Beyond Mismatch Repair Deficiency: Characterizing MMR-Proficient Colorectal Cancer in Lynch Syndrome - Day 1 Hereditary Cancer Awareness Week!

Lynch syndrome (LS), driven by germline pathogenic variants in the DNA mismatch repair (MMR) genes

(MLH1, MSH2, MSH6, PMS2, and EPCAM deletions), is classically associated with MMR-deficient (MMR-D) or microsatellite instability–high (MSI-H) colorectal cancer (CRC). These tumors carry prognostic and therapeutic significance: improved outcomes relative to microsatellite stable disease, lack of benefit from fluorouracil-based adjuvant chemotherapy, and strong predictive value for response to immune checkpoint blockade.

However, a recent study published in JCO Precision Oncology by Ranganathan et al. highlights a clinically significant subset of MMR-proficient (MMR-P), microsatellite stable (MSS) CRCs in patients with LS—challenging the conventional assumption that all LS-associated CRCs are MMR-D.

Study Overview

• Cohort: 17,617 patients underwent matched tumor–normal sequencing (MSK-IMPACT); 242 (1.4%) carried germline pathogenic/likely pathogenic MMR variants (diagnostic of LS).

• CRC subset: 86 LS carriers had at least one CRC profiled, totaling 99 tumors with available MMR/MSI data.

• Prevalence of MMR-P CRC: 10% (10/99) of tumors were MMR-P, representing 3.7% (9/242) of LS carriers.

Distinctive Features of MMR-P CRC in LS

1. Genotype associations

   • 89% (8/9) of patients with MMR-P CRC carried MSH6 or PMS2 variants, compared with only 30% in the MMR-D cohort (p = .001).

   • Nearly 46% of PMS2 carriers developed at least one MMR-P CRC.

   • No MMR-P tumors were observed in carriers of MLH1 or EPCAM deletions; one case occurred in an MSH2 carrier.

2. Age of onset and clinical presentation

   • Median age at diagnosis: 58 years for MMR-P vs 43 years for MMR-D (p = .07).

   • Despite later onset, 40% of MMR-P cases occurred <50 years.

   • Stage distribution: 60% of MMR-P CRCs presented with metastatic disease vs 13% of MMR-D (p = .002).

3. Tumor location

   • Non-significant trend toward left-sided distribution: 70% of MMR-P vs ~50% of MMR-D.

4. Surveillance considerations

   • 30% of MMR-P CRCs were diagnosed despite high-intensity surveillance (1–2 yearly colonoscopy), suggesting possible differences in tumorigenesis and detection windows.

Clinical and Genetic Counseling Implications

• Therapeutic stratification:

  • Eligibility for immune checkpoint blockade is determined by tumor MMR/MSI status, not germline status. LS carriers with MMR-P tumors are not candidates for immunotherapy on the basis of their germline diagnosis alone.

  • Stage II MMR-P CRCs may still warrant consideration of fluorouracil-based adjuvant therapy, unlike their MMR-D counterparts.

• Familial risk assessment:

  • Approximately one-third of MMR-P CRC patients would not have met prior NCCN testing criteria based on family history or early onset. This supports updated guidelines recommending universal germline panel testing for CRC, independent of tumor MMR/MSI status.

  • For relatives, the occurrence of MMR-P CRC in a proband raises a critical question: does this represent an LS-related cancer with atypical biology, or a sporadic tumor co-occurring in a germline carrier? Current data suggest some of these tumors may arise via alternative molecular pathways. This nuance complicates risk estimation for family members who test negative for the familial variant.

• Pathogenesis:

  • Absence of biallelic inactivation or LOH in corresponding MMR genes in most MMR-P tumors supports the possibility of non–MMR-driven oncogenesis in LS carriers.

Key Takeaways

This study provides the first large-scale evidence that ~10% of LS-associated CRCs are MMR-P/MSS, with distinctive clinical and genetic correlates:

• Enrichment in MSH6 and PMS2 carriers.

• Later onset but higher metastatic burden.

• Potential for sporadic-like tumorigenesis within the LS population.

For clinicians, the implications are clear:

1. Do not assume MMR deficiency in LS-associated tumors—comprehensive tumor testing is essential.

2. Treatment decisions must be guided by tumor MMR/MSI phenotype, not germline status.

3. Surveillance and family counseling may require refinement, particularly in families where probands develop MMR-P CRC.

   
   

The recognition of MMR-P CRC in LS underscores the importance of integrating germline and somatic testing to optimize both patient care and familial risk management.

Prevalence, genotype distribution, and clinical characteristics between MMR-D and MMR-P CRC in Lynch syndrome.

Citation: Ranganathan S, Shia J, Stadler ZK, Mandelker DL, Kemel Y, Middha S, Selcuklu SD, et al. Mismatch Repair–Proficient Colorectal Cancer in Patients With Lynch Syndrome. JCO Precis Oncol. 2023;7:e2200352. doi:10.1200/PO.22.00352