Beyond adenomatous polyposis coli: Redefining the genetic architecture of familial adenomatous polyposis through recurrent variants of uncertain significance

Abstract

This editorial provides a critical commentary on the forthcoming prospective study published in the World Journal of Gastroenterology by Tóth et al. Familial adenomatous polyposis (FAP), as the prototypical hereditary colorectal cancer syndrome, has long been regarded as a monogenic disorder solely driven by germline adenomatous polyposis coli (APC) mutations. Tóth et al confirmed this classic paradigm in their Hungarian cohort, identifying pathogenic APC variants in > 90% of clinically suspected cases. However, their extended whole-exome sequencing approach unveiled a more complex genetic landscape. Nearly all patients exhibited a striking enrichment of recurrent variants of uncertain significance, particularly in the DNA polymerase epsilon catalytic subunit and mechanosensitive ion channel genes. This finding challenges the binary APC or not APC dichotomy and suggests that FAP is a polygenic or oligogenic disorder, wherein the core APC defect is modulated by a constellation of co-occurring genetic variants. The authors urge the field to move beyond the traditional single-gene diagnostic lens and embrace a systems genetics framework to more deeply understand the variable expressivity, penetrance, and extracolonic manifestations of FAP. Critical questions remain unresolved. Do these recurrent variants of uncertain significance s act as disease modifiers influencing polyp burden, age of cancer onset, or extraintestinal tumor risk? Can they account for the phenotypic heterogeneity observed among individuals harboring identical APC mutations? Most crucially, what is the functional interplay between APC, the DNA polymerase epsilon catalytic subunit, and the mechanosensitive ion channel in driving colonic tumorigenesis? Despite these unknowns, the work by Tóth et al represents more than a population-specific genetic report - it is a conceptual recalibration that redefines FAP as a genomic ecosystem. Only by fully deciphering its intrinsic complexity can we achieve truly individualized risk prediction and precision management.

Key Words: Familial adenomatous polyposis; Adenomatous polyposis coli; The DNA polymerase epsilon catalytic subunit; The mechanosensitive ion channel; Genomic ecosystem

Core Tip: This commentary reinterprets a recent Hungarian cohort study on familial adenomatous polyposis (FAP) to propose a paradigm shift in our understanding of the disease. We argue that FAP is not a simple monogenic disorder but a genomic ecosystem, where the core adenomatous polyposis coli mutation is modified by a constellation of co-occurring variants, most notably in POLE and PIEZO1. We integrate recent findings on the role of POLE in generating an ultramutated, immunotherapy-responsive phenotype and the function of PIEZO1 as a key mechanosensor in the gut to explain the clinical heterogeneity of FAP and chart a course for precision management.

This editorial refers to “Genetic differences in familial adenomatous polyposis syndrome in a Hungarian population: A prospective single center study” by Tóth et al, 2026; https://dx.doi.org/10.3748/wjg.v32.i1.110043.

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INTRODUCTION

From monolithic gene to genomic ecosystem

Familial adenomatous polyposis (FAP) has long served as the textbook example of a monogenic, autosomal dominant disorder, driven by germline loss-of-function mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. APC is located on the long arm of human chromosome 5 (5q21), and encodes a massive multifunctional scaffold protein of approximately 2843 amino acids. Its most established and critical function is as a key negative regulator in the canonical Wnt/β-catenin signaling pathway[1-3]. In normal physiology, the APC protein forms a destruction complex with axin and glycogen synthase kinase-3β. This complex phosphorylates cytoplasmic β-catenin, leading to its ubiquitin-mediated proteasomal degradation. As a result, β-catenin levels remain low and stable - essential for proper differentiation, polarity, and directional migration of colonic epithelial cells. Once the APC gene suffers a loss-of-function mutation, the destruction complex collapses. This leads to abnormal accumulation of β-catenin in the cytoplasm and its translocation into the nucleus. Inside the nucleus, β-catenin binds to T-cell factor/Lymphoid enhancer factor transcription factors and constitutively activates pro-proliferative, anti-differentiation target genes, such as MYC and cyclin D1. This cascade ultimately drives uncontrolled cell proliferation and adenoma formation[4].

Our deep understanding of the function of APC has been facilitated by pioneering studies in genetically engineered mouse models. Over the past three decades, these models have become indispensable tools for dissecting the pathogenesis of colorectal cancer (CRC). Notably, models with mutations in the murine homolog APC, such as ApcMin and ApcΔ716, recapitulate the core FAP phenotype: The development of dozens to hundreds of adenomatous polyps in the small intestine during the juvenile stage[2,3]. These models confirmed that APC inactivation is the earliest and most critical event in colorectal carcinogenesis, and unveiled its crucial roles beyond the Wnt pathway, including in cytoskeletal regulation, cell polarity, and directed cell migration[2,3].

However, a key phenotypic discrepancy exists between these mouse models and human FAP: The polyps in mice are predominantly located in the small intestine, whereas in humans, they are primarily colonic[2]. This discrepancy prompted researchers to develop more complex, genetically modified mouse models. For instance, by introducing modifier genes like CDX2 or BubR1 into APC-mutant mice, scientists successfully redirected polyp formation to the colon and significantly increased the tumor burden. This provides powerful experimental evidence for understanding the phenotypic heterogeneity of FAP[2,3]. Despite their success in elucidating the central role of APC, these mouse models also highlight the limitations of a purely monogenic model. These models faithfully replicate the classic FAP phenotype caused by the complete loss of APC function. However, they fail to explain the wide clinical spectrum in patients, ranging from individuals with thousands of polyps to those with attenuated FAP, who develop only a few dozen polyps[5,6]. This heterogeneity strongly implies that, beyond the primary APC driver mutation, other genetic and environmental factors must act as modifiers.

In this context, the recent prospective study published in the World Journal of Gastroenterology by Tóth et al[7] in a Hungarian population offers a breakthrough perspective on the genetic architecture of FAP[7,8]. Their work robustly confirmed the central role of APC (identifying pathogenic APC variants in > 90% of clinically suspected cases) while simultaneously uncovering a previously underappreciated layer of complexity: Nearly all patients carried a modifier landscape of recurrent variants of uncertain significance (VUSs); most prominently in the DNA polymerase epsilon catalytic subunit (POLE) and mechanosensitive ion channel (PIEZO1) genes. This finding fundamentally challenges the monogenic disease paradigm of FAP. It suggests that the complete FAP phenotype is not composed of a single “main melody” from the APC mutation, but is instead a symphony co-written by the core APC defect and a “harmony” of coexisting, modifying genetic variants. POLE, as a key guardian of DNA replication fidelity, may modulate the pace of tumorigenesis by influencing genomic stability. Conversely, PIEZO1, as a sensor linking the physical microenvironment to intracellular signaling, may shape tumor aggressiveness by affecting the mechanosensation and migratory capacity of a cell. These modifiers likely interact epistatically with the APC defect by influencing critical pathways beyond Wnt signaling, such as the DNA damage response, mechanotransduction, and the immune microenvironment, collectively determining each patient’s unique clinical destiny.

This emerging genomic ecosystem model for FAP is conceptually distinct from the established genetic paradigms of other hereditary polyposis syndromes. For instance, MUTYH-associated polyposis (MAP) is a classic autosomal recessive disorder caused by biallelic loss-of-function mutations in the MUTYH gene, a key player in the base excision repair pathway[7-9]. In stark contrast, lynch syndrome (LS), while not a polyposis syndrome per se, is a common hereditary CRC syndrome caused by heterozygous germline mutations in DNA mismatch repair genes (mutL homolog 1, mutS homolog 2, mutS homolog 6, and post-meiotic segregation increased 2)[10,11]. LS tumors exhibit microsatellite instability (MSI) and a hypermutated phenotype, which is mechanistically and clinically distinct from the chromosomal instability seen in classic FAP. Critically, both MAP and LS are defined by discrete, biallelic (MAP) or haploinsufficient (LS) molecular lesions in a single pathway. The FAP genomic ecosystem model, however, proposes a novel hybrid architecture: A dominant, monogenic driver (APC) whose phenotypic output is quantitatively and qualitatively modulated by a variable background of co-occurring, heterozygous modifier variants (e.g., in POLE and PIEZO1). This qualitative distinction - that FAP is neither purely monogenic nor a simple recessive/MSI disorder, but a dynamic interplay between a core driver and a modifier landscape - underscores the need for its own unique conceptual framework. Thus, the work by Tóth et al[7] goes beyond a population-specific mutation report: It represents a conceptual paradigm shift. It urges us to redefine FAP as a genomic ecosystem, where the APC mutation forms the core of the ecological niche, and the many modifying variants act as key environmental factors that shape its dynamic equilibrium and phenotypic output[9]. This new perspective opens a promising path toward unraveling the mystery of the clinical heterogeneity of FAP and achieving truly personalized risk prediction and precision management (Figure 1).

Figure 1 A proposed model of the “genomic ecosystem” in familial adenomatous polyposis. This schematic illustrates how a germline adenomatous polyposis coli (APC) mutation, the core driver of familial adenomatous polyposis, interacts with co-occurring variants in modifier genes like the DNA polymerase epsilon catalytic subunit (POLE) and mechanosensitive ion channel (PIEZO1) to shape the disease phenotype. The initiating event is a germline loss-of-function mutation in the APC gene. This leads to the failure of the β-catenin destruction complex, resulting in cytoplasmic and nuclear accumulation of β-catenin. Within the nucleus, β-catenin binds T-cell factor/Lymphoid enhancer factor transcription factors, causing hyperactivation of the Wnt/β-catenin pathway and the upregulation of oncogenes such as MYC and cyclin D1, which drive uncontrolled cell proliferation. This core oncogenic process is modulated by other genetic factors. (1) POLE (purple): A variant of uncertain significance in POLE may subtly impair DNA replication fidelity. This acts as a “mutational accelerator,” increasing the tumor mutational burden and potentially hastening the acquisition of secondary mutations that drive malignant progression; and (2) PIEZO1 (green): A variant of uncertain significance in PIEZO1, a mechanosensitive ion channel, may disrupt the sensing of physical forces from the intestinal microenvironment. This can lead to aberrant activation of downstream effectors like Yes-associated protein/transcriptional coactivator with PDZ-binding motif, further promoting tumorigenesis and potentially contributing to the development of polyps in extracolonic sites, such as the stomach and duodenum. This model conceptualizes familial adenomatous polyposis not as a simple monogenic disorder, but as a dynamic “genomic ecosystem” where the phenotypic outcome is determined by the interplay between the primary APC defect and a constellation of modifying genetic variants. APC: Adenomatous polyposis coli; YAP/TAZ: Yes-associated protein/transcriptional co-activator with PDZ-binding motif; TCF/LEP: T-cell factor/Lymphoid enhancer factor; MYC: MYC proto-oncogene; COND1: Cyclin D1; POLE: DNA polymerase epsilon, catalytic subunit; PIEZO1: Piezo-type mechanosensitive ion channel component 1.

DECONSTUCTING THE GENOMIC ECOSYSTEM: THE POTENTIAL MODIFIER ROLES OF POLE AND PIEZO1

The most striking finding of the Tóth et al[7] study is the recurrent co-occurrence of VUSs in the POLE (n = 5) and PIEZO1 (n = 4) genes within their cohort. This phenomenon is not random noise but points to two previously underappreciated biological axes of FAP pathogenesis that intertwine with the core Wnt/β-catenin pathway to form a more complex genomic ecosystem.

POLE: From guardian of the genome to sculptor of the tumor immune landscape

The POLE gene encodes the catalytic and proofreading subunit of DNA polymerase epsilon, which is central to high-fidelity DNA replication and repair in eukaryotic cells[12]. Germline or somatic mutations in its exonuclease domain cause a proofreading deficiency, leading to an ultramutated phenotype with a tumor mutational burden (TMB) exceeding 100 mutations per megabase; far higher than that of MSI-high tumors[13].

Recent research has dramatically broadened our understanding of POLE-mutant tumors. Critically, these ultramutated tumors possess a unique immunogenicity. Similar to MSI-high tumors, their high TMB generates a plethora of neoantigens, resulting in dense intratumoral T-cell infiltration and upregulation of immune checkpoint molecules like programmed death protein-1/programmed death-ligand 1[13]. A recent landmark study by Ambrosini et al[13] definitively demonstrated that metastatic CRC patients with POLE/POLD1 proofreading-deficient tumors exhibit a remarkable, durable clinical response to immune checkpoint inhibitors. This has established a new therapeutic paradigm for this rare subtype. The POLE P436S VUS identified in the Tóth et al[7] study, while classified as a VUS by the American College of Medical Genetics and Genomics (ACMG) guidelines, resides in exon 13, a known hotspot for pathogenic mutations. Patients in their cohort who carried a POLE VUS (e.g., ID3, ID4, or ID7) presented with complex phenotypes ranging from colon cancer (ID3) and an ovarian tumor (ID7) to high-grade dysplasia (ID4).

We hypothesize that in the context of an APC-deficient, Wnt-hyperactive background, a POLE VUS may subtly impair DNA replication fidelity, leading to an accelerated but controlled mutational phenotype. This effect might be insufficient to cause classic polymerase proofreading-associated polyposis on its own, but it could be potent enough to accelerate the malignant transformation of APC-mutant cells from adenoma to carcinoma or to broaden the spectrum of susceptible tissues (e.g., ovary). This not only explains why some APC mutation carriers develop cancer earlier and more severely but also proposes a revolutionary concept: That an APC/POLE co-mutation could potentially transform FAP from a purely surgical disease into one amenable to immunotherapy.

We further hypothesize that the interaction between APC and POLE is sequential and synergistic. In an APC-deficient colonic crypt - where Wnt-driven hyperproliferation already creates a permissive environment for clonal expansion - a concurrent POLE VUS may act as a mutational accelerator. By subtly compromising the proofreading fidelity of DNA polymerase epsilon, it could elevate the local TMB, thereby increasing the probability of acquiring secondary gatekeeper mutations (e.g., in KRAS and TP53) that are critical for driving the adenoma-to-carcinoma transition. This synergistic interaction may explain the earlier cancer onset and more aggressive phenotypes (e.g., extracolonic tumors like ovarian cancer in ID7) observed in the POLE VUS carriers in Tóth et al’s cohort[7]. In essence, while an APC loss initiates the oncogenic process, a POLE defect may dictate its pace and trajectory.

PIEZO1: The mechanosensor decoding the intestinal physical microenvironment

PIEZO1 encodes a mechanosensitive cation channel that transduces physical forces from the extracellular matrix, such as matrix stiffness, fluid shear stress, and epithelial stretch, into intracellular biochemical signals[14]. The colonic epithelium is a dynamic tissue, constantly subjected to mechanical forces from peristalsis and luminal contents. The gastrointestinal (GI) tract, as a whole, experiences a myriad of such mechanical forces while orchestrating digestion and barrier immunity. A central conductor of these processes, the enteric nervous system (which harbors approximately 500 million neurons, detects luminal pressure to regulate peristalsis independently of extrinsic input. Recent foundational research has established that the mechanosensor Piezo1 is functionally expressed in cholinergic enteric neurons, directly linking mechanical force to neural activity and gut homeostasis[15]. In this context, the Tóth et al’s study[7] found that siblings ID1 and ID2, who carried PIEZO1 VUS (R849H and M711K), had > 100 colonic polyps and presented with multiple polyps in both the stomach and duodenum. Their upper GI polyp incidence was 50%, compared to just 21.1% in patients with only an APC mutation[9]. This compelling clinical observation suggests that PIEZO1 variants may disrupt the normal mechanosensory function of the enteric nervous system, thereby altering epithelial homeostasis and creating a permissive environment for polyp formation across various segments of the GI tract that are exposed to distinct mechanical stresses. In summary, the recurrent co-occurrence of POLE and PIEZO1 VUSs expands the genetic architecture of FAP from a single genetic-replication axis to a four-dimensional network encompassing genetic replication-physical microenvironment-immune response. This multidimensional interplay is the essence of the complexity of the genomic ecosystem.

A NEW PARADIGM WITH PROFOUND CLINICAL IMPLICATIONS

Redefining FAP as a genomic ecosystem modulated by multiple genetic factors has profound clinical implications, demanding a shift from a one-size-fits-all management strategy to a precise, individualized risk management approach.

Moving beyond the APC-centric genetic testing paradigm

Traditional FAP genetic testing has been almost exclusively focused on the APC gene. The Tóth et al’s study[7] strongly suggests that this strategy overlooks critical risk information[8]. For patients with a classic clinical FAP phenotype but a negative APC germline test (8 such cases in their study), an extended whole-exome sequencing (WES) panel should be considered to screen for VUSs in modifier genes like POLE and PIEZO1. More importantly, for patients with a confirmed pathogenic APC mutation, the copresence of a POLE VUS should prompt consideration of its potential sensitivity to immunotherapy in a metastatic setting, while a PIEZO1 VUS should elevate concerns about extracolonic tumor risk (e.g., gastric/duodenal polyps), informing the creation of a truly individualized surveillance plan.

While a formal health economic model is beyond the scope of this editorial, it is important to acknowledge both the economic rationale and the practical challenges of integrating multi-gene testing into routine FAP care. The primary feasibility barriers include higher upfront costs of WES or large-panel testing compared to single-gene APC analysis, inconsistent insurance coverage for VUS screening, and limited access to specialized genomic counseling, particularly in community or resource-limited settings[10]. However, a growing body of evidence suggests that this investment may be cost-effective in the long term. For instance, the downstream savings from preventing a single case of metastatic colorectal or ovarian cancer, through earlier, risk-stratified surveillance or avoiding ineffective therapies, do not outweigh the initial sequencing cost[11]. The CAPP2 trial of patients with LS demonstrated that aspirin chemoprevention, guided by genetic diagnosis, significantly reduced cancer incidence, yielding substantial cost savings[10]. A similar logic applies to FAP: Identifying a POLE VUS co-mutation could justify the use of immune checkpoint inhibitors in the metastatic setting - highly effective but expensive therapy - only in the patients most likely to benefit, thereby optimizing resource allocation. As a practical solution, the rapidly declining cost of WES and the increasing integration of comprehensive genomic panels into national healthcare systems (e.g., the United Kingdom National Health Service Genomic Medicine Service) are improving accessibility[11]. Pilot programs at high-volume FAP centers, which bundle testing with expert variant interpretation and counseling, could serve as scalable models for broader implementation.

Mosaicism: The internal geographic diversity of the ecosystem

The familial transmission of VUSs in the Tóth et al’s study[7] (e.g., the ID1/ID2 siblings sharing a PIEZO1 VUS) resonates with the well-established importance of mosaicism[16]. Studies have shown that up to 20% of de novo FAP cases are caused by somatic mosaicism[16,17]. This means that different cell populations within the same individual may harbor distinct sub-ecosystems of their genome. This explains the focal and atypical phenotypes in some patients and poses a significant challenge for genetic counseling: Even if a parent tests negative in peripheral blood, their gonadal mosaicism could still transmit a high-risk APC mutation to their offspring[17]. Therefore, the interpretation of any VUS must also consider its potential mosaic state within the individual.

Medulloblastoma: A systemic output of the ecosystem

While Tóth et al’s study focused on the GI tract, the effects of the FAP ecosystem are systemic[7]. A study on medulloblastomas associated with germline APC pathogenic variants found that, while these tumors have an excellent prognosis (comparable to CTNNB1-mutant medulloblastomas), the patients face a high risk of second primary extracolonic tumors, particularly desmoid tumors[17]. This demonstrates that the genomic ecosystem established by an APC mutation has far-reaching consequences for the development and homeostasis of multiple organ systems throughout the body, reiterating the absolute necessity of lifelong, systemic surveillance for all FAP patients.

Evolution of ACMG classification standards: Validating the ecosystem

Fortunately, the genetics community has recognized the limitations of the monogenic model and is now developing gene-specific variant interpretation guidelines. The revised ACMG/the Association for Molecular Pathology guidelines for APC variants, created by the ClinGen-InSiGHT expert panel, serve as a prime example[18]. This framework introduces a quantitative phenotypic scoring system that incorporates clinical features like polyp number and extracolonic manifestations to support or refute a variant’s pathogenicity. This deep integration of genotype with clinical phenotype is the correct approach to managing the complexity of the genomic ecosystem[18]. In the future, similar gene-specific interpretation frameworks must be established for potential modifier genes like POLE and PIEZO1 in the context of polyposis syndromes.

FUTURE DIRECTIONS: MAPPING AND MANIPULATING THE ECOSYSTEM

The study by Tóth et al[7] has provided us with the initial sketch of the FAP genomic ecosystem. To truly master and leverage this knowledge, we must pursue the following avenues of research.

Build a national FAP registry

The Tóth et al’s study was limited by its small sample size[7]. Establishing a Hungarian national FAP registry with detailed clinical, pathological, and genetic data is the key to validating the modifying role of POLE/PIEZO1 VUSs, discovering additional modifier genes, and ultimately mapping the complete ecosystem.

Conduct functional studies to elucidate mechanisms

It is imperative to validate whether these VUSs truly modulate the biology of APC-mutant cells (e.g., proliferation, migration, genomic stability, mechanoresponsiveness) using in vitro (e.g., organoids) and in vivo (e.g., conditional knock-in mouse models) systems. Integrating cutting-edge immunological and biomechanical tools will be crucial to deciphering how POLE mutations shape the tumor immune microenvironment and how PIEZO1 mutations regulate cellular mechanics.

Develop integrated risk prediction models

Future risk models should move beyond the APC mutation locus alone. They must integrate modifier VUS status, mosaicism burden, detailed clinical phenotype (polyp count, distribution, and extracolonic manifestations), and even microenvironmental metrics (e.g., TMB and immune infiltration scores) to provide truly individualized cancer risk assessment and screening recommendations.

Explore ecosystem-targeted therapeutic strategies

Understanding the composition of the ecosystem may reveal novel therapeutic entry points. For instance, the use of immune checkpoint inhibitors should be actively explored in metastatic cancers from patients with an APC/POLE co-mutation[10]. Similarly, inhibitors of the PIEZO1 signaling pathway could potentially and specifically curb the growth and invasion of tumors in patients with an APC/PIEZO1 co-mutation.

CONCLUSION

The paradigm shift toward viewing FAP as a genomic ecosystem necessitates concrete, actionable steps to translate this conceptual advance into improved patient care. First, multicenter national or international FAP registries - integrating deep phenotyping with comprehensive germline and somatic genomic profiling - are urgently needed to validate the modifying roles of POLE, PIEZO1, and other candidate genes across diverse populations. Second, functional studies using patient-derived organoids and genetically engineered mouse models carrying both APC and modifier VUSs must be prioritized to dissect the molecular and biomechanical crosstalk that drives phenotypic heterogeneity. Third, clinical practice must evolve: Genetic testing panels should be expanded beyond APC alone, and surveillance protocols should be stratified by modifier status - for instance, intensified upper GI screening for PIEZO1 VUS carriers and early discussion of immunotherapy eligibility for metastatic cases with POLE covariants. Finally, the development of integrated risk prediction algorithms that combine APC genotype, modifier VUSs, mosaicism burden, and microenvironmental biomarkers will be pivotal for enabling truly personalized prevention and intervention strategies. Only through such a coordinated research-clinical effort can we transform the genomic ecosystem from a compelling metaphor into a practical framework for precision medicine in FAP.