What does the surgeon need to know about microsatellite instability in gastric cancers?

Abstract

Microsatellite instability (MSI) is a molecular subtype of gastric cancer caused by DNA mismatch repair defects, leading to mutations and neoantigen production. This profile influences tumor behavior, prognosis, and response to therapy, making it important for surgical decision-making. This article reviews the molecular basis of MSI gastric cancer, its clinical relevance, and its impact on management. A narrative analysis integrates evidence on pathophysiology, diagnostic strategies, and treatment implications of MSI in gastric cancer, with a focus on surgical oncology. MSI tumors exhibit a high mutational burden due to impaired DNA repair, resulting in increased immunogenicity and potential responsiveness to programmed death 1/programmed death ligand-1 (PD-L1) inhibitors. Retrospective studies suggest that patients with MSI-high gastric cancer often have a better prognosis and limited benefit from fluoropyrimidine-based chemotherapy, supporting upfront surgical resection in selected cases. Immunohistochemistry for mismatch repair proteins has become the preferred diagnostic tool, replacing microsatellite testing as the primary screening method. For tumors escaping immune surveillance via PD-L1 expression, targeted immunotherapy offers clinical benefit. Integrating MSI status into the treatment algorithm has shifted gastric cancer management, requiring surgeons to apply molecular oncology principles to optimize outcomes and enhance multidisciplinary coordination.

Key Words: Gastric cancer; Microsatellite instability; Mismatch repair; Immunotherapy; Surgical oncology

Core Tip: This is an overview of the biological foundations, molecular mechanisms, diagnostic approaches, and clinical relevance of microsatellite instability in gastric cancer, emphasizing its role as a prognostic biomarker. The text also discusses therapeutic implications, including personalized surgical decision-making, treatment stratification, and the growing importance of integrating immunotherapy within multidisciplinary oncologic care.

INTRODUCTION

The increasing application of molecular biology to clinical practice is a welcome change to the landscape of therapeutic tools for our patients with gastric cancer. These changes require the surgeon to become more familiar with many of these innovations and terms[1-3]. Among gastric cancer surgeons, the molecular classification proposed by The Cancer Genome Atlas (TCGA) brought to the forefront the importance of fully understanding these new aspects of the surgeon's decision matrix.

Despite growing evidence on the molecular characterization of gastric cancer, there is a critical gap in literature specifically addressing the practical implications of microsatellite instability (MSI) for surgical decision-making, highlighting the need for a surgeon-oriented synthesis that bridges molecular oncology and operative management.

In this review, we aim to synthesize current evidence on the molecular basis, diagnostic strategies, and clinical implications of MSI in gastric cancer, emphasizing its impact on surgical decision-making and multidisciplinary management.

BIOLOGICAL FOUNDATIONS OF MSI

DNA replication is a dynamic process based on the capacity of an enzyme – DNA polymerase, to add specific nucleotides according to a template of DNA creating a complementary strand of the double helix DNA[4,5]. The process of adding nucleotides to the nascent strand of DNA has been compared to typing a text according to a template to be read almost in real time. Sometimes, typeset errors occur[6].

There are only four nucleotides composing DNA, these are T, C, A, and G. Since DNA is a double strand, each nucleotide is coupled with one specific partner. While working on DNA duplication, the polymerases need to add the correct partner to each nucleotide, i.e., if there is a T, the enzyme needs to add an A; if it is a G, a C will be added, in a very dynamic process[7].

Due to the sheer volume of events and the speed required, errors will occur, and a wrong nucleotide will be added. In such cases, one of the “quality control” systems often takes over[6]. The DNA repair system related to MSI cancers is composed of proteins that are able to identify errors and replace nucleotides with the correct ones[8,9].

ANALOGIES BETWEEN DNA REPAIR AND SURGICAL PRACTICE

The DNA repair mechanism can be seen as analogous to a typical surgical procedure. This comparison is schematically illustrated in Figure 1, which shows similarities between the molecular repair machinery and surgical conduct in their operational mechanisms.

Figure 1 Two fundamental processes in the context of biological lesions and their respective surgical approaches to repair. In the top panel (surgical inventory), the first step is the identification and resection of a bowel lesion, followed by segment-loss reconstruction, representing excision and intestinal anastomosis. Meanwhile, the bottom panel (DNA repair mechanism) describes the DNA repair processes. The first step involves screening for DNA lesions, with damage-recognizing enzymes acting analogously to a “surgical inventory” of lesions. The second step illustrates the excision and replacement of damaged DNA fragments without loss of genetic information, with DNA synthesis and repair similar to the suturing of a biological wound. The analogies between the two processes are intended to facilitate understanding of the similarities between surgery and molecular repair.

The surgeons usually perform an inventory to check every potential lesion in the abdominal cavity and if they identify an abnormality, like a bowel segment inflammation or tumor, this will be removed, and the remaining segments will be reconnected by an anastomosis, leading to an elimination of the “error” and reconstruction of the intestinal “sequence”, with a loss of the resected segment.

In the case of DNA repair mechanism, the involved proteins will check the DNA, find the error, remove it, re-synthase the correct DNA sequence, and insert de correct nucleotides into the DNA sequence, in this case, restoring it without loss of any DNA segment. Let’s wait for such evolution of not losing organs segments in the surgical field.

Using this analogy, the consequences of failing to identify and/or adequately correct any abdominal “error”, by the surgeon, may result in a wide possibility of troubles that may or may not threaten the patient’s health, according to what was lost.

Similarly, if the DNA repair fails in identifying and correct the DNA mismatches, the consequences for the cell, and for the patients’ health, will depend on what was lost. Fortunately, most of non-repaired DNA errors falls in regions of the DNA that are not transcribed or, if so, do not threaten the cell and the patients’ health. Actually, at each cell division a few DNA unrepaired errors persist, but usually do not cause any trouble.

DIAGNOSIS OF MSI PHENOTYPE IN GASTRIC CANCER

The frequency of such unrepaired errors are considerable, even having an effective DNA repair apparatus, since the amount of DNA to be checked and, if necessary, removed, re-synthase and correctly relinked to the DNA sequence is enormous.

The continuous hard work of DNA synthesis, checking, and fixing errors can be compared to the production of an important textbook - the life textbook, in this case. Deletion and retyping events during the production of this long text occurs frequently, similarly to the errors generated in DNA replication that need to be identified and be restored by the DNA repair machinery. Should this system malfunction, either because it is unable to recognize the error or replace it with the correct one, the new DNA strand will retain the “wrong sequence”, just like the “wrong words or sentences” in a sent text.

Fortunately, as discussed, most such errors, although occurring in every cycle of DNA replication, rarely will cause troubles, as these “typeset” errors seldom provoke misinterpretation of the text meaning. Nonetheless, if the mismatched DNA base results in a significant modification of the encoded protein, a new epitope may be created which is different from those recognized by the immune system as “self”, may be produced[10,11].

MSI high gastric cancers are characterized by the incompetence of this DNA repair system, resulting in the production of plenty of new antigens that the immune system will recognize as foreign[9]. One of the ways of checking the occurrence of such deficiency in the mismatch repair system used to be by looking at microsatellites. Since microsatellites are repetitions of nucleotide sequences, they are prone to errors during the polymerase’s activity. While reading and typing a code, like the barcode numbers of a bank document, large repetitions, such as six or seven consecutive zeros, favor “typesetting” mistakes, like mismatch errors in microsatellites.

Backing to the surgical field, there are many signs that helps the surgeon to suspect that something is wrong in the abdominal cavity, like tachycardia, abdominal pain, distension and reaction, among others. These are not the cause of the real problem but guides the surgeon to identify the problem.

Similarly, to the cited concomitant but not causal events of the abdominal injury, MSI, instead of representing a causal mechanism of this tumor type, refers to a strategy for identifying a subgroup of cancers resulting from mismatch repair gene deficiencies. Conversely to what the subgroup's name may suggest, the microsatellites, usually, do not cause a molecular event important to the carcinogenesis but rather represents just a consequence of the actual causal mechanism. And, provides an accessible way of inferring the occurrence of the subjacent causal mechanism – the inability to identify and/or correct a type of DNA error[4,9].

The diagnosis and classification of the named MSI tumors moved from checking microsatellites to verifying the expression of the mismatch repair proteins by immunohistochemistry. Nevertheless, the molecular gastric cancer type will still be named MSI[1,12].

PROGNOSTIC AND THERAPEUTIC IMPLICATIONS

The molecular event peculiar to the MSI gastric cancer type is a deficiency in the mechanism that reduces the persistence of errors during DNA synthesis[12].

Thus, if a pathology report notes “lacking expression of mismatch repair proteins”, one must consider that multiple neoantigens may be produced and can thus serve as targets for an unleashed immune system. This is usually good for the patient and represents a status of probable immunocompetence, and the prognosis is often better than for those with stability of microsatellites[8].

According to retrospective studies, gastric cancers with MSI high have a better prognosis and seem not to benefit from neoadjuvant fluoropyrimidines-based chemotherapies[2,3,13]. Upfront surgery has emerged as a viable option for such cases.

Another important molecular feature affecting the management of MSI tumors is the programmed death 1 (PD-1) pathway expression[14]. Although the neoantigens created in MSI cancers can generate an immune response, some tumor cells escape immune destruction, taking advantage of a mechanism that regulates immune responses. These control mechanisms avoid excessive responses that might harm normal cells[12]. This is the case of the PD-1 pathway. Tumor cells that express or induce expression of programmed death ligand-1 (PD-L1), which is a PD-1 binding protein, activates this break of the immune response, resulting in the avoidance of these cancer cells’ immune destruction[15].

When an MSI high tumor escapes the immune surveillance that was triggered by the neoantigens produced due to the deficiency in mismatch repair genes, by overexpression of the PD-1 pathway, this is not necessarily the end of the story. Antibodies against PD-1 or anti-PD-L1 can avoid the activation of the PD-1 pathway by the cancer cells and improves clinical outcomes. In this case, science, and the patient may be the final winner. These antibodies are currently indicated for MSI-high (MSI-H) gastric cancers, according to approved protocols[16].

The molecular discoveries, while translated to clinical practice, deeply impact the medical management, including the surgical strategies. The current understanding of the mechanisms and impacts of MSI-H strongly modified traditional approaches including surgical management of these tumors.

The recently proposed modification on the indications of fluoropyrimidines-based neoadjuvant chemotherapy for MSI-type gastric cancers, is one of these novelties requiring moving the surgeons to increase their molecular understanding[1-4].

According to recent guidelines, these drugs may be avoided and replaced by upfront surgery, due to lack of clinical benefit in such molecular GC type, impacting clinical management.

In addition, immunotherapy is now indicated for treating MSI-H GC, including as a neoadjuvant approach[17].

Another potential application among the surgical treatment strategies is to considerer a less extended lymphadenectomy, since MSI-H gastric tumors may exempt radical lymphadenectomy in selected cases.

In many areas of the world, the surgeons are often the team leader in gastric cancer management. Therefore, surgeons must have a full comprehension of these new “molecular players” as relevant medical decisions will continue to evolve.

Among the potential future directions, avoiding surgery in cases of MSI-H tumors treated preoperatively and achieving complete pathological response are on the horizon. On the other hand, cases currently considered outside surgical therapeutic indications due to advanced stage may become potentially operable after immunotherapy. Between these extreme examples, tailoring each GC case to molecular features is a need that requires the surgeon, as team leader, to be involved.

CONCLUSION

MSI gastric cancer is the TCGA molecular type that has led to most of the current modifications in GC clinical management. This has impacted both the surgeon’s and the clinical oncologist's approaches to many patients, aiming for more favorable patient outcomes. Understanding the new and evolving molecular landscape and incorporating this knowledge into surgical oncology will benefit multidisciplinary teams. This will promote more harmonious decision-making in real-world practice and must be part of the GC surgeon’s repertoire.