Introduction

Colorectal adenomatous polyposis (CAP) is a common intestinal polyposis and a precancerous lesion associated with colorectal cancer (CRC) [1]. Since Crisp described the first case of CAP in 1882 [2], it has attracted widespread attention. Then, in the 1980s, adenomatous polyposis coli (APC) was discovered as a susceptibility gene for CAP with a clear familial aggregation, and this type of CAP was named familial adenomatous polyposis (FAP) [3]. In subsequent studies, researchers detected no pathogenic mutations of APC in cases of CAP and explained these CAPs with other susceptibility genes. With advances in our understanding of CAP, researchers globally have proposed that CAP is used as an umbrella term, with FAP considered a subtype of CAP [4]. APC mutation-negative CAP was defined as APC (-)/CAP.

To date, the reported APC(-)/CAP include autosomal recessive MUTYH-associated CAP (MAP) [5], NTHL1-associated CAP (NAP) [6], CAP caused by constitutional mismatch repair deficiency syndrome (CMMRD) [7], autosomal dominant polymerase proofreading genes POLE/POLD1-associated CAP (PPAP) [8], AXIN2-associated CAP (AAP) [9], and DUOX2-associated CAP (DAP) [10] (Fig. 1).

Fig. 1
figure 1

Specific classification of APC (-)/CAP. Genetic characteristics of APC (-)/CAP, including autosomal recessive and autosomal dominant inheritance; several APC (-)/CAP classifications, including MAP, NAP, CMMRD, PPAP, AAP, and DAP, and APC (-)/CAP susceptibility genes, including MUTYH, NTHL1, MMR genes, POLE/POLD1, AXIN2, and DUOX2

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The clinical phenotypes of autosomal recessive APC (-)/CAP in MAP, NAP, and CMMRD differ, as do the clinical phenotypes of autosomal dominant PPAP, AAP, and DAP. The clinical phenotype differences of APC (-)/CAP could be attributed to different genetic mutations. However, few reports have summarized this aspect. In this review, we provide a comprehensive overview of the association between pathogenic genes causing autosomal recessive and dominant CAP and clinical phenotypes with APC mutation-negative CAP.

Autosomal Recessive APC (-)/CAP

MUTYH-Associated Polyposis (MAP)

Discovery of MAP

MAP is an autosomal recessive disease caused by biallelic germline mutations in MUTYH [11]. MUTYH, also known as MYH, is a gene that encodes a glycosylase involved in DNA base excision repair (BER), which plays a key role in cellular defense against oxidative damage. The MUTYH protein excises adenine in the nascent strand opposite 8-oxo-G in template DNA and restores G:C base-repair to maintain DNA replication fidelity [12]. AI-Tassan et al. first reported that the germline mutation in MUTYH caused APC (-)/CAP [5]. Farrington et al. further confirmed that MUTYH is the driving gene for some APC(-)/CAP, which is associated with BER defects and is therefore named MUTYH-associated polyposis (MAP) [13]. This is the first time a new susceptibility gene for CAP was identified since the discovery of APC, and MUTYH is the first APC (-)/CAP susceptibility gene of BER to be validated.

Genetic Background of MAP

It is estimated that the MUTYH mutation accounts for 20% of APC(-)/CAP. MUTYH mutations are the most common in APC(-)/CAP [10]. According to the Catalogue Of Somatic Mutations In Cancer (COSMIC) database, missense mutations in MUTYH account for 53.49%, nonsense mutations for 3.49%, and synonymous mutations for 12.79% of APC (-)/CAP in colorectal tissues (Fig. 2). Y179C and G396D are the two most common pathogenic mutations in MUTYH in the Northwestern European MAP population [14, 15], with the Y179C mutation being a high-risk factor for adenoma and is associated with its aggressiveness [16, 17]. Mutations in MAP are often characterized by G:C > T:A transversions due to the dysfunctional MUTYH in the BER pathway [18]. In European populations, the majority of pathogenic mutations are found in the exon 7 region of MUTYH, which is presumed to be the mutation cluster region (MCR) of MUTYH. However, very few mutations in exon 7 were detected in the MAP mutation profile in patients from Asian countries, such as China, Japan, and Korea [15, 19,20,21]. A comprehensive analysis of several ethnicities also demonstrates the difference in MCR of MUTYH mutations between ethnicities [22].

Fig. 2
figure 2

Overviews of the types of mutations in susceptibility genes (include MUTYH, NTHL1, MMR genes, POLE/POLD1, AXIN2, DUOX2) in colorectal tissues for APC (-)/CAP. The data were obtained from the COSMIC database. It can be seen that missense mutations are the mutation type with the largest proportion of mutations in all susceptibility genes

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Clinical Implications of MAP

The clinical phenotype of MAP is similar to that of attenuated FAP (AFAP). The number of intestinal polyps is often less than 100, and it is prevalent in the left hemicolon (71%). The risk of CRC from MAP is high, and CRC caused by MAP is usually diagnosed around the age of 50, with a good prognosis [23,24,25,26]. Owing to the similarities in the clinical phenotypes, only genetic testing can distinguish the mutational features between MAP and AFAP. Further, MUTYH acts as a multiple-effect gene. Mutations in MUTYH cause widespread multiorgan and multisystem lesions [24]. Many studies have linked MAP extraintestinal lesions to ovarian, bladder, breast, thyroid, duodenal, sebaceous gland, skin, and endometrial cancers [24,25,26,27,28,29], the most of which are ovarian and bladder cancers [24, 28]. Therefore, for MAP patients, ovarian and bladder lesions should be routinely screened.

NTHL1-Associated Polyposis (NAP)

Discovery of NAP

NTHL1-associated polyposis is an autosomal recessive disease caused by biallelic germline mutations in NTHL1 [30]. Similar to MUTYH, NTHL1 encodes a DNA glycosylase and participates in the BER pathway. NTHL1 mutations increase the risk of colorectal adenomas [31, 32]. In 2015, Weren et al. first reported the pathogenic mutation in NTHL1 associated with CAP [6]. Further studies confirmed that NTHL1 is a potential susceptibility gene for APC (-)/CAP and then Kuiper et al. named it NTHL1-associated polyposis (NAP) [30, 33, 34]. After the BER gene MUTYH, NTHL1 is secondly identified and demonstrated to cause BER abnormalities, which are involved in the occurrence of CAP.

Genetic Background of NAP

The Q90X mutation in NTHL1 has been characterized and is common in NAP patients [6, 35]. According to the COSMIC database, missense mutations, nonsense mutations, and synonymous mutations in NTHL1 account for 73.33%, 3.33%, and 13.33% of APC (-)/CAP, respectively (Fig. 2). So far, no MCR in NTHL1 have been reported. The majority of NAP patients are European, with a Dutch predominance. However, there are currently very few NAP patients reported in Asian countries [36, 37]. Grolleman et al. and Terradas et al. [38, 39] further established the differences in the frequency of NTHL1 mutations among ethnic groups, and entire open reading frame sequencing was suggested for NTHL1 mutations.

Clinical Implications of NAP

The gastrointestinal disease of NAP is similar to MAP and AFAP. The polyp burden of NAP patients varies from fewer than 10 polyps to 50–100 polyps, with the polyposis mainly presenting in adulthood [40]. However, the detection rate of NAP is much lower than that of MAP (only about 1/5 of MAP) [40]. Mutations in NTHL1 can lead to a multisystem tumor susceptibility syndrome [41]. Extraintestinal lesions of NAP include breast, endometrial, skin, duodenal, brain, and bladder cancers [30, 31, 35]. Breast and endometrial cancers are frequently associated with NAP, screening for breast and endometrial lesions in NAP is suggested by the French Oncogenetics Consortium, and the surveillance protocols for NAP are established based on MAP recommendations [31]. Furthermore, Laura et al. reported that in the absence of adenomatous polyposis, NAP is not a multi-tumor syndrome [42].

Constitutional MMR Deficiency Syndrome (CMMRD)

Discovery of CMMRD

CMMRD is an autosomal recessive disorder caused by biallelic germline mutations in the MMR genes [43, 44]. MMR genes are a group of housekeeping genes and four of them, including MLH1, MSH2, MSH6, and PMS2, have been reported to be involved in the process of DNA replication. They function to recognize and repair base mismatches during DNA replication or recombination and play an important role in maintaining genetic stability [45]. Children and adolescent patients with CMMRD are susceptible to a variety of diseases, especially colorectal tumors [46]. In 2011, Jasperson et al. reported a proband of APC (-)/CAP presenting with an MMR mutation and her sister with a similar colorectal disease also presenting with an MSH6 mutation [7]. Additional studies confirmed the association between the remaining MMR genes, PMS2, MLH1, and MSH2 with APC (-)/CAP [26, 47, 48]. These results established that MMR genes are susceptibility genes for APC (-)/CAP and that errors in the DNA replication process play a critical role in the occurrence of CAP.

Genetic Background of CMMRD

Among the four MMR genes, patients harboring mutations in MSH2 are at the highest risk of adenoma, while patients with mutations in MLH1 and MSH2 suffer a higher risk of CRC [49]. The COSMIC database shows the proportion of mutations in colorectal tissues for the 4 genes, with missense mutations in MLH1, MSH2, MSH6, and PMS2 of 47.13%, 41.60%, 16.62%, and 51.85%; nonsense mutations of 13.41%, 22.90%, 6.41%, and 6.67%; and synonymous mutations of 4.98%, 11.83%, 2.62%, and 19.26%, respectively (Fig. 2). Additionally, very rare mutations in MLH2 [49] are reported to be associated with APC (-)/CAP. In each MMR gene, no mutation hot spot or MCR has been identified. Co-occurrence of various MMR genes is observed; for instance, concurrent loss of MLH1/PMS2 and loss of MSH2/MSH6 are frequently observed [50]. MMR genes and APC are also partially synergistic, and Engel et al. reported that patients with monoallelic mutations in MMR genes, as well as mutations in APC, also present a CAP phenotype [49]. Although CMMRD is typically aggressive, immunotherapy has been an emerging and effective treatment for it [44]. Recently, the American College of Medical Genetics and Genomics (ACMG) recommended routine genetic screening for MLH1, MSH2, MSH6, and PMS2 in patients with CAP [26].

Clinical Implications of CMMRD

Owing to variable gastrointestinal lesions associated with CMMRD, it is difficult to determine whether it overlaps with the classic FAP (CFAP) or AFAP phenotype [51]. Typical clinical features of gastrointestinal polyps are early age of onset, high variability in the number of polyps (usually less than 100 polyps), age-related gastrointestinal manifestations, and rapid development of “adenoma cancer” [48, 52]. Colorectal polyposis typically appears as the first symptom in most cases. CMMRD is reported to present with multisystem disorders. The extraintestinal diseases associated with CMMRD mainly include multiple café-au-lait maculae (CALM); early-onset brain tumors; leukemia, endometrial, ureteral, and renal pelvic carcinomas; and papillary migratory cell carcinoma of the bladder [7, 43, 47, 52, 53]. Because CALM has been identified as the most distinguishing phenotype and is detectable in almost all patients with CMMRD [49], attention to CALM is needed and emphasized by Durno et al. [53, 54]. Furthermore, clinical phenotypes, such as CALM, highly atypical hyperplasia, and early-onset tumors, may help differentiate CMMRD from other types of CAP. The clinical phenotypes of the four MMR genes are reported to differ. For example, patients with CMMRD-harboring mutations in PMS2 have a higher risk of developing left hemicolon cancer concurrent with brain tumors, while patients harboring MLH1 and MSH2 mutations have a higher risk of developing hematologic tumors [47].

Autosomal Dominant APC (-)/CAP

Polymerase Proofreading-Associated Polyposis (PPAP)

Discovery of PPAP

PPAP is an autosomal dominant disease caused by monoallelic germline mutations in POLE/POLD1 [55]. POLE and POLD1, DNA polymerase subunits, participate in proofreading the resulting daughter strand and excising the generated mismatch bases during DNA replication, ensuring the accuracy of replication [8, 56]. Mutations in the exonuclease domain (ED) of POLE/POLD1 affect the proofreading ability of the polymerase, resulting in the accumulation of base substitutions during replication, thereby causing hypermutations. This ultimately leads to CAP and a variety of cancers [8, 55, 57]. Palles et al. were the first to report families of CAP caused by germline mutations in POLE and POLD1, revealing that the two genes are susceptibility genes for APC (-)/CAP [8]. Briggs et al. [55] then named APC (-)/CAP with POLE/POLD1 mutations as PPAP.

Genetic Background of PPAP

The exonuclease domain (ED) plays a vital role in the proofreading activity of POLE and POLD1. Almost all the pathogenic mutations have been reported to be located within the ED of POLE/POLD1 [58, 59], while outside ED mutations are most likely nonpathogenic and not associated with PPAP [57]. According to the COSMIC database, the mutation distribution of POLE and POLD1 in colorectal tissue is 66.23% and 61.33% for missense mutations, 3.25% and 5.22% for nonsense mutations, and 12.12% and 21.78% for synonymous mutations, respectively (Fig. 2). Neither of the genes have been reported to have MCR. Of the two genes, POLE-L424V and POLD1-S478N mutations are most frequently reported in PPAP [60]. Patients harboring POLE mutations have a better prognosis and respond better to immune checkpoint inhibitor (ICI) therapy [8, 61, 62]. However, POLD1 mutations in PPAP are rare but more aggressive, and the efficacy of ICI therapeutics for these patients is unclear [63], indicating that screening for POLE and POLD1 genotypes may help identify patients who could benefit from immunotherapy. Concurrent mutations in POLE/POLD1 and other genes have cumulative effects such as POLD1-ATM and POLE-MSH2 simultaneous mutations leading to disease with more aggressive behavior [57]. Guidelines have included POLE/POLD1 in the genetic screening index for APC(-)/CAP [26].

Clinical Implications of PPAP

The intestinal lesions of PPAP overlap with those of CFAP and AFAP partially. Polyps appear in adulthood and range in number from 0 to 100 with a mean of 16, and the lifetime risk of CRC is 50–90% [64]. Extraintestinal symptoms, including endometrial, ovarian, breast, and brain cancers, as well as hypothyroidism, are reported frequently in PPAP [64,65,66]. Since the most prevalent are endometrial and ovarian cancers with high risk [57, 65], routine screening for mutations in POLE/POLD1 may help in the early diagnosis of patients with CAP who also have endometrial and ovarian lesions. For example, genotype–phenotype correlations for extraintestinal lesions are confirmed in PPAP. Both POLE and POLD1 have been reported to cause endometrial and brain cancers [8, 67]. However, hypothyroidism is only found in patients who have both NTHL1 and POLE mutations [66], while breast cancer is mainly associated with mutations in POLD1 [26, 58]. We suggest that when determining the genotype of PPAP, its phenotype be referred.

AXIN2-Associated Polyposis (AAP)

Discovery of AAP

AAP is an autosomal dominant disease caused by monoallelic germline mutations of AXIN2 [68]. AXIN2 is a negative regulator of the WNT signaling pathway that encodes for an axial inhibitory protein, and the product AXIN2 forms a catenin protein complex with APC, GSK3β, and CK1α in the WNT signaling pathway [69,70,71]. AXIN2 mutants (mtAXIN2) compete with wild-type AXIN2 (wtAXIN2) for binding to the β-catenin complex, preventing degradation and leading to β-catenin nucleation, thereby promoting tumorigenesis [72,73,74,75]. Lammi et al. reported a case in which an AXIN2 mutation led to the development of CAP with familial permanent hypoplasia, indicating that AXIN2 is a susceptibility gene of APC (-)/CAP [9]. Marvin and Rivera et al. further confirmed it, and we proposed to name this type of APC (-)/CAP as AAP [75, 76].

Genetic Background of AAP

The majority of AAP mutation sites in AXIN2 are concentrated at 1900-bp downstream of exon 7 [9, 75,76,77,78]. Furthermore, mutations in exon 7 region of AXIN2 are hotspot mutations causing hypodontia syndrome, CAP, and multiple cancers, indicating that exon 7 may be an MCR of AXIN2 [77]. The COSMIC database shows that in colorectal tissues, missense mutations in AXIN2 account for 39.93%, while nonsense mutations account for 5.30% and synonymous mutations account for 12.97% (Fig. 2). In addition to mutations in exonic regions, some synonymous mutations in AXIN2 were also shown to be associated with APC (-)/CAP [79].

Clinical Implications of AAP

The intestinal phenotype of AAP differs from that of AFAP or CFAP with a high degree of variability in the number, type, and location of intestinal polyps [75, 76]. The number of polyps ranges from 10 to 100 [77, 78], and odontoma is the most characteristic extraintestinal lesion. Beard et al. suggested that patients harboring the AXIN2 mutation could develop a variety of lesions, including oligodontia, ectodermal dysplasia (abnormal development of skin, hair, nails, or sweat glands), and CAP [77]. Furthermore, ovarian and endometrial cancers have been identified as potential extraintestinal manifestations of AAP [80, 81]. Since the dental anomaly is a characteristic extraintestinal manifestation of both FAP and AAP [82], it is recommended to include genetic screening for AXIN2 in CAP patients.

DUOX2-Associated Polyposis (DAP)

Discovery of DAP

DAP is an autosomal dominant disease caused by monoallelic germline mutations in DUOX2. DUOX2 encodes a double oxidase, an important NADPH oxidase family member that catalyzes the production of H2O2 from the parietal membrane of thyroid follicular epithelial cells [83]. Mutations in DUOX2 have been linked to colorectal diseases, such as inflammatory bowel disease (IBD) [84] and colorectal cancer [85], and it has been proposed that DUOX2 plays an important role in innate immune responses in the intestinal mucosa and maintains immune homeostasis by producing H2O2, which forms the first line of defense of the intestinal epithelium [86]. Yang et al. have recently identified DUOX2 as a susceptibility gene for CAP. The mutation in DUOX2 is reported to cause endoplasmic reticulum (ER) retention and induction of unfolded protein response (UPR), which results in abnormal cell proliferation and leads to CAP development [10]. We proposed to name this type of APC (-)/CAP as DAP.

Genetic Background of DAP

According to Yang’s report, the truncated protein hDUOX2 is found to be overexpressed in adenomas, and the germline nonsense mutation (K530X) of DUOX2 is considered to play a key role in the pedigree in relation to adenomatous polyposis [10]. In addition, two unrelated APC-negative patients were found to carry DUOX2 missense variants (R1110 and L1343F), which may exert a negative influence on the function of hDuox2 [10]. According to the COSMIC database, missense mutations account for 60.99%, nonsense mutations account for 2.13%, and synonymous mutations account for 17.73% in DUOX2 in colorectal tissues (Fig. 2). However, the presence of MCR or hotspots in DUOX2 is uncertain.

Clinical Implications of DAP

Yang’s report found three DAP patients with intestinal adenomatous polyps ranging from 10 to 100 bp [10]. The proband, a female, was detected to have 20–30 renal tubular adenomas in her proximal colon at the age of 26. At the age of 24, her sister was discovered to have hundreds of adenomatous polyps primarily in the right colon. Their mother died of colon cancer, despite a history of intestinal polyps [10]. Furthermore, endoscopy of the proband’s maternal uncle, who was 51 years old at the time, revealed colon adenomas and adenocarcinomas [10]. Additional studies are required to understand specific intestinal phenotypes and extraintestinal manifestations of DAP.

Interactions Between the Genes of APC (-)/CAP

The APC (-)/CAP susceptibility genes have been shown to interact with one another, which may influence the development and phenotype of the disease. For example, BER, polymerase proofreading activity, and MMR genes all play important roles in maintaining accuracy during DNA replication, and interactive synergies between these three systems have been demonstrated during the onset and progression of CAP (Fig. 3).

Fig. 3
figure 3

Interaction between APC (-)/CAP susceptibility gene. MUTYH interacts with MSH6, MMR gene interacts with POLE/POLD1, POLD1 is involved in the BER signaling pathway, and POLE interacts with NTHL1

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Correlation Between BER and MMR

MUTYH is reported to interact with MSH6 during DNA repair [87]. Patients with CRC-harboring MUTYH mutations have a higher rate of MSH6 mutations compared to those without MUTYH mutations [88]. Furthermore, patients who have both MUTYH and MMR gene mutations are at a significantly higher risk of developing CRC [89]. These findings suggest that MUTYH-mediated BER prevents mutations during DNA replication by working in conjunction with MMR genes.

Correlation Between Polymerase Proofreading Genes and MMR

POLD1 (and possibly POLE) has been reported to be involved in both the BER and MMR pathways [55]. A study revealed that patients harboring POLE/POLD1 mutations have a higher rate of mutations in MMR genes [57, 90]. However, mutations in POLD1 have a lesser impact on MMR but are associated with microsatellite instability [91]. Furthermore, Shlien et al. revealed that all of the patients in their study who had CMMRD hypermutations (abnormally high somatic mutations) also had POLE/POLD1 somatic mutations, indicating a synergistic relationship between polymerase proofreading genes and MMR genes [92].

Correlation Between Polymerase Proofreading Genes and BER

POLD1 (and possibly POLE) has been reported to participate in the BER pathway [55]. A population study by Lorca et al. reported a case of a patient harboring a concurrent mutation in NTHL1 and POLE [66], indicating a synergistic effect of NTHL1 and POLE.

Conclusions and Future Perspectives

In summary, as shown in Fig. 4, the six APC (-)/CAP types can be divided into two groups based on their genetic characteristics: (1) autosomal recessive APC (-)/CAP (including MAP, NAP, and CMMRD) and (2) autosomal dominant APC (-)/CAP (including PPAP, AAP, and DAP) or three categories based on the roles of these genes: (1) APC (-)/CAP by BER pathway (including MAP and NAP), polymerase proofreading pathway (including PPAP), and mismatch repair pathway (including CMMRD) are involved in proofreading and repair during DNA replication; (2) APC(-)/CAP by WNT signaling pathway regulation (including AAP); and (3) DAP (Fig. 4). The interaction between multiple susceptibility genes produces a partial synergy for the onset and progression of CAP. Details are shown in Table 1. In addition, several genes, such as PTEN, GREM1, and GSK3β, are potential susceptibility genes for CAP(CRC) [1, 93].

Fig. 4
figure 4

A Venn diagram shows classification of APC (-)/CAP. Based on genetic characteristics, APC(-)/CAP can be divided into (1) autosomal recessive APC (-)/CAP (including MAP, NAP, and CMMRD) and (2) autosomal dominant APC (-)/CAP (including PPAP, AAP, and DAP). Based on the roles of the genes, APC(-)/CAP can be divided into (1) APC (-)/CAP by BER pathway (including MAP and NAP), polymerase proofreading pathway (including PPAP), and mismatch repair pathway (including CMMRD) are involved in proofreading and repair during DNA replication; (2) APC(-)/CAP by WNT signaling pathway regulation (including AAP); and (3) DAP

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Table 1 Detailed description of genetic characteristics of APC (-)/CAP, CAP types, pathogenic mechanisms, mutation cluster region or polymorphism, pathogenesis, interactions between susceptibility genes, and clinical phenotype, including number of polyps and extraintestinal lesions
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Interaction of genes associated with APC (-)/CAP suggests that CAP is a polygenic disease, with CAP occurring as a result of the synergistic effects of multiple genes. In terms of genetic characteristics, APC (-)/CAP has dominant and recessive inheritance characteristics, as well as germline mutation characteristics of monoallelic and diallelic mutations. It indicates that genes associated with APC (-)/CAP have different inheritance patterns; however, dominant genes and diallelic mutations are clearly more harmful. Moreover, all the reported genes inherited in autosomal dominant patterns are monoallelic, whereas all genes inherited in autosomal recessive patterns are diallelic. It is worth investigating whether there is a correspondence between the two. In terms of clinical phenotype, there are variations between the number of polyps, the probability, timing of intestinal polyp malignancy, and extraintestinal lesions between different APC (-)/CAP. Identifying pathogenic genes by their clinical phenotypes (e.g., dominant or recessive genetic characteristics combined with the number of polyps and other phenotypes to determine their corresponding pathogenic genotypes) can significantly improve the detection rate of pathogenic genes. This approach could be used for future studies. In terms of clinical treatment, studies on the association between APC (-)/CAP susceptibility genes could be useful for the early diagnosis and treatment of patients. For example, both MAP and NAP mediate their pathogenic effects by altering the BER signaling pathway, so therapies targeting the BER signaling pathway could be effective for the treatment of both APC (-)/CAP types despite the difference in mutation pattern. However, MAP and AAP mediate their pathogenic effects via different signaling pathways. Despite the shared APC (-)/CAP, different therapeutic approaches are required for the two treatments of patients with MAP and APP.

There are some limitations. For treatments options for APC (-)/CAP, since genotype–phenotype diversity is likely a source of difficulty for diagnostics and treatment, further research is required to better understand the key components of APC (-)/CAP susceptibility and optimal management strategies. And for Modifier alleles, there is evidence to suggest that phenotypic differences are caused by modifier alleles that can influence individual susceptibility to cancer by enhancing or suppressing disease initiation, growth, and/or progression. Modifier alleles are present in APC (-)/CAP, however, more evidence is needed for deep research, and modifier alleles may be an important direction for future research on APC (-)/CAP.

In this review, we elaborate on the genetic features of APC (-)/CAP as well as the genotype–phenotype relationship comprehensively. Although the cause of many APC (-)/CAP remains unknown, the use of family-linkage analysis techniques, as well as the availability of high-throughput sequencing, may aid in accurately defining APC (-)/CAP types and identifying unknown APC (-)/CAP susceptibility genes. Designing therapeutic strategies targeting different genes and corresponding signaling pathways would benefit such patients. Furthermore, additional studies on CAP as a precancerous lesion in CRC will provide new insights into the management of CRC. To our knowledge, this is the first review that provides an outline of pathogenic genes causing autosomal recessive and dominant CAP and clinical phenotypes with APC mutation-negative CAP.