PMS2 Gene Mutation and Breast Cancer: Latest Insights

Genetic mutations play a significant role in cancer risk, with certain inherited alterations increasing susceptibility to specific cancers. While BRCA1 and BRCA2 mutations are well known for their link to breast cancer, research suggests that mutations in mismatch repair (MMR) genes, including PMS2, may also contribute. Understanding PMS2 mutations is essential for improving genetic screening and personalized treatment strategies.

Recent studies have examined how PMS2 mutations influence tumor development and their overlap with other hereditary cancer syndromes. Ongoing research into the molecular mechanisms involved is refining risk assessment and clinical management.

PMS2 Function in Mismatch Repair

The PMS2 gene encodes a protein essential to the DNA mismatch repair (MMR) system, which maintains genomic stability by correcting replication errors such as base mismatches and small insertion-deletion loops. PMS2 functions as a heterodimeric partner to MLH1, forming the MutLα complex, which coordinates repair events after mismatch recognition by MutSα (MSH2-MSH6) or MutSβ (MSH2-MSH3).

Once a mismatch is detected, PMS2 recruits exonucleases and other repair proteins to remove the erroneous DNA segment. Its endonuclease activity, dependent on MLH1 interaction, introduces a single-strand break near the mismatch site, allowing exonucleases to degrade the faulty DNA strand. DNA polymerase then synthesizes the correct sequence, and DNA ligase seals the strand, restoring genomic integrity. Mutations in PMS2 can impair this process, leading to an accumulation of replication errors that increase tumorigenesis. PMS2-deficient cells exhibit a mutator phenotype, characterized by elevated mutation rates and microsatellite instability (MSI), a hallmark of defective MMR.

Beyond replication error correction, PMS2 is involved in DNA damage response pathways, particularly apoptosis and cell cycle regulation. It interacts with p53 to promote apoptosis in response to extensive DNA damage, preventing the survival of highly mutated cells that could become malignant. Loss of PMS2 function weakens MMR efficiency and the response to genotoxic stress, increasing cancer susceptibility.

Structural Variants and Their Consequences

Structural variants in PMS2 include large deletions, duplications, and complex rearrangements that disrupt its mismatch repair function. Unlike single-nucleotide variants, which may result in point mutations, these larger alterations often lead to complete or partial gene inactivation, increasing cancer risk. Studies using multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS) have identified recurrent structural variants in PMS2, particularly in Lynch syndrome and other hereditary cancer syndromes. Exon deletions affecting critical functional domains of PMS2 have been linked to increased MSI and a heightened mutational burden.

Characterizing PMS2 structural variants is complicated by homologous pseudogenes, particularly PMS2CL, which can interfere with genetic testing. This challenge necessitates specialized long-read sequencing methods to distinguish pathogenic alterations from benign polymorphisms. Research shows that structural variants involving PMS2 often co-occur with alterations in other mismatch repair genes, amplifying genomic instability. Large deletions spanning PMS2 and MLH1 have been reported in individuals with early-onset colorectal and endometrial cancers, highlighting the impact of multi-gene disruptions on cancer risk.

Loss of PMS2 due to large deletions also impairs DNA damage response pathways, particularly apoptosis and checkpoint activation. This defect allows cells with accumulated mutations to evade growth control mechanisms, facilitating tumorigenesis. Experimental models show that PMS2-deficient cells exhibit increased resistance to chemotherapeutic agents such as temozolomide and cisplatin, which rely on intact mismatch repair for effectiveness. Identifying structural variants in PMS2 is clinically significant, as they may inform treatment decisions and predict therapeutic resistance.

Clinical and Molecular Characteristics of PMS2-Associated Tumors

Tumors associated with PMS2 mutations have distinct clinical and molecular features. While PMS2-related cancers often exhibit microsatellite instability (MSI), the extent varies based on mutation type and tumor histology. Unlike MLH1- or MSH2-deficient tumors, which frequently display high MSI (MSI-H), PMS2-associated malignancies sometimes have lower MSI levels, complicating classification within traditional Lynch syndrome criteria. MSI testing alone may not reliably detect PMS2-driven tumorigenesis, necessitating complementary analyses such as immunohistochemistry (IHC) to confirm protein loss.

Breast cancers linked to PMS2 mutations display heterogeneous pathological characteristics, sometimes resembling hereditary nonpolyposis colorectal cancer (HNPCC) spectrum tumors. Histological examination often reveals poorly differentiated or medullary-like morphology, consistent with the aggressive nature of other MMR-deficient cancers. Increased lymphocytic infiltration has been observed in PMS2-deficient tumors, providing diagnostic clues, particularly in individuals with a family history of Lynch syndrome.

The molecular landscape of PMS2-associated tumors includes an elevated mutational burden, which influences therapeutic response. Whole-exome sequencing of PMS2-deficient cancers has identified recurrent mutations in genes involved in cell cycle regulation and chromatin remodeling, suggesting broader genomic instability beyond mismatch repair deficiency alone. Some PMS2-driven tumors exhibit resistance to specific chemotherapeutic agents due to MMR’s role in mediating cytotoxic responses to DNA-damaging treatments. This resistance pattern underscores the need for personalized treatment approaches.

Overlap With Other Lynch Syndrome Genes

Lynch syndrome is linked to mutations in MLH1, MSH2, MSH6, and PMS2, all of which contribute to mismatch repair (MMR) deficiency. While PMS2 mutations have been considered lower-penetrance compared to MLH1 or MSH2, emerging genomic studies suggest they play a more significant role. Large-scale analyses of Lynch syndrome cohorts indicate that PMS2 mutations are frequently detected in individuals with atypical Lynch-associated cancers, including breast cancer, expanding the clinical spectrum of the condition. The incomplete penetrance and variable expressivity of PMS2 mutations make it challenging to assess their independent contribution, especially when they co-occur with other MMR gene alterations.

Compound heterozygosity, where individuals inherit pathogenic variants in two different MMR genes, complicates risk assessment. Cases of biallelic mismatch repair deficiency (bMMRD), often involving PMS2 with MLH1 or MSH6, exhibit aggressive cancer phenotypes with early-onset malignancies beyond the classical Lynch syndrome spectrum. Multiple MMR gene mutations amplify genomic instability, accelerating tumorigenesis and altering therapeutic responses. This phenomenon is particularly relevant in genetic counseling, where distinguishing between isolated PMS2 mutations and multi-gene involvement is critical.