Updates on DNA Repair Gene Deficiency in Colorectal Cancer (dMMR)

Abstract

Objective

This study explores the role of DNA mismatch repair (MMR) deficiency (dMMR) in colorectal cancer (CRC). We review how it influences the development of cancer, how it is diagnosed, and the latest treatments available, including how patients with dMMR respond to specific therapies differently than others.

Methods

We conducted a thorough review of current research, focusing on studies that address how dMMR affects people with colorectal cancer. We excluded studies on animals or cases that weren't directly relevant to human colorectal cancer. The focus was on how new knowledge and treatments change patient care.

Results

Around 15% of colorectal cancer cases involve dMMR, which is often linked to Lynch Syndrome and specific genetic changes. Patients with dMMR tend to have better outcomes in the early stages of cancer but respond poorly to traditional chemotherapy. However, these patients show significant improvement with immunotherapy, especially treatments targeting immune checkpoint proteins. Advances in diagnostic tools like microsatellite instability (MSI) testing and next-generation sequencing are helping doctors identify these cases earlier and choose better treatment options.

Conclusions

Recognizing dMMR in colorectal cancer is crucial for deciding the best treatment plan. Immunotherapy is proving to be particularly effective for these patients, and as diagnostic methods improve, we expect even better outcomes, especially for those with a hereditary risk like Lynch Syndrome.

Keywords

colorectal cancer - DNA mismatch repair deficiency - microsatellite instability - immunotherapy - lynch syndrome

Introduction

Colorectal cancer is one of the leading causes of morbidity and mortality worldwide, making the third type of cancer more common and the second leading cause of death related to cancer. Globally, colorectal cancer causes approximately 1.8 million new cases and 880,000 deaths each year.[1] This alarming scenario requires continuous advances in understanding, preventing, and treating this complex disease. Colorectal carcinogenesis is a multifactorial process that involves a series of genetic and epigenetic alterations. The deficiencies in DNA repair genes are now identified as a critical factor. The mismatch repair genes (MMR) MLH1, MSH2, MSH6, and PMS2 are essential for correcting errors during DNA replication. When genes are deficient, genetic instability is characterized by an accumulation of mutations that contribute to colorectal cancer development.[2] [3]

Mismatch-repair (MMR) deficiency (dMMR) is responsible for a significant proportion of cases of colorectal cancer. This hereditary condition increases the risk of various types of cancer, including colorectal cancer. Studies indicate that approximately 15% of colorectal cancer cases can present with MMR deficiency.[4] [5] [6]

Given dMMR prevalence and clinical implications, its identification has become a crucial component in the management of colorectal cancer. Precise MMR deficiency diagnosis has important prognostic, therapeutic, and preventive implications. Patients with dMMR patients have a better prognosis at early stages but limited response to traditional chemo.[7] On the other hand, patients usually show a robust response to immunotherapy, particularly to immunosuppressants, which are responsible for a real revolution in the last years in the treatment of colorectal cancer with dMMR.[8] [9] Families of dMMR carriers need different prevention measures, with more preliminary tests in younger ages, since the diagnostic risk is more significant at older ages. Moreover, the surgical treatment may eventually differ from that of the pMMR CCR population.[10]

This article aims to review and update the current knowledge about DNA repair genes and their role in colorectal cancer, from biological foundations to the most recent advances in diagnosis and treatment. A comprehensive literature search was conducted using the PubMed and Google Scholar databases. The following search terms were employed: (“mismatch repair deficiency” OR “dMMR”) AND (“colorectal cancer”) AND (“diagnosis” OR “treatment” OR “prognosis”). Studies included in this review were limited to those published in English and focused on human subjects with colorectal cancer. Studies were excluded if they were case reports, animal studies, or did not directly address dMMR in colorectal cancer. Other papers not listed on the first search but cited by these authors were included if any explanation, description, relationship, or result needed to be detailed or clarified.

Biology of DNA Repair Genes

DNA repair genes are crucial in genetic stability management and carcinogenesis prevention. In colorectal cancer, this group of genes responsible for DNA duplication incompatibility repair (MMR) is particularly relevant. This system corrects errors during DNA replication, such as incorrect bases and small indels (insertions and deletions). dMMR leads to increased mutation rates and microsatellite instability (MSI) in many colorectal cancers.[11] [12] [13]

The main components of the MMR system are proteins from genes named after them:

• MLH1 (MutL Homologue 1): A heterodimer of PMS2 (MutLα), essential for the repair of incompatibilities. Loss of MLH1 function, frequently due to promoter hypermethylation, is one of the most common causes of dMMR in sporadic colorectal cancer.

• MSH2 (MutS Homologue 2): Heterodimeric form linked more frequently to MSH6 (MutSα) but also to MSH3 (MutSβ), responding to the initial recognition of inappropriate patterns of bases or small indels. Mutations in MSH2 can lead to dMMR, whether inherited or acquired.

• MSH6 (MutS Homologue 6): Together with MSH2, it recognizes and binds base performance errors during DNA replication. Its deficiency can lead to dMMR and the development of colorectal cancer.

• PMS2 (Postmeiotic Segregation Increased 2): Forms a heterodimeric complex with MLH1 and plays a crucial role during the processing and excision stages to repair incompatibilities. The mutations in PMS2, yet rare, result in dMMR.

Two other genes, EPCAM and BRAF, are also crucial for DNA repair:

• EPCAM (Epithelial Cell Adhesion Molecule): involved in cell adhesion. There can be a disruption in this process when not expressed and lead to a deletion that results in the loss of MSH2 expression

• BRAF: a specific mutation called v600 occurs in position 600 of the BRAF gene, causes uncontrolled cell proliferation, and is directly responsible for hypermethylation of MLH1, which results in sporadic colorectal cancer related to dMMR.

The mechanism of action of the MMR system is based on repairing DNA duplication incompatibilities and can be divided into three basic steps ([Fig. 1]):

Fig. 1 Mechanism of action of the MMR complex. Cells typically use the MMR DNA replication system to ensure genetic fidelity by identifying (MSH2 and MSH6 complexes) and repairing (MLH1/PMS2 complexes) DNA replication errors. In tumor cells, on the other hand, the presence of a deficient MMR system results in the inability to repair DNA microsatellites, causing an accumulation of mutations in different codons. Adapted from Puliga et al.[14]

Error recognition, where the MutSα (heterodimer for MSH2-MSH6) or MutSβ (heterodimer for MSH2-MSH3) complexes identify pairing errors of bases or small indels during DNA replication, followed by incision and excision, when recognized, the MutLα (heterodimer for MLH1-PMS2) complex is recruited, facilitating DNA incision after error recognition for excising the defective segment. These two initial steps are the responsibility of the MMR system. Finally, synthesis and ligation, when DNA polymerase fills the gap with correct nucleotides, DNA ligase separates into a new DNA strand, completing the repair process.[14]

MMR Deficiency

A deficiency in the DNA MMR system results in incorrect correction of replication errors, leading to microsatellite instability (MSI), a characteristic that distinguishes various colorectal cancers. MSI is genetic hypermutability due to defects in the MMR system, typically manifested as alterations in DNA sequences, reflecting an inability to repair minor defects. This characteristic leads to the formation of small functionless DNA fragments accumulated during DNA replication, known as microsatellites. Tumors with high levels of MSI (MSI-High or MSI-H) have a distinct mutational profile and are more frequently immunogenic, triggering an immune response with significant therapeutic implications.[15]

Relationship with Lynch Syndrome

Lynch syndrome (LS) is formerly known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Cancer Family syndrome, but both nominations are no longer used. It is the most common cause of hereditary cancer related to MMR deficiency. It is characterized by germinative mutations in the MMR gene, which means they are present in all individual cells, significantly raising the predisposition to develop colorectal and other types of cancer at an early age, with an autosomal dominant inheritance pattern.[6] [16]

To diagnose Lynch syndrome, a detailed family history and clinical evaluation are carried out. In the past, criteria like the Amsterdam II or revised Bethesda criteria have been widely used to drive this diagnosis.[17] Immunohistochemical analysis is necessary to confirm the absence of mismatch repair (MMR) protein expression, indicating potential deficiencies in the MMR system. Following this, genetic testing can be performed, including DNA sequencing to identify germline mutations in MMR genes (MLH1, MSH2, MSH6, PMS2) and methylation-specific PCR to assess the MLH1 promoter region. If MLH1 promoter methylation is detected, Lynch syndrome is less likely. This comprehensive approach helps distinguish LS from sporadic colorectal cancers.[18]

Premature diagnosis and treatment of individuals with Lynch syndrome are essential for the implementation of effective preventive and therapeutic measures.[19] [20]

Differences Between MSI and MSS Colorectal Cancer

Microsatellite instability (MSI) colorectal cancer (CRC) presents distinct clinical, pathological, and molecular characteristics compared to microsatellite stable (MSS) CRC. These differences are essential for tailoring treatment decisions, and they highlight the importance of MSI testing in managing CRC and guiding therapeutic decisions, especially regarding the use of immune checkpoint inhibitors, which have shown significant efficacy in MSI-high tumors.[12] [16] [21]

Clinical Characteristics

MSI CRC is predominantly located in the right colon (proximal colon) than MSS tumors, which are more evenly distributed throughout the colon. MSI CRCs are more likely to be confined to the colon than to spread to other organs.

MSI is associated with advanced tumors in younger patients, but in older patients, the immune response may be impaired and the disease more aggressive. In early-stage cancers, MSI CRCs often have a better prognosis compared to their MSS counterparts. In the metastatic stage, MSI CRCs are usually more aggressive and have a poorer prognosis. However, additional factors such as specific mutations like BRAF V600E may be essential to set prognosis.

MSI-CRC patients may also develop other cancers, such as endometrial, urothelial, stomach, or pancreatic cancer, and they can be found in MSI individuals or families with or without CRCs and are common findings in these families.

Pathological and Molecular Characteristics

MSI CRCs are often poorly differentiated and exhibit a high mucinous component. They tend to have a higher proportion of mucinous adenocarcinoma histology than MSS CRCs. MSI CRCs have a high mutational burden, affecting cell growth and division genes, such as BRAF and TGFBR2, and others involved in DNA mismatch repair. MSI is a direct result of deficient mismatch repair (dMMR), which leads to the accumulation of mutations in short repetitive sequences of DNA (microsatellites). This high number of mutations leads to the production of abnormal proteins (neoantigens) not found in normal cells or MSS CRCs. Therefore, MSI tumors exhibit a distinct molecular profile.[22]

MSI CRCs are characterized by a dense Tumor-Infiltrating Lymphocytes (TILs) population. This condition reflects the high immunogenicity of these tumors. Despite being associated with more advanced tumor grades, MSI CRC does not necessarily correlate with a poorer prognosis. In fact, MSI status has been associated with a better prognosis in early-stage CRC.[23] It can be attributed to the robust immune response elicited by the high number of mutations and tumor-infiltrating lymphocytes.

Epidemiology and Risk Factors of dMMR in Colorectal Cancer

dMMR is found in about 15% of colorectal cancers.[5] [24] [25] This condition is characterized by microsatellite instability (MSI), a marker of defects in the incompatibility repair system (MMR). dMMR can be sporadic or hereditary and affects prognosis and treatment.

Sporadic Colorectal Cancer with dMMR

In around 15% of sporadic colorectal cancers, MMR deficiency is present. Most of these cases are associated with the hypermethylation of the MLH1 gene promoter, leading to its initiation. These tumors tend to occur in older adults and are often localized in the proximal colon.[26] [27] [28]

Hereditary Colorectal Cancer (Lynch Syndrome)

Lynch syndrome accounts for around 3-5% of colorectal cancer cases. Patients with Lynch syndrome carry a germinative mutation of MMR genes (MLH1, MSH2, MSH6, or PMS2). Patients who develop colorectal cancer at a younger age (especially before 50 years) face an increased risk of other types of cancer, including endometrial, gastric, ovarian, and urothelial ([Fig. 2]).[16] [29]

Fig. 2 Cumulative incidence of cancer stratified by mutation and lack of genetic expression. Adapted from Ryan et al.[55]

Terminology ([Fig. 3])

Fig. 3 types of colorectal cancer associated with dMMR. Adapted from Weiss et al.[12]

HNPCC has been associated with patients or families who met the Amsterdam I or II criteria. Now it has turned into a term that embraces a wide group of hereditary cancers ([Fig. 3]). Lynch syndrome (LS) is designated for patients and families with a genetic basis linked to a germline mutation in DNA MMR genes or the EPCAM gene. Lynch-like syndrome describes cases where molecular testing shows the presence of MSI and/or abnormalities in MMR gene protein expression through IHC testing of tumor tissue, but no pathogenic germline mutation is found. Familial colorectal cancer type X applies to patients and families that meet the Amsterdam criteria but lack the MSI characteristic of LS upon tumor testing. Muir-Torre syndrome, a rare variant of LS, is characterized by LS and sebaceous gland neoplasms with identifiable MSI. Patients diagnosed with both colorectal cancer and brain neoplasia, primarily glioblastomas, are classified under Turcot's syndrome. Biallelic mutations in DNA MMR genes are indicative of Constitutional mismatch repair deficiency syndrome, characterized by café au lait spots, early onset (childhood or teenage years) of colorectal or other LS-related cancers, along with brain tumors or hematologic malignancies.[13] [30]

Diagnosis of dMMR

The precise diagnosis of DNA repair gene deficiency (dMMR) Accurate dMMR diagnosis is essential for colorectal cancer treatment. The identification of dMMR has important prognostic and therapeutic implications, especially with the increasing effectiveness of immunotherapy in patients with dMMR.

Detection of DNA repair gene deficiency (dMMR) in colorectal cancer can be performed by various diagnostic techniques, each with specificities, advantages, and limitations.[31] [32]

Immunohistochemistry (IHC) is widely used to detect the expression of MMR proteins (MLH1, MSH2, MSH6, and PMS2) in tumor tissue. This technology is widely available in pathology centers in Brazil and worldwide, making it relatively quick, inexpensive, and efficient. The interpretation of the results may depend on the quality of the specimen and the technology used. If one or more MMR proteins are not expressed, this suggests dMMR. However, further testing is needed to confirm the specific cause.[33]

Another essential technique is the microsatellite instability test (MSI), which indicates the presence of instability at specific microsatellite sites in tumor DNA. MSI is a highly sensitive test, typically done with PCR and capillary electrophoresis. MSI is more expensive than IHC but is needed to detect MLH1 hypermethylation when MMR proteins are not expressed hypermethylation to determine if the CCR is related to Lynch Syndrome or sporadic[34] [35] when MLH1 proteins are not expressed in IHC.

Near genome sequencing (NGS) is an advanced technology that allows the simultaneous analysis of multiple genes to identify mutations in our MMR genes and other genetic alterations. This technique offers a comprehensive analysis of the genetic profile of the tumor, which is particularly useful for a detailed characterization of the cancer. The use of NGS is growing in research institutions and large hospitals despite its high cost and the need for bioinformatics expertise to interpret data.[12]

Clinical Diagnostic Protocol

A typical protocol for diagnosing dMMR in colorectal cancer, as with initial triage using IHC, on-site tumor tissue samples are evaluated for the expression of MMR proteins. If the IHC indicates dMMR, the next step is confirmation with the MSI test to assess satellite instability. In isolated cases, analysis of MLH1 promoter methylation may be performed to determine if hypermethylation is caused by MLH1 deficiency. The next generation sequencing (NGS) can be used for further analysis, especially if Lynch syndrome is suspected.[34] [35] [36] [37]

Clinical Implications of dMMR

The identification of MMR deficiency and satellite instability presents essential clinical implications. The presence of dMMR in colorectal cancer has many critical clinical consequences.[38] Firstly, patients with colorectal cancer dMMR generally show a better prognosis when compared to those with pMMR, especially at the initial stages of treatment. dMMR/MSI-H tumors are less responsive to traditional 5-fluorouracil (5-FU)- based chemotherapy but respond well to immunotherapy. These treatments demonstrated significant efficacy in advanced and metastatic cases of colorectal cancer with dMMR. They frequently respond robustly to immunotherapy with immune checkpoint inhibitors, such as pembrolizumab, dostarlimab, and nivolumab.[39] [40] [41] In addition, the identification of dMMR can lead to the diagnosis of Lynch syndrome, allowing for the prevention of colorectal cancer and other associated cancers in the family. It also helps choose the best surgical technique when necessary. The need to optimize resources for screening treatment and follow-up is also a critical issue, and knowledge of MMR status can help 21, 31, and 43.

Precise detection of dMMR, using techniques such as immunohistochemistry (IHC) and PCR for MSI, is crucial for guiding therapeutic decisions and optimizing patient management.[8] [42]

Impact of Inclusion of dMMR Tests in Colorectal Cancer Diagnosis

Including DNA mismatch repair gene (dMMR) tests in colorectal cancer diagnosis offers a significant opportunity to improve clinical care and patient outcomes.[3] [18] [38]

Better Prognosis

Identifying dMMR allows patients to be stratified with a better prognosis at the initial stages. Patients with dMMR have a lower recurrence rate after surgery and better overall survival.

Therapeutic Orientation

The presence of dMMR can influence the proposed surgery technique since the most extensive resections can be justified by the increased risk of synchronic or metachronic tumors[12] [43] but can also predict robust response to immunotherapy with immune checkpoint inhibition. Precocious dMMR identification can direct patients to more effective and personalized treatments, significantly improving clinical outcomes.

Diagnosis of Lynch Syndrome

Detection of dMMR can lead to a diagnosis of Lynch syndrome, allowing preventive staging of colorectal cancer and other associated cancers in the family. Identifying patients with Lynch syndrome is crucial to implementing preventive measures and active monitoring, reducing mortality associated with this hereditary condition.[3]

Cost-Effectiveness

Including dMMR tests in the initial diagnosis can be cost-effective in the long term. Early identification of patients who respond to immunotherapy can reduce the need for painful and ineffective treatments and save money. Diagnostic technologies are improving and becoming more accessible. Adopting a comprehensive approach that includes precise diagnostics, personalized therapies, and preventive care can transform the profile of colorectal cancer. The ongoing research, technological innovation, and compromise must be used to access and ensure that all patients can benefit from the latest diagnostic and therapeutic advances for dMMR colorectal cancer. More dMMR testing can lead to more appropriate treatments and implement adequate and timely preventive measures in affected families, resulting in improved clinical outcomes, reduced mortality, and improved quality of life for patients and their families. While challenges exist, the opportunities for diagnostic and therapeutic advances are substantial. The education of health professionals is probably the most important single action to take on this path.

Challenges and Solutions for the Implementation of dMMR Diagnostics

Implementing many dMMR tests, especially in developing countries like Brazil, faces significant disadvantages. The lack of access to advanced diagnostic tests is a barrier that must be overcome by public health policies that guarantee adequate funding and infrastructure.

Continuous training of physicians, pathologists, and laboratory technicians is essential to ensure competence in performing and interpreting dMMR tests. In other words, patient awareness programs are necessary to increase the patient's adhesion to the tests and recommended treatments.

Investments in laboratory infrastructure are critical to increasing the capacity to conduct advanced tests such as NGS and methylation analyses. Public-private partnerships and government funding can help improve the availability of these technologies throughout the health system.

Treatment

The fundamental differences between the management of patients with dMMR and pMMR colorectal cancer lie in the response to treatment and the monitoring strategies. Patients with dMMR present a better prognosis at the initial stages but also a limited response to 5-FU-based chemotherapy, requiring alternative therapies such as immunotherapy. Post-operative and family monitoring is more intensive in cases of dMMR due to the increased risk of relapse and the presence of potential hereditary syndromes such as Lynch syndrome. Surgery can also have different indications in dMMR CRC.[12] These aspects highlight the importance of a personalized treatment based on the tumor's genetic profile and the patient's characteristics.

Immunotherapy has been revolutionizing the treatment of colorectal cancer, especially for patients with DNA repair gene deficiency (dMMR). Tumors containing dMMR present a high mutational load and express numerous neoantigens, making them particularly susceptible to immunotherapy.[40] This advance represents a paradigmatic change in the treatment of colorectal cancer, offering new hope to patients who previously had limited options. The scientific basis for dMMR immunotherapy is these tumors' high mutation burden (TMB), which produces numerous neoantigens. These neoantigens are recognized as foreign to the immunological system, increasing the probability of an effective immune response.[44] [45] In addition, microsatellite instability (MSI), a characteristic of dMMR tumors, results in a highly immunogenic tumor environment. The higher the mutation burden, the better result with immunotherapy is achieved.

Future directions include a continuous translational search for the molecular mechanisms underlying dMMR, which can lead to the development of new therapies and treatment strategies. Adopting emerging technologies, such as liquid biopsy and artificial intelligence, can improve early detection and dynamic monitoring of the response to treatment.

Immune Checkpoint Inhibitors

Pembrolizumab is a monoclonal antibody that blocks the PD-1 protein, a control bridge that inhibits T-cell activation. By inhibiting PD-1, it restores the ability of the immune system to attack tumor cells. In a pivotal study, pembrolizumab demonstrated significant efficacy in patients with colorectal cancer (dMMR). The KEYNOTE-177 study indicates that improving disease progress can be achieved compared to standard chemotherapy.[44] Patients treated with pembrolizumab will face a total response rate of 40% and a higher disease control rate of 90%. Based on the results, pembrolizumab has been approved by the FDA and other regulatory agencies for treating patients with colorectal cancer, dMMR, or MSI-H.

Nivolumab is another inhibition of PD-1, which functions like pembrolizumab. It blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, allowing T cells to be recognized and destroyed as cancerous cells. Using dual immune checkpoint inhibition in the CHECKMATE-142 study[46] [47] in patients with colorectal cancer dMMR/MSI-H shows an objective response rate of 31% and a control rate of 69%, with long-term and improved responses overall. The combination of nivolumab and ipilimumab showed increased antitumor immunological response. Ipilimumab blocks CTLA-4, another checkpoint protein while increasing T-cell activation even more. Other studies also found this combination of nivolumab and ipilimumab to be responsible for high rates of clinical response even in advanced-stage tumors.[48]

Other ICIs are being tested with various responses. Dostarlimab alone has shown an impressive response in dMMR early-stage CRC in recent studies in rectal cancer and similarly excellent results in colon cancer.[40] Cercek[39] was able to show 100% clinical response in dMMR rectal cancer in a sustained period of 6 months, with very unimportant side effects. However, this ICI is still under investigation, and as it is not yet an evidence-based approach, it should only be undertaken under clinical/scientific protocols.

Surgery

Patients with early-stage dMMR colorectal cancer are generally candidates for curative surgery, which involves resection of the primary tumor with adequate surgical margins and lymphadenectomy. Studies demonstrate that these patients have a favorable prognosis after surgical resection, with survival rates like or even higher than those of patients with pMMR colorectal cancer. The presence of dMMR is often associated with favorable clinical features, such as tumor location in the right colon and a prominent intratumoral lymphocytic infiltrate, which may contribute to better clinical outcomes.

For patients with advanced disease (III-IV), the surgical approach remains an essential part of treatment. However, the decision to perform curative surgery in advanced stages depends on several factors, including response to neoadjuvant therapies and the presence of resectable metastases.

The risk of metachronous cancer after partial colectomy can be as high as 19%, even using vigilant colonoscopic surveillance. Considering that this risk can be minimized to as low as 0% and the life expectancy can be significantly raised using a strategy of subtotal colectomy, while the quality of life remains the same, this alternative is to be considered as a first option treatment over partial colectomy.[12] [13]

In patients with metastatic colorectal cancer, surgery to resect liver or lung metastases may be indicated, depending on the response to systemic therapy and the location of the metastases.

Ideally, every CCR patient should be evaluated in multidisciplinary treatment planning. In cases of dMMR colorectal cancer, for example, patients may respond poorly to 5-FU-based chemotherapy, which could alter the timing and sequencing of surgery relative to other treatments, such as immunotherapy.

The type of mismatch repair (MMR) genetic mutation, however, generally does not directly influence the choice of surgical procedure in colorectal cancer patients. Surgical decisions are primarily based on factors such as tumor location, stage, and other patient-specific factors, like age, comorbidities, and overall health status. Thus, while the MMR mutation type informs broader treatment strategies (e.g., potential for immunotherapy in dMMR tumors), the choice of surgery itself primarily depends on anatomical and oncological considerations rather than the specific genetic mutation.

Future Directions

DNA repair gene (dMMR) deficiency in colorectal cancer is a molecular marker with profound clinical, prognostic, and therapeutic implications. The increasing scientific evidence highlights the critical importance of incorporating dMMR tests in the initial diagnosis of all patients with colorectal cancer. The importance of diagnosing dMMR is reflected in various aspects. Patients with colorectal cancer dMMR generally present a more favorable prognosis at the initial stages of treatment. Identifying dMMR allows the selection of more effective therapies, particularly immunotherapy with immune checkpoint inhibition, such as pembrolizumab, dostarlimab, and nivolumab, which results in more prolonged responses and superior clinical efficiency. However, detection of dMMR has important implications for cancer detection and prevention in the patient's family. The benefits of adequate screening and treatment are evident. Identification of patients with this condition enables genetic screening of families, facilitating premature detection of colorectal cancer and other types of associated cancer. For patients diagnosed with Lynch syndrome, active monitoring and preventive measures can reduce the risk of developing secondary cancer.

The development of cancer vaccines in CRC, particularly those related to dMMR, represents a promising area of research. They aim to leverage the immune system to prevent cancer development by targeting specific neoantigens derived from frameshift mutations. Ongoing studies are crucial to validate the efficacy and safety of these vaccines, paving the way to more personalized and effective cancer prevention strategies.[49] [50]

Translational Research: Continuing research on the molecular mechanisms underlying dMMR can lead to the development of new therapies and treatment strategies.[28] [42] [47] [48] [51] Studies on the interaction between the tumor microenvironment and the immunological system are particularly promising.

Technological Innovation: Adopting emerging technologies, such as liquid biology and artificial intelligence, can improve early detection and dynamic monitoring of the response to treatment.[52] [53] These technologies offer opportunities for less invasive and more precise diagnostics and therapies.

Screening and Follow-up of dMMR Patient

Deficient MMR CRC is characterized by an increased lifetime risk of CRC (30%–73%) and extracolonic malignancies such as endometrial (30%–51%), ovarian (4%–15%), gastric (up to 18%), small bowel (3%–5%), urinary tract (2%–20%), pancreatic (4%), brain or cutaneous gland tumors. The carriers of pathogenic variants in MLH1 and MSH2 genes have a substantially higher risk of CRC cancer at younger age at diagnosis compared with carriers of MSH6 or PMS2 pathogenic variants. The cumulative incidence of endometrial and urinary tract cancers is higher in MSH2 carriers.[36]

Primary-grade family members of patients with colorectal cancer (dMMR) must be submitted for genetic tests to identify germinative mutations in our MMR genes (MLH1, MSH2, MSH6, PMS2). Genetic advice is essential to inform families about the risks and implications of test results, a practice that is not routine for families of patients with pMMR. Identification of patients with dMMR CRC, however, enables family genetic screening, facilitating early detection of colorectal cancer and other types of associated cancer. Family screening can significantly reduce mortality by allowing preventive interventions and more effective treatments.

For patients diagnosed with dMMR CCR, active monitoring and preventive measures, including regular colonoscopy exams, gynecological vigilance, and other monitoring strategies tailored to the individual risk profile, can reduce the risk of developing secondary cancer.[16] [54]

Colorectal surveillance is recommended at the age of 20-25 years for MHL1 and MSH2 carriers and at 30-35 years for MSH6 and PMS2 mutation carriers or persons at risk (first-degree relatives of affected). In all cases, the age of onset in the family's youngest member should be considered, and surveillance should start five years earlier. The age of onset in the family's youngest member should be regarded, and surveillance should start five years earlier. High-definition colonoscopy should be recommended every year[10] [36]

There is no clear evidence to support upper gastrointestinal surveillance[31] in all dMMR patients, but a routine upper endoscopy every three years, starting at 35 years, is advisable. In the same way, evidence to support the need for surveillance of urinary cancer is lacking. Pancreatic surveillance using magnetic resonance imaging can be considered.

Gynecological surveillance in women with dMMR CRC should be undertaken using transvaginal ultrasound despite its poor sensitivity and specificity for endometrial cancer. Along with gynecological examination, CA125 test and endometrial biopsies starting at age 35 years are recommended for LS patients. Despite the risk and side effects, a prophylactic hysterectomy with bilateral oophorectomy can be offered and discussed with mutation carriers who have completed childbearing or are post-menopausal.[10] [36]

Post-surgery CRC Monitoring

Patients with colorectal cancer dMMR require a rigorous monitoring protocol after surgery. Diagnostic reevaluation includes IHC and MSI testing on the removed tumor tissue to confirm the presence of dMMR and investigate the possibility of Lynch syndrome through additional genetic testing such as MMR gene sequencing. This follow-up is more frequent than in patients with pMMR, who have a higher risk of relapses and the potential presence of associated hereditary syndromes.

After surgery, it is essential to perform IHC and MSI tests using removed tumor tissue to confirm the presence of dMMR. If dMMR is identified, the possibility of Lynch syndrome should be investigated through additional genetic tests, such as MMR gene sequencing.

Performing imaging tests (TC, RM) and dosing of tumor markers (CEA) every 3-6 months in our first two years, followed by annual tests. A yearly colonoscopy is recommended for monitoring and detecting premature new polyps or recurrent tumors.[12] [36] [43]

Conflict of Interest

The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

Special acknowledgment must be given to Dr. Marcello Imbrizi Rabello for the excellent and detailed revision.

Author Contributions

Conceptualization of the work and manuscript drafting, GSP.

CSRC and CARM directly provided contributions, read, and approved the final manuscript,

All authors have read and agreed to the published version of the manuscript.

• References

• 1 Sung H, Ferlay J, Siegel RL. et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71 (03) 209-249 10.3322/caac.21660
• 2 Ahadova A, Gallon R, Gebert J. et al. Three molecular pathways model colorectal carcinogenesis in Lynch syndrome. Int J Cancer 2018; 143 (01) 139-150 10.1002/ijc.31300
• 3 Taieb J, Svrcek M, Cohen R, Basile D, Tougeron D, Phelip JM. Deficient mismatch repair/microsatellite unstable colorectal cancer: Diagnosis, prognosis and treatment. Eur J Cancer 2022; 175: 136-157 10.1016/j.ejca.2022.07.020
• 4 Stoffel EM, Mangu PB, Limburg PJ. American Society of Clinical Oncology, European Society for Medical Oncology. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology clinical practice guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology clinical practice guidelines. J Oncol Pract 2015; 11 (03) e437-e441 10.1200/jop.2015.003665
• 5 Flecchia C, Zaanan A, Lahlou W. et al. MSI colorectal cancer, all you need to know. Clin Res Hepatol Gastroenterol 2022; 46 (09) 101983 10.1016/j.clinre.2022.101983
• 6 Boland CR. Recent discoveries in the molecular genetics of Lynch syndrome. Fam Cancer 2016; 15 (03) 395-403 10.1007/s10689-016-9885-5
• 7 Tomasello G, Ghidini M, Galassi B, Grossi F, Luciani A, Petrelli F. Survival benefit with adjuvant chemotherapy in stage III microsatellite-high/deficient mismatch repair colon cancer: a systematic review and meta-analysis. Sci Rep 2022; 12 (01) 1055 10.1038/s41598-022-05065-6
• 8 Cohen R, Colle R, Pudlarz T. et al. Immune Checkpoint Inhibition in Metastatic Colorectal Cancer Harboring Microsatellite Instability or Mismatch Repair Deficiency. Cancers (Basel) 2021; 13 (05) 1149 10.3390/cancers13051149
• 9 Bernstein I, Therkildsen C, Seppälä TT. Editorial: Identification, risk stratification, and optimized management for Lynch Syndrome. Front Oncol 2023; 13: 1223568 10.3389/fonc.2023.1223568
• 10 Giardiello FM, Allen JI, Axilbund JE. et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Dis Colon Rectum 2014; 57 (08) 1025-1048 10.1097/dcr.000000000000000
• 11 Truninger K, Menigatti M, Luz J. et al. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology 2005; 128 (05) 1160-1171
• 12 Weiss JM, Gupta S, Burke CA. et al. NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2021. J Natl Compr Canc Netw 2021; 19 (10) 1122-1132 10.1164/jnccn.2021.0048
• 13 Giardiello FM, Allen JI, Axilbund JE. et al; US Multi-Society Task Force on Colorectal Cancer. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology 2014; 147 (02) 502-526 10.1053/j.gastro.2014.04.001
• 14 Puliga E, Corso S, Pietrantonio F, Giordano S. Microsatellite instability in Gastric Cancer: Between lights and shadows. Cancer Treat Rev 2021; 95: 102175 10.1016/j.ctrv.2021.102175
• 15 Buckowitz A, Knaebel HP, Benner A. et al. Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases. Br J Cancer 2005; 92 (09) 1746-1753 10.1038/sj.bjc.6602534
• 16 Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009; 76 (01) 1-18 10.1111/j.1399-0004.2009.01230.x
• 17 Gologan A, Sepulveda AR. Microsatellite instability and DNA mismatch repair deficiency testing in hereditary and sporadic gastrointestinal cancers. Clin Lab Med 2005; 25 (01) 179-196 10.1016/j.cll.2004.12.001
• 18 Wang C, Wang Y, Hughes KS, Parmigiani G, Braun D. Penetrance of Colorectal Cancer Among Mismatch Repair Gene Mutation Carriers: A Meta-Analysis. JNCI Cancer Spectr 2020; 4 (05) pkaa027 10.1093/jncics/pkaa027
• 19 Benson AB, Venook AP, Al-Hawary MM. et al. Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19 (03) 329-359 10.6004/jnccn.2021.0012
• 20 Herzig DO, Buie WD, Weiser MR. et al. Clinical Practice Guidelines for the Surgical Treatment of Patients With Lynch Syndrome. Dis Colon Rectum 2017; 60 (02) 137-143 10.1097/dcr.0000000000000785
• 21 Ryan E, Sheahan K, Creavin B, Mohan HM, Winter DC. The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing. Crit Rev Oncol Hematol 2017; 116: 38-57 10.1016/j.critrevonc.2017.05.006
• 22 Seth S, Ager A, Arends MJ, Frayling IM. Lynch syndrome - cancer pathways, heterogeneity and immune escape. J Pathol 2018; 246 (02) 129-133 10.1002/path.5139
• 23 Bai Z, Zhou Y, Ye Z, Xiong J, Lan H, Wang F. Tumor-Infiltrating Lymphocytes in Colorectal Cancer: The Fundamental Indication and Application on Immunotherapy. Front Immunol 2022; 12: 808964 10.3389/fimmu.2021.808964
• 24 Stoffel EM, Mangu PB, Gruber SB. et al; American Society of Clinical Oncology, European Society of Clinical Oncology. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol 2015; 33 (02) 209-217 10.1200/jco.2014.58.1322
• 25 Boland PM, Yurgelun MB, Boland CR. Recent progress in Lynch syndrome and other familial colorectal cancer syndromes. CA Cancer J Clin 2018; 68 (03) 217-231 10.3322/caac.21448
• 26 Zhang Q, Li J, Shen L, Li Y, Wang X. Opportunities and challenges of immunotherapy for dMMR/MSI-H colorectal cancer. Cancer Biol Med 2023; 20 (10) 706-712 10.20892/j.issn.2095-3941.2023.0240
• 27 Han K, Tang JH, Liao LE. et al. Neoadjuvant Immune Checkpoint Inhibition Improves Organ Preservation in T4bM0 Colorectal Cancer With Mismatch Repair Deficiency: A Retrospective Observational Study. Dis Colon Rectum 2023; 66 (10) e996-e1005 10.1097/dcr.0000000000002466
• 28 Mulet-Margalef N, Linares J, Badia-Ramentol J. et al. Challenges and Therapeutic Opportunities in the dMMR/MSI-H Colorectal Cancer Landscape. Cancers (Basel) 2023; 15 (04) 1022 10.3390/cancers15041022
• 29 Sunga AY, Ricker C, Espenschied CR. et al. Spectrum of mismatch repair gene mutations and clinical presentation of Hispanic individuals with Lynch syndrome. Cancer Genet 2017; 212-213: 1-7 10.1016/j.cancergen.2017.01.003
• 30 Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW. American College of Gastroenterology. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015; 110 (02) 223-262, quiz 263 10.1038/ajg.2014.435
• 31 Campos FG, Figueiredo MN, Martinez CAR. Current evidence for universal molecular testing for colorectal cancer patients. J Coloproctol (Rio J) 2017; 37 (03) 174-178 10.1016/j.jcol.2017.06.003
• 32 Martinez CAR, Campos FG. Current guidelines for the management of rectal cancer patients: a review of recent advances and strategies. Rev Assoc Med Bras (1992) 2024; 70 (Suppl. 01) S112 10.1590/1806-9282.2024s112
• 33 Eikenboom EL, van der Werf-'t Lam AS, Rodríguez-Girondo M. et al. Universal immunohistochemistry for Lynch Syndrome: a systematic review and meta-analysis of 58,580 colorectal carcinomas. Clin Gastroenterol Hepatol 2022; 20 (03) e496-e507 10.1016/j.cgh.2021.04.021
• 34 Li K, Luo H, Huang L, Luo H, Zhu X. Microsatellite instability: a review of what the oncologist should know. Cancer Cell Int 2020; 20 (01) 16 10.1186/s12935-019-1091-8
• 35 Huang W, Ho CL, Lee CT. et al. High concordance rate of capillary electrophoresis workflow for microsatellite instability analysis and mismatch repair (MMR) immunostaining in colorectal carcinoma. PLoS One 2023; 18 (04) e0284227 10.1371/journal.pone.0284227
• 36 Stjepanovic N, Moreira L, Carneiro F. et al; ESMO Guidelines Committee. Electronic address: [e-mail]. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2019; 30 (10) 1558-1571 10.1093/annonc/mdz233
• 37 Chen L, Pan X, Hu X. et al. Gene expression differences among different MSI statuses in colorectal cancer. Int J Cancer 2018; 143 (07) 1731-1740 10.1002/ijc.31554
• 38 Catalano F, Borea R, Puglisi S. et al. Targeting the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Colorectal Cancer. Cancers (Basel) 2022; 14 (06) 1388 10.3390/cancers14061388
• 39 Cercek A, Sinopoli JC, Shia J. et al. Durable complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer. J Clin Oncol 2024; ; 42 (17, suppl) LBA3512-LBA3512 10.1200/jco.2024.42.17_suppl.lba3512
• 40 Cercek A, Lumish M, Sinopoli J. et al. PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. N Engl J Med 2022; 386 (25) 2363-2376 10.1056/nejmoa2201445
• 41 Cercek A, Dos Santos Fernandes G, Roxburgh CS. et al. Mismatch Repair-Deficient Rectal Cancer and Resistance to Neoadjuvant Chemotherapy. Clin Cancer Res 2020; 26 (13) 3271-3279 10.1158/1078-0432.ccr-19-3728
• 42 Liska D. Research Perspective on: Systematic Review of Neoadjuvant Immunotherapy for Mismatch Repair-Deficient Locally Advanced Colon Cancer: An Emerging Strategy. Dis Colon Rectum 2024; 67 (06) 772-772 10.1097/dcr.0000000000003325
• 43 Gupta S, Provenzale D, Llor X. et al; CGC, CGC, CGC. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 2.2019. J Natl Compr Canc Netw 2019; 17 (09) 1032-1041 10.6004/jnccn.2019.0044
• 44 Shiu KK, Andre T, Kim TW. et al. KEYNOTE-177: Phase III randomized study of pembrolizumab versus chemotherapy for microsatellite instability-high advanced colorectal cancer. J Clin Oncol 2021; 39 (3, suppl) 6-6 10.1200/jco.2021.39.3_suppl.6
• 45 André T, Shiu KK, Kim TW. et al; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med 2020; 383 (23) 2207-2218 10.1056/nejmoa2017699
• 46 Overman MJ, McDermott R, Leach JL. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18 (09) 1182-1191 10.1016/s1470-2045(17)30422-9
• 47 Lenz HJ, Overman MJ, Cutsem EV. et al. First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) in patients (pts) with microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): 64-month (mo) follow-up from CheckMate 142. J Clin Oncol 2024; 42 (03) , suppl) 97-97 10.1200/jco.2024.42.3_suppl.97
• 48 Chalabi M, Verschoor YL, Tan PB. et al. Neoadjuvant Immunotherapy in Locally Advanced Mismatch Repair-Deficient Colon Cancer. N Engl J Med 2024; 390 (21) 1949-1958 10.1056/nejmoa2400634
• 49 Sei S, Ahadova A, Keskin DB. et al. Lynch syndrome cancer vaccines: A roadmap for the development of precision immunoprevention strategies. Front Oncol 2023; 13: 1147590 10.3389/fonc.2023.1147590
• 50 Hernandez-Sanchez A, Grossman M, Yeung K, Sei SS, Lipkin S, Kloor M. Vaccines for immunoprevention of DNA mismatch repair deficient cancers. J Immunother Cancer 2022; 10 (06) e004416 10.1136/jitc-2021-004416
• 51 Loria A, Ammann AM, Olowokure OO, Paquette IM, Justiniano CF. Systematic Review of Neoadjuvant Immunotherapy for Mismatch Repair Deficient Locally Advanced Colon Cancer: An Emerging Strategy. Dis Colon Rectum 2024; 67 (06) 762-771 10.1097/dcr.0000000000003263
• 52 Anagnostou V, Velculescu VE. Pushing the Boundaries of Liquid Biopsies for Early Precision Intervention. Cancer Discov 2024; 14 (04) 615-619 10.1158/2159-8290.cd-24-0037
• 53 Lone SN, Nisar S, Masoodi T. et al. Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments. Mol Cancer 2022; 21 (01) 79 10.1186/s12943-022-01543-7
• 54 Hampel H, Pearlman R, Beightol M. et al; Ohio Colorectal Cancer Prevention Initiative Study Group. Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer. JAMA Oncol 2018; 4 (06) 806-813 10.1001/jamaoncol.2018.0104
• 55 Ryan NAJ, Morris J, Green K. et al. Association of Mismatch Repair Mutation With Age at Cancer Onset in Lynch Syndrome: Implications for Stratified Surveillance Strategies. JAMA Oncol 2017; 3 (12) 1702-1706 10.1001/jamaoncol.2017.0619

Publication History

Received: 01 November 2024

Accepted: 05 February 2025

Article published online:
28 March 2025