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
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
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
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
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]
Bibliographical Record
Gustavo Sevá-Pereira, Claudio Saddy Rodrigues Coy, Carlos Augusto Real Martinez. Updates
on DNA Repair Gene Deficiency in Colorectal Cancer (dMMR). Journal of Coloproctology
2025; 45: s00451805009.
DOI: 10.1055/s-0045-1805009
