The hereditary polyposis syndromes are a heterogeneous group of diseases characterized by multiple intestinal polyps. Most of these syndromes predispose to colorectal cancer, and they are divided into two groups on the basis of their pathology and clinical features. The first group has a high risk of colorectal cancer and is associated with the presence of adenomas of the bowel (adenomatous polyposis) and the second group is associated with hamartomas, although adenomas may also occur (hamartomatous polyposis).
Hereditary adenomatous polyposes have been traditionally divided into three syndromes; familial adenomatous polyposis (FAP), Gardner syndrome (GS) and Turcot's syndrome. Although FAP, GS and Turcot's syndrome were originally considered as three separate conditions, they are now generally thought to be different manifestations of the same disorder, particularly as retinal lesions have been reported in each of these syndromes (Stein and Brady, 1988; Berk et al., 1988; Munden et al., 1991).
1.1.1 Familial adenomatous polyposis, Gardner syndrome and Turcot's syndrome
FAP was first reported by Chargelaigue in 1859, when he described this condition in two patients (Chargelaigue, 1859). FAP is characterized by an early onset of multiple adenomatous polyps of the colon and rectum. The high risk of colorectal cancer related to FAP was described as early as 1887 by Smith, and a few years later Handford recognized that sporadic adenomas could give rise to cancers (Smith, 1887; Handford, 1890). FAP patients develop colorectal cancer usually by the fourth decade of life and they are also at increased risk for several extracolonic malignancies, like cancers of the thyroid, small intestine, stomach, and brain (Jagelman et al., 1988; Giardiello, 1995). Varieties of benign extracolonic features have also been reported, the most common being polyps in the upper gastrointestinal tract (Ranzi et al., 1981; Järvinen et al., 1983). Other important diagnostic features reported in FAP patients are ocular, cutaneous, and skeletal manifestations (Bussey 1975; Krush et al. 1988). Cutaneous lesions include epidermoid cysts, fibromas, lipomas and sebaceous cysts. Desmoid tumors are fibromatous lesions occuring in the extremities, abdominal wall and the mesentery of approximately 10% of FAP patients (Clark and Phillips, 1996; Gardner and Richards, 1953). The most common skeletal manifestations are osteomas which develop in the skull, long bones and characteristically in the mandible at the angle of the jaw (Brett et al., 1994).
Although, approximately 1 in 10,000 individuals are affected with FAP, less than one percent of all colon cancer cases occur in FAP patients, in part because of prophylactic colectomies (Boland et al., 1995; Kinzler and Vogelstein, 1998).
The milder variant of FAP is the so-called attenuated adenomatous polyposis coli (AAPC) which is characterized by a reduced number of intestinal polyps (less than 100 polyps) and delayed age of onset (approximately 10 to 15 years later than those observed in patients with classical FAP), although the lifetime risk for colorectal cancer remains unchanged (Leppert et al., 1990; Spirio et al., 1992).
The most common variant of FAP is the Gardner syndrome (GS). This syndrome was first reported by Gardner and his colleagues when they described a group of patients with multiple colonic adenomas and familial colon cancer like those in FAP, but who also had osteomas of the skull and multiple epidermal cysts and other skin lesions (Gardner and Richards, 1953; Gardner, 1962). Soft-tissue tumors, dental abnormalities, and congenital hypertrophy of the retinal pigment epithelium (CHRPE) were later added to the manifestations of the syndrome (Gardner and Richards, 1953; Gardner, 1962; Lewis et al., 1984; Stein and Brady, 1988).
In 1959, Turcot and colleagues reported two siblings with adenomatous polyposis coli, one of them also developed a medulloblastoma of the spinal cord and the other developed glioblastoma of the frontal lobe (Turcot, 1959). Turcot's syndrome is characterized by adenomas of the colon, tumors of the central nervous system and multiple skin lesions (Turcot et al., 1959; Everson and Fraumeni, 1976). The majority of Turcot's syndrome are thought to be variants of FAP, but in most cases patients have less than 100 colonic adenomas which is not typical for FAP (Hamilton et al., 1995).
Hamartomas are developmentally disorganized, benign tumors, which may occur in many organ systems. Hamatomatous polypose syndromes are traditionally classified into four subgroups; Peutz-Jeghers syndrome (PJS), juvenile polyposis (JP), Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR), although most recent studies have suggested that CS and BRR might be phenotypic variants of the same disorder.
In 1896 Hutchinson described twins with mucocutaneous pigmentation; one of them died of an intussusception and the other developed breast cancer (Hutchinson, 1896). The disease was later more carefully described by Peutz and Jeghers (Peutz, 1921; Jeghers et al., 1949). The main feature of a Peutz-Jeghers syndrome (PJS) is the hamartomatous polyps of the gastrointestinal tract. The polyps occur primaly in the small intestine, but they can also be found in the colon and stomach. The characteristic feature of Peutz-Jeghers polyp is a core of smooth muscle arising from the muscular mucosa that extends into the polyp like the trunk and branches of a tree. Another characteristic feature of PJS is mucocutaneous pigmentation. Usually these melanin spots are flat and dark brown, and they are located on the lips, buccal mucosa and hands (Spiegelman et al., 1995).
In the early literature cancer was not associated with PJS. Later, reports indicating an increased risk of gastrointestinal cancer in PJS appeared (Utsunomiya et al., 1975; Folley et al., 1988). It is now well documented that PJS patients are at an increased risk for both gastrointestinal and extra-gastrointestinal cancer. It has been estimated that PJS patients have an 18-fold increased risk of adenocarcinoma as compared with the general population (Giardiello et al., 1987). The most common gastrointestinal cancers in PJS are cancers of colon, stomach and small intestine, whereas cancers of the pancreas, breast, ovary and testis are frequently diagnosed extraintestinal cancers (Dozois et al., 1970; Wilson et al., 1986; Giardiello et al., 1987; Spigelman et al., 1989, Hizawa et al., 1993; Boardman et al., 1998).
Cowden syndrome (CS), also known as multiple hamartoma syndrome or multiple hamartoma and neoplasia syndrome, was first described by Lloyd and Dennis (Lloyd and Dennis 1963). CS is characterized by multiple hamartomatous lesions, especially of the skin, mucous membranes, breast, thyroid and gastrointestinal tract, and by a high incidence of malignant tumors of the breast and thyroid gland (Starink et al., 1986; Eng, 1997). The life time risk of CS patients to develop breast cancer is estimated to be 25-50% and the risk for thyroid cancer is 3-10% (Brownstein et al., 1978; Starink et al., 1986; Hanssen and Fryns, 1995; Longy and Lacombe, 1996). CS may also include central nervous system manifestations, like macrocephaly, Lhermitte-Duclos disease or dysplastic gangliocytoma of the cerebellum, and sometimes also mental retardation (Albrecht et al., 1992; Eng et al., 1994).
1.2.3 Bannayan-Riley-Ruvalcaba syndrome
This disorder was first described in a single patient by Bannayan and colleagues in 1971. Few years later Zonana and colleagues described the same disorder in a father and 2 sons (Zonana et al., 1976). Bannayan-Riley-Ruvalcaba syndrome (BRR) which is also known as Bannayan-Zonana syndrome (BZS), Ruvalcaba-Myhre-Smith syndrome and Riley-Smith syndrome, is a congenital syndrome with characteristic features of macrocephaly, cognitive and motor dysfunction, subcutaneous and visceral lipomas and hemangiomas, pigmentary spotting of the penis, and juvenile type of polyps in the colon (Bannayan, 1971; Zonana et al., 1976; Gorlin et al., 1992). Unlike in CS, an increased risk of malignancy has not been documented of patients with BRR (Marsh et al., 1998a).
Although CS and BRR have distinct phenotypic features, the presence of macrocephaly, intestinal polyposis, and lipomas in both diseases suggests a partial clinical overlap. Moreover, the presence of features common in CS and BRR within the same family has been reported in a few kindred (Fargnoli et al., 1996).
Juvenile polyposis syndrome was first described by McColl and colleagues in 1964. Two years later Smilow and colleagues reported the first familial cases of this syndrome (McColl et al., 1964; Smilow et al., 1966). Juvenile polyposis (JP) is a rare condition characterized by the occurrence of multiple juvenile polyps in the gastrointestinal tract. It is estimated that JP affects approximately 1 in 100,000 people (Burt et al., 1993). The most widely accepted definition for JP requires any one of the following: (a) more than five juvenile polyps of the colorectum; (b) juvenile polyps throughout the gastrointestinal tract; (c) any number of juvenile polyps with a family history of juvenile polyposis (Jass et al., 1988). The number of polyps in JP patients can vary between few to few hundred, which is clearly less than in FAP (Veale et al., 1966, Stemper et al., 1975; Järvinen et al., 1993). Macroscopically, the polyps are 5-50 mm in size and have a spherical head and a narrow stalk. Microscopically, a polyp contains dilated or cystic epithelial tubules and an excess of lamina propria. The muscularis mucosa does not reach to the stalk, in contrast to Peutz-Jeghers polyps (Järvinen, 1993; Desai et al., 1995).
Juvenile polyposis differs from PJS by the absence of consistent extraintestinal manifestations, which could serve as diagnostic markers in symptom-free family members. However, a variety of associated malformations have been detected in many patients with juvenile polyposis. These include arteriovenous malformations, porphyria, psoriasis, mental retardation, congenital heart disease, cleft lip/palate, epilepsy, hereditary haemorrhagic telangiectasia (HHT), digital clubbing, hypertrophic pulmonary osteoarthropathy and malrotation of the gut (Restrepo et al., 1978; Cox at al., 1980; Järvinen et al., 1993; Desai et al., 1998, Inoue et al., 1999).
Juvenile polyps were originally defined as non-neoplastic hamartomatous epithelial tumors with no potential for malignant or premalignant transformation, and this is still largely true for solitary juvenile polyps (Rozen and Baratz, 1982; Järvinen and Franssila, 1984; Jass et al., 1988; Nugent et al., 1993). The adenomatous and carcinomatous changes in juvenile polyps were originally considered to be occasional findings (Stemper et al., 1975; Liu et al., 1978; Billingham et al., 1980; Friedman et al., 1982). The malignant potential of juvenile polyposis was first recognized in the 1970s and, at present, it is agreed that juvenile polyposis is a precancerous condition. The risk of JP patients to develop gastrointestinal malignancy has been estimated to be from 9 percent to as high as 50 percent (Järvinen and Franssila, 1984; Jass et al., 1988; Howe et al., 1998a; Agnifili et al., 1999). Recently, 24 studies reporting gastrointestinal cancers among JP patients______________ were reviewed and it was concluded __________that among 133 familial JP patients, there were 42 cases of colorectal cancer (31.5%), 15 cases of stomach cancer (11.3%), and one case each of pancreatic and duodenal cancer (0.75%). Overall, 58 of these 133 patients (44.4%) developed gastrointestinal cancer (Howe et al., 1998a).
Hereditary mixed polyposis syndrome (HMPS) is a rare condition in which patients develop characteristic polyps of the large bowel. These polyps closely resemble juvenile polyps, but show significant histological differences. Also adenomatous and hyperplastic polyps may occur in affected individuals. Typically less than 15 polyps are found at colonoscopy and there is no extracolonic disease associated with the development of the polyps (Whitelaw et al., 1997). HMPS is also known to predispose to colorectal cancer. It is still unclear whether HMPS is a variant of juvenile polyposis or a distinct disease (Murday and Slack, 1989).
The inherited nature of FAP was first noted by Bickersteth in 1890, when he described a mother and son with the condition (Bickersteth, 1890). It took almost one hundred years before Herrera and colleagues described a constitutional interstitial deletion of chromosome arm 5q in a patient with Gardner syndrome (Herrera et al., 1986). Like Herrera et al., also Kobayashi et al. (1991) described an interstitial deletion of 5q in a boy with Gardner syndrome, mental retardation and multiple minor anomalies. This deletion involved chromosome band 5q22.1-q31.1 (Kobayashi et al., 1991). Similarly, Hockey and colleagues (1989) described an interstitial deletion of 5q15-q22 in two brothers with FAP (Hockey et al., 1989). These observations suggested that a tumor suppressor gene on chromosome 5q could be responsible for the condition of these patients. This proposal was later confirmed by linkage analysis, which established the linkage of FAP to chromosome 5q21 markers in all the kindreds analyzed (Leppert et al., 1987; Bodmer et al., 1987). At the same time, as the linkage to chromosome 5q was found, Nakamura and colleagues (1988) made a linkage study with three FAP and three Gardner syndrome families, and succeeded in refining the genetic localization of the polyposis locus to a position at 5q21-q22 (Nakamura et al., 1988). Four genes were later mapped to this region; MCC, TB2, SRP19 and APC (Kinzler et al., 1991; Joslyn et al., 1991).
One of these genes, APC, was found to be mutated in the germline of FAP patients (Nishisho et al., 1991; Groden et al., 1991) and later also in sporadic colorectal tumors (Nishisho et al., 1991, Miyoshi et al., 1992; Powell et al., 1992). The APC gene has been examined in over 500 FAP kindreds and coding region mutations are detected in majority of them (Nagase and Nakamura, 1993; Powell et al., 1993). APC is a large gene and the majority of mutations seen in FAP patients occur in the first half of the last exon (the last exon contains a 6579 bp uninterrupted open reading frame) (Miyoshi et al., 1992). The manifestations of FAP can vary considerably and in some cases this is due to a specific mutation. CHRPE for example is associated with truncating mutations between codons 463 and 1387 (Olschwang et al., 1993; Wallis et al., 1994; Caspari et al., 1995). Another example is AAPC. Spirio and colleagues (1993) have shown that terminating mutations located close to the 5' end of APC gene result in a milder phenotype of FAP (Spirio et al., 1993). However, patients with identical mutations can develop dissimilar clinical features. For example some patients with identical truncating mutations develop features of GS while others do not (Giardiello et al., 1994).
Mutations in APC gene have also been found in patients with Turcot's syndrome, although the correlation between APC mutations and Turcot's syndrome is not straightforward (Van Meir, 1998). Hamilton and colleagues (1995) studied 14 Turcot syndrome families and they detected germline APC mutation in ten of them. In addition, germline mutations in the mismatch-repair gene MLH1 or PMS2 were found in two families. Their findings indicate that Turcot's syndrome can result from two distinct types of germline defects: mutation of the APC gene or mutation of a mismatch-repair gene (Hamilton et al., 1995).
The APC gene encodes a cytoplasmic protein that can bind to and promote the degradation of β-catenin. β-catenin binds to members of the Tcf family of transcription factors and activates gene transcription. Recently, the c-MYC oncogene was identified as a target gene in this pathway (He et al., 1998). It was further proposed that in normal colorectal epithelial cells, wild type APC prevents β-catenin from forming a complex with Tcf-4 and activating c-MYC. In colorectal tumors with APC mutations or activating β-catenin mutations an increased β-catenin/Tcf-4 activity leads to overexpression of c-MYC, which then promotes neoplastic growth (He et al., 1998).
There has been few attempts to localize the gene for PJS. In 1996, Markie and colleagues reported a pericentric inversion of chromosome 6 in a patient with PJS (Markie et al., 1996), but a linkage was not detected in PJS families (Tomlinson et al., 1996). Another locus was suggested on chromosome band 1p32-34, a result that was obtained by the linkage analysis of two families. However, the linkage study with extended pedigrees conflicted the previous results (Tomlinson and Houlston, 1997) and the analysis of new set of families excluded linkage to 1p (Tomlinson et al., 1996).
The PJS gene was finally localized in 1997 by Hemminki and colleagues. A novel strategy was used for the localization. Multiple PJS polyps from a single PJS patient were used in comparative genomic hybridization (CGH). It revealed a subtle loss at 19p in 6 of 16 polyps examined. LOH analysis using microsatellite markers from 19p confirmed the CGH results. 12 PJS families of different ethnic origin were used for linkage analysis and all families showed the linkage to 19p13.3. Other studies confirmed 19p13.3 as the PJS predisposing locus (Amos et al., 1997; Mehenni et al., 1997; Olschwang et al., 1998).
The gene predisposing to PJS was identified in 1998 (Hemminki et al., 1998). First, the PJS region was narrowed down to 800 kilobases (kb) by meiotic recombination mapping in PJS families (around markers D19S886 and D19S883). Transcripts in this interval were identified by database searches and direct cDNA selection. The 27 transcripts identified in this region were screened for mutations, and truncating germline mutations were identified in LKB1(STK11) gene locating in 19p13.3. At the same time, Jenne and colleagues (1998), demonstrated mutations in LKB1 (STK11) in five PJS patients (Jenne et al., 1998). These finding were confirmed also by other groups. Resta and colleagues reported four germline mutations in nine PJS cases and Wang and colleagues reported germline mutations in seven out of 12 PJS patients, respectively (Resta et al., 1998; Wang et al., 1998a). Gruber and colleagues studied six families with PJS from the John's Hopkins Polyposis Registry, and they confirmed linkage to 19p13.3. They also identified germline mutations in LKB1 in all six families studied (Gruber et al., 1998).
LKB1 was originally identified as a serine/threonine protein kinase expressed in human fetal liver (Nezu, GenBank accession number U63333). LKB1 shows strong homology with the cytoplasmic serine/threonine kinase XEEK1 of Xenopus laevis (Su et al., 1996) and shows weaker similarity to many other protein kinases. Most of the LKB1 mutations identified in PJS are truncating and are located in the kinase core domain of the protein (Hemminki et al., 1998; Jenne et al., 1998; Mehenni et al., 1998; Ylikorkala et al., 1999). It is likely that LKB1 is a tumor-suppressor gene, since loss of the normal allele was observed in the polyps from a PJS patient with germline mutation on the other allele (Hemminki et al., 1998). However, the frequency of LKB1 somatic mutations in a wide range of sporadic tumors seem to be low (Avizienyte et al., 1998; Avizienyte et al., 1999). Only a small number of somatic changes have been reported in sporadic colorectal, breast and gastric cancers (Resta et al., 1998; Bignell et al., 1998; Park et al., 1998). An exception was the study by Dong and colleagues (1998), who reported frequent mutations in LKB1 in left-sided colon cancers (Dong et al., 1998). LKB1 promoter hypermethylation has been demonstrated in a few cases of colorectal and testicular tumors, but in general, it seems to be a rare event in sporadic cancers (Esteller et al., 1999, submitted). LKB1 appears to be restricted to the genetic pathway of tumorigenesis in gastrointestinal hamartomas and adenocarcinomas of PJS patients and other tumor types developing in PJS patients.
CS and BRR are both autosomal dominantly inherited syndromes. The gene responsible for CS was localized by a genome wide search using dinucleotide repeat markers at 10-20 cM intervals. Nelen and colleagues (1996) examined 12 CS families and a maximum lod score of 8.92 at theta = 0.02 was obtained with the marker D10S573, locating on chromosome band 10q22-q23 (Nelen et al., 1996). It was suggested that the susceptibility gene for CS is likely a tumor suppressor gene as evidenced indirectly by loss of heterozygosity in the CS critical interval on 10q22-23 in various CS related tumors (Marsh et al., 1997; Marsh et al., 1998b).
At the time as the CS gene was localized to 10q22-23, a new putative tumor suppressor gene was identified at this same region. PTEN/MMAC1(phosphatase and tensin homolog deleted on chromosome ten) was originally isolated from cancer cell lines harboring homozygous deletions on the chromosome region 10q23. PTEN encodes a dual-specificity protein phophatase, which shows homology to the focal adhesion molecules tensin and auxillin (Li et al., 1997; Steck et al., 1997; Myers., 1998). One of PTEN's major endogenous substrates is phosphotidylinositol-3,4,5-triphosphate Ptd-Ins(3,4,5)P3, a phospholipid in the phoshatidylinositol 3-kinase (PI-3 kinase) pathway, which previously has been shown to be important in cell growth signaling (Stambolic et al., 1998; Myers et al., 1998; Dahia et al., 1999; Maehama and Dixon, 1998). In this pathway, PTEN may act as a 3-phosphatase to dephosphorylate Ptd-Ins(3,4,5)P3 to Ptd-Ins(3,4)P2. Mutant or decreased PTEN leads to the accumulation of Ptd-Ins(3,4,5)P3, which is required for activation of protein kinase B (PKB)/Akt, a known cell survival factor (Stambolic et al., 1998; Myers et al., 1998; Dahia et al., 1999; Li et al., 1998).
Several PTEN mutations have been identified in sporadic tumors and cancer cell lines from various tissues including brain, endometrium, prostate, breast, thyroid, and melanoma (Risinger et al., 1997; Cairns et al., 1997; Rhei et al., 1997; Dahia et al., 1997). Germline mutations of PTEN were first found to be associated with CS (Tsou et al., 1997; Liaw et al., 1997; Nelen et al., 1997; Lynch et al., 1997) and later also with BRR (Marsh et al., 1997). Up to now, germline mutations in the PTEN have been found in 13-81% of CS patients (Tsou et al., 1997; Liaw et al., 1997; Nelen et al., 1997; Lynch et al., 1997; Marsh et al., 1998a) and in 57-60% of BRR cases (Marsh et al., 1998a; Longy et al., 1998). The PTEN mutation frequency in CS patients varies widely in different studies. One possible explanation is that some patients screened in these studies are not true CS patients. Marsh and colleagues (1998c) analyzed mutations in the PTEN gene in 64 unrelated Cowden syndrome-like families and identified only one mutation, in a male with follicular thyroid carcinoma. It was concluded that germline PTEN mutations play a relatively minor role in Cowden syndrome-like families (Marsh et al., 1998c).
Celebi and colleagues (1999) were the first to describe a family with two female members phenotypically fulfilling the criteria for CS and two male members with the phenotypic findings of BRR that all associated with a single germline mutation in the PTEN coding sequence (Celebi et al., 1999). Marsh and colleagues (1999) analyzed PTEN mutations among 43 unrelated BRR cases, including a subset of 11 families with both BRR and CS, and they detected mutations in 26 of them (60%) (Marsh et al., 1999). Interestingly, ten of 11 BRR/CS (91%) overlap families were shown to have germline PTEN mutations. So, the overlap of a number of clinical features and the sharing of identical PTEN mutations in CS and BRR patients suggests that CS and BRR are different presentations of a single syndrome, which could be named "PTEN hamartoma-tumor syndrome" (PHTS) (Marsh et al., 1999).
Linkage studies in JP families have been limited. There is one report excluding APC and MCC as the genes for JP (Leggett et al., 1993). Other genetic studies, originally stimulated by the finding of an interstitial deletion in the chromosomal region 10q22-24 in an infant with multiple colonic juvenile polyps and several congenital abnormalities, have focused on the region of the PTEN gene (Jacoby et al., 1997a). Evaluation for LOH in 10q22 within juvenile polyps revealed somatic deletions within the lamina propria in 83% of polyps derived from 16 unrelated patients (13 familial and 3 patients with sporadic JP). Maps indicating the contiguous extent of deletion for each individual polyp were constructed from LOH data, showing that the shortest overlapping region was the 3-cM interval between microsatellite markers D10S219 and D10S1696. This interval was considered as a putative JP locus and was named JP1 (Jacoby et al., 1997b).
To further clarify the genetic background of JP, Howe and colleagues (1998b) performed a focused genome screen to identify a gene locus predisposing to JP. The genotyping was performed on 43 individuals, of whom 13 were affected (the Iowa kindred). The linkage strategy involved the typing of markers at loci known to play an important role in colorectal polyposis or cancer (including regions where MSH2, MLH1, MCC, APC, HMPS, PTEN, KRAS2, TP53, DCC and LKB1 genes are located). Linkage to JP was established with several markers from chromosome 18q21.1. The maximum lod score was 5.00, with marker D18S1099. There was no evidence of linkage to other markers. Analysis of critical recombinants placed the JP gene in an 11.9 cM interval between markers D18S1118 and D18S487 (Figure 1), a region that also contains the tumor-suppressor genes DCC and SMAD4 (DPC4), both of these being good candidates for the JP gene (Howe et al., 1998b).
Figure 1. Schematic representation of markers and genes in 18q21 (modified from Howe et al., 1998b). JP gene is located between markers D18S1118 and D18S487. This region includes two genes: DCC and SMAD4. SMAD2 is located outside of the JP region.
Like JP, hereditary mixed polyposis syndrome (HMPS) is inherited in an autosomal dominant manner. It is still unclear whether HMPS is a variant of JP or a distinct disease (Murday and Slack, 1989). To clarify the molecular genetic background of HMPS, Thomas and colleagues (1996) genotyped one large HMPS family. As a result, the linkage of HMPS to the APC, MSH2, TP53 and DCC loci were excluded and evidence of linkage was found in chromosome 6q. Multipoint linkage analysis gave a maximum lod score of 3.93 between markers D6S468 and D6S283. (Thomas et al., 1996). Also Whitelaw and colleagues (1997) have reported that HMPS is unlinked to candidate loci with importance in colorectal tumorigenesis, such as APC, MSH2 and MLH1 (Whitelaw et al., 1997). The gene for HMPS has not yet been identified and the genetic events behind HMPS are still unclear.