer risk compared to carriers of other MMR gene mutations, which may influence surveillance and management decisions 3, 4.

Pitfalls to Avoid

1. Misattribution: Not all isolated loss of PMS2 protein expression indicates PMS2 mutation; MLH1 promoter hypermethylation should be ruled out 6
2. Over-surveillance: Given the lower cancer risks, excessive surveillance for cancers not significantly associated with PMS2 mutations may cause unnecessary anxiety and procedures 4
3. Under-recognition: Due to technical challenges in testing and lower penetrance, PMS2 mutations may be underdiagnosed 5