Hereditary Colorectal Cancer Syndromes: Comparison
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Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Hereditary CRC syndromes account for approximately 5–10% of all CRC, with a lifetime risk of CRC that approaches 50–80% in the absence of endoscopic or surgical treatment. Hereditary CRC syndromes can be phenotypically divided into polyposis and non-polyposis syndrome, mainly according to the conditions of polyps. 

  • hereditary colorectal cancer syndromes
  • predisposing genes
  • prevention strategies

1. Adenomatous Polyposis Syndromes

Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome. FAP is a rare autosomal dominant disorder characterized by multiple adenomatous polyps of the gastrointestinal mucosa and various extraintestinal lesions, with a 100% lifetime risk of CRC if not treated [6][1] (Table 1). FAP can be classified into classic and attenuated types. Attenuated FAP (AFAP) is a milder form, with a delayed age of onset, fewer polyps (0–100), a lower overall risk of CRC (60–80%), and mostly in the right hemicolon. Early identification and management of FAP are essential due to the nearly 100% lifetime risk of CRC without intervention. Germline mutations in the APC (MIM: 611731) gene can be detected in more than 90% of FAP cases. APC testing should be taken into consideration when one of the following occurs: (1) more than 20 adenomas in the colorectum over the course of the patient’s lifetime, (2) a family history of FAP, or (3) 10 cumulative adenomas discovered after a colonoscopy. Screening colonoscopy has been proven to lower the risk of CRC in patients with FAP until the polyp burden is unmanageable by endoscopic methods. In families with classic FAP, a high-quality colonoscopy is recommended beginning between the ages of 10–15 years and repeated every year if an APC variant is identified. Early colonoscopy initiation may be taken into consideration for patients who have a family history of CRC with very early onset. Due to the attenuated character of AFAP, colonoscopy can be started at a slightly later age (late teens) and repeated every 1–2 years [6,7][1][2]. Extraintestinal manifestations in FAP involve duodenal adenomas, desmoids, thyroid tumors, and central nervous system tumors [8,9][3][4]. Consequently, monitoring and treating extracolonic lesions is also extremely crucial.
Table 1.
Risk of hereditary colorectal cancer syndromes.
Cancer Syndromes CRC Lifetime Risk Average Age of CRC Diagnosis Age of Screening Initiation Intervals of Screening Incidence in CRC Population
Sporadic 4.3% 67 50 10 65–85%
FAP (AFAP) 100% (70%) 40 (55) 10–15 1 ~1%
MAP 43–100% 48 20–25 1–3 <1%
JPS 39% 44 15 1–3 <1%
PJS 39% 42–46 15 2–3 <1%
PHTS 9–18% 35 35 5 <1%
LS 50–80% 45 20–25 1–2 2–3%
Note: FAP, familial adenomatous polyposis; AFAP, attenuated familial adenomatous polyposis; MAP, MUTYH-associated polyposis; JPS, juvenile polyposis syndrome; PJS, Peutz–Jeghers syndrome; PHTS, PTEN-hamartoma tumor syndrome; LS, Lynch syndrome.
Polymerase proofreading-associated polyposis (PPAP) has been identified as a novel adenomatous polyposis syndrome, which is an autosomal dominant diseasecaused by germline pathogenic variants in the exonuclease (proofreading) domains of POLE (MIM: 174762) and POLD1 (MIM: 174761) [10][5]. Although the clinical phenotype has not been established, the available evidence showed that PPAP has a high-penetrant susceptibility to polyposis, CRCs, and other extracolonic tumors.
MUTYH-associated polyposis (MAP) is considered to be the second most common adenomatous polyposis syndrome. MAP is an autosomal recessive condition with high penetration and is linked to biallelic germline variants in the DNA glycosylase gene MUTYH (MIM: 604933). The identification of MUTYH lays the foundation for the base excision repair (BER) pathway in polyposis and CRC. Carriers of biallelic MUTYH variants exhibit a high lifetime risk of CRC, while it is debatable whether patients with a monoallelic mutation have an increased genetic susceptibility to CRC (1.5–2 fold) [11,12][6][7]. Patients with MAP display a very broad and diverse clinical spectrum, which is generally more compared to AFAP. Therefore, endoscopic surveillance is recommended from age 18 with a 1–2 years interval, according to the findings [13][8].
Recently, two novel adenomatous polyposis-predisposing syndromes with autosomal recessive inheritance have been proposed. NTHL1 (MIM: 602656) is the second DNA glycosylase gene identified for the BER pathway [14][9]. Biallelic mutations of MSH3 (MIM: 600887), an MMR gene not linked to LS, were detected in families with polyposis and gastrointestinal malignancy, thereby identifying as another recessive subtype of colorectal adenomatous polyposis syndromes [15][10].
Constitutional MMR deficiency syndrome (CMMRD) is an uncommon, inherited cancer predisposition syndrome caused by biallelic germline pathogenic variants in four MMR genes, MLH1 (MIM: 120436), MSH2 (MIM: 609309), MSH6 (MIM: 600678), and PMS2 (MIM: 600259). Such cases with biallelic germline mutations in the MMR gene are distinct from classic LS. Patients with CMMRD have a higher risk of developing cancers as early as childhood and adolescence. It was estimated that 80% of patients experience their first cancer before 18 years old [16][11].

2. Hamartomatous Polyposis Syndromes

A hamartoma is a disordered and uncontrolled proliferation of normal cells. Based on this, the hamartomatous polyposis syndromes are distinguished from the adenomatous polyposis syndromes. Even though there is no direct evidence, hamartomatous polyposis syndromes have an estimated prevalence of 1/100,000 [17][12]. The types of gastrointestinal hereditary hamartomatous syndromes mainly include Peutz–Jeghers syndrome (PJS), PTEN-hamartoma tumor syndrome (PHTS), and juvenile polyposis syndrome (JPS). The evaluation criteria have been created by National Comprehensive Cancer Network (NCCN). The patient’s medical history, a skin-focused physical examination, and the feature of gastrointestinal polyps should be taken into consideration during the diagnostic process. Surprisingly, colonoscopy almost reduces the risk of CRC to the level of the general population.
Peutz–Jeghers Syndrome (PJS) is a rare inherited autosomal dominant syndrome known as mucocutaneous pigmentations because nearly all individuals exhibit melanotic macules or “spots” on their lips, buccal mucosa, fingertips, and toe tips. Hamartomatous polyps are mainly found in the small intestine (60–90%), colon (50–64%), or extraintestinal organs such as the gallbladder or bladder [18][13]. PJS is linked to an increased risk of CRC, and the majority of cases result from mutations in the tumor suppressor gene LKB1/STK11 (MIM: 602216).
Juvenile polyposis syndrome (JPS) is also an inherited autosomal dominant syndrome driven by mutations in either BMPR1A (MIM: 601299) or SMAD4 (MIM: 600993) [19][14]. Patients with JPS are characterized by multiple hamartomatous polyps in the gastrointestinal tract, primarily colon polyps, occasionally stomach polyps, and infrequently small intestine polyps. There is no extra risk of non-gastrointestinal cancer reported in JPS.
PTEN-hamartoma tumor syndrome (PHTS) is a disorder caused by mutations in the tumor suppressor gene PTEN (MIM: 601728) and is linked to increased risk for cancer in multiple organs, including the breast, thyroid, kidney, and skin. The gastrointestinal manifestations of PHTS are mainly gastrointestinal hamartomatous polyps. Although there is a moderate risk of CRC, colonoscopic surveillance can be delayed until after the age of 35. Notably, although most cases of PHTS correspond to Cowden syndrome (CS), PHTS also includes Bantayan–Riley–Ruvalcaba syndrome (BRRS).

3. Other Polyposis Syndromes

Serrated polyposis syndrome (SPS) is a hereditary condition known as multiple serrated polyps throughout the colorectum, including hyperplastic polyps, sessile serrated lesions, sessile serrated lesion with dysplasia, and conventional serrated adenomas [20][15]. Patients with SPS have an increased risk (16–29%) of CRC [21][16]. RNF43 (MIM: 612482), along with BRAF (MIM: 164757) mutation, has been identified in rare cases of serrated polyposis [22][17]. However, high-penetrance germline mutations have not been found yet.
Mixed polyposis syndrome (MPS) is a rare autosomal dominant disease and is characterized by the presence of multiple histologic polyps, including adenomas, hamartomas, and serrated lesions, with an increased risk of CRC. Some affected people have been found to have GREM1 (MIM: 603054) germline variants [23,24][18][19], while the genetic basis of most MPS families is still unclear, and there are insufficient data to prove the optimal monitoring interval.

4. Non-Polyposis Syndromes

LS is the most common hereditary non-polyposis syndrome, accounting for 2–4% of all CRCs, and was initially identified by Lynch in 1996 [25,26][20][21]. LS is an autosomal dominant condition caused by a germline mutation in one of the DNA MMR genes MLH1, MSH2, MSH6, and PMS2, which preserve genome integrity by postreplicative proofreading and editing. LS has a significantly higher risk of CRC, and an estimated 60–80% of MMR mutations will lead to CRC progression [27][22]. Patients with LS also have an increased risk of developing extra-colon cancers such as endometrial, ovarian, stomach, and small intestine cancers, especially if they have mutations in the MLH1, MSH2, and MSH6 genes.
In contrast to polyposis syndromes, LS does not exhibit any characteristic endoscopic signs, making it a particularly difficult condition to diagnose. The Amsterdam criteria, which had been developed in 1991, served as the basis for the initial diagnosis [28][23]. These criteria concentrated on age at onset and family history, which could help to select families for genetic identification research. Following the discovery of a germline mutation in an MMR gene, Bethesda guidelines further use microsatellite instability (MSI) to select patients for genetic testing [29][24]. Neither of these criteria is optimal in identifying LS cases, prompting the recommendation to offer genetic testing to all newly diagnosed CRC patients [30,31][25][26]. All people with a molecular diagnosis of LS should have a colonoscopy starting at 20–25 [7][2]. Vasen et al. tracked 205 LS families and found a decreased incidence of CRC with colonoscopy intervals of 1–2 years vs. 2–3 years [32][27]. NCCN recommendations urge surveillance colonoscopy every 1–2 years for mutation carriers [33][28]. Given the decreased cancer risk in MSH6 and PMS2 mutation carriers, surveillance at age 25–30 may be considered [34][29].
Familial Colorectal Cancer Type X (FCCTX) is a kind of hereditary non-polyposis CRC with autosomal dominant inheritance, which also meets Amsterdam criteria Ⅱ. Unlike LS, its MMR gene has no germline mutation and shows microsatellite stability (MSS) [35][30]. This genetic difference is important because it determines the management strategies. The age at diagnosis of FCCTX is later than that of LS (approximately 40 years), and they do have a 2-fold increased risk compared to the general population. Although there is currently no standard follow-up protocol for monitoring and intervention, patients are recommended to get screening at the age of 40, but not before.

References

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