APC gene mutations causing familial adenomatous polyposis in ...

J Appl Genet 49(4), 2008, pp. 407–414

Original article

APC gene mutations causing familial adenomatous polyposis in Polish patients Andrzej Plawski, Ryszard Slomski Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland

Abstract. Familial adenomatous polyposis (FAP) is a well-known hereditary condition characterised by alimentary system tumours. Tens to thousands of polyps occur in the colon and rectum of the patients. There is a high heterogeneity with regard to the number and time of the occurrence of polyps. The occurrence of FAP is associated with mutations in the APC tumour suppressor gene, which was described in 1991. Since then, many studies have been done to analyse the distribution of mutations in individual populations and to determine the function of the gene and a diagnostic approach to FAP. Here the APC gene was studied with respect to the occurrence of small mutations and large rearrangements in 300 unrelated Polish FAP families. Ninety-seven mutations were identified in 164 families. Out of these mutations, 80 were small mutations, including 58 small mutations that were first identified in the Polish population (42 novel and 16 described previously). An increased frequency of mutation c.3927_3931delAAAGA was observed in 10% of the Polish group. Seventeen large rearrangements were found in 29 families. Out of those rearrangements, 8 repeat rearrangements occurred in 20 families. A problem in fast molecular diagnostics of FAP is a high heterogeneity of mutations in the APC gene. It seems that a multiplex ligation-dependent probe amplification test and searching for small mutations by the use of screening methods at the 5’ end of exon 15 and exons 14, 9, 11, 13, 5, and 3, help to improve the molecular diagnostics of FAP in Polish patients. Keywords: FAP, APC gene, colorectal cancer, familial adenomatous polyposis, multiplex ligation-dependent probe amplification.

Introduction Familial adenomatous polyposis (FAP) is a disorder that is inherited in an autosomal dominant manner, with a predisposition to the occurrence of a large number of polyps in the colon. First symptoms of FAP are diarrhoea and blood in stool. Weight loss and weakness are observed when tumour development is advanced. The incidence of FAP is one per 10 000 newborns (Cruz-Correa and Giardiello 2003). The classic form of FAP is characterised by the occurrence of more than 100 polyps, which appear in the second decade of life. The average time of polyp occurrence is 15 years (Cruz-Correa and Giardiello 2003). The earliest symptoms of polyposis were observed in a

5-year-old child (Krush et al. 1988). The polyps have a high potential for development towards malignant tumours. This can occur from the late childhood to the 70s. Attenuated adenomatous polyposis coli (AAPC) cases are characterised by a benign course of the disease, as opposed to the classic FAP. Symptoms of this disorder are observed at the age of 35–45. There are usually 10–100 adenomatous polyps (adenomas) and flat adenomas in the colon. The occurrence of extraintestinal symptoms is not as common as in the classic FAP. Many papers have documented symptoms like polyps of the fundus of the stomach and adenomatous polyps or intra-ductal papillary mucinous neoplasms of the pancreas (Chetty et al. 2005; Matsubara et al. 2000; Moisio et al. 2002;

Received: June 11, 2008. Accepted: September 5, 2008. Correspondence: A. Plawski, Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60–479 Poznan, Poland; email: [email protected]

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Soravia et al. 1998). In 1991, a relationship between the APC gene and FAP was discovered. This was followed by a number of molecular studies, which generated a large number of data on the mutation spectrum in new countries or ethnic groups. Currently, the most up-to-date database of mutations of the APC gene can be found at the Institute of Medical Genetics in Cardiff, http://www. hgmd.cf.ac.uk/ac/index.php (Stenson et al. 2003). It contains data on 858 types of mutations. Small deletions (356) are the majority of mutations in the APC gene. They make a change in the open reading frame (ORF) and shorten the gene product. The 235 mutations are missense or nonsense mutations that proceed to the Stop codon at the site of mutation. So far, only 131 small insertions have been described. Large deletions (54), mutations in splicing areas (49), small deletions connected with insertions (17), large insertions (7), and rearrangements (6) were rare, and in regulatory sequences only (3) mutations were found. Most mutations in the APC gene contribute to the change in the ORF and shortening of the gene product. Deletions or insertions of a few base pairs (68% of all mutations) lead to the frame shift. As a result, the Stop codon develops close to the mutation site. Substitutions constitute 30% of all cases, and where the Stop codon appears, it is the site of change. Most of germline mutations are at the 5’ end of the gene. The mutation cluster region (MCR) with a higher frequency of germline mutations was identified in the APC gene. The MCR is between codons 1250 and 1464 (Cetta and Dhamo 2007). Mutations are heterogeneous in the APC gene. Two of them exhibit an increased frequency: deletion of 5 bp at codon 1309 (c.3927_3931delAAAGA) and 5 bp at codon 1061 (c.3183_3187delACAAA). The mutation c.3927_3931delAAAGA is the most frequent mutation in the APC gene. Its frequency varies from 0% in southwest Spain through 2.4% in the Australian population, 5% in the Dutch population, 7% in the Israeli population, and up to 16% in Italian FAP patients (Gavert et al. 2002; Ruiz-Ponte et al. 2001; Schnitzler et al. 1998; Varesco et al. 1993a). The frequency of the second mutation, c.3183_3187delACAAA, varies from 0% in north Spain through 1.5% in the Israeli population, and up to 8.4% in FAP patients from Australia (Gavert et al. 2002; Ruiz-Ponte et al. 2001; Schnitzler et al. 1998; Varesco et al. 1993a). The optimization of molecular diagnostics of hereditary predispositions to the incidence of can-

cerous disorders is very essential for the lowering of costs and improving the testing efficiency. To improve molecular diagnostics, it is important to describe the nature and frequency of mutations in various ethnic groups. The aim of this study was to recognise the spectrum of small mutations and large rearrangements in the APC gene. This study, based on the investigation of 300 unrelated FAP patients from all over Poland, made it possible to determine the most effective way to detect APC gene mutations in Polish FAP patients.

Materials and methods The studied group consisted of 300 unrelated FAP patients, derived from all over Poland, whose DNA samples were collected in the DNA bank of Polish FAP families, established in 1997 at the Institute of Human Genetics in Poznan. FAP patients were diagnosed in the health centres appropriate to patients’ place of residence, cooperating with this Institute. Patients who agreed to the genetic tests were directed to molecular tests by gastroenterology clinics or genetic centres. The control group comprised 100 individuals, who consisted of 50 unrelated men and 50 unrelated women randomly chosen from the Polish population. Our investigations were approved by the Ethical Committee of the Medical University in Poznan. DNA extraction

The collected blood samples on anticoagulant, together with the patients’ permissions to carry out genetic tests, were sent to the Institute of Human Genetics in Poznan. DNA was extracted from peripheral blood cells with the phenol purification method (Lahiri and Schnabel 1993). Molecular analysis of small mutations

The earlier described primers were used to amplify the fragments that included individual exon-splicing sites. The amplified fragments of the APC gene were screened for mutations involving the heteroduplex analysis (HD) and detection of single-stranded conformational polymorphism (SSCP) (Plawski et al. 2001). The heteroduplex DNA fragments detected in the HD analysis or various patterns in the SSCP analysis were further analysed by direct PCR product sequencing, using MEGABace 500 sequencer (General Electric Health Care USA) according to the manufacturer’s specifications.

APC mutations in Polish FAP patients

Detection of large rearrangements in the APC gene

Multiplex ligation-dependent probe amplification (MLPA) analysis was conducted on extracted DNA from 165 probands, in which previously no small sequence alterations were identified. The MLPA kit was used for the analysis of locus APC; SALSA MLPA KIT P043 APC (MCR Holland Amsterdam, The Netherlands). The analysis was conducted according to the manufacturer’s recommendations (http://www.mrc-holland.com).The analysis of fragments was conducted with the use of the MegaBACE 500 kit (General Electric Health Care USA). The ET-550 marker (General Electric Health Care USA) was employed as a molecular weight marker.

Results Small sequence alterations

We screened 300 probands for small mutations in the APC gene. Eighty types of small mutations in 135 families were identified (Table 1). The most frequent mutation in the Polish FAP patients was the deletion c.3927_3931delAAAGA. This mutation occurred in 10.3% of families. The second deletion, c.3183_3187delACAAA, was observed in 4% of families. Mutation c.3202_3205delTCAA was found in 5 probands (1.7%). Ten repeat mutations occurred in 65 families, which constituted 47.4% of all the diagnosed families with small mutations, or 21% of all studied patients. Out of the 80 small mutations found in the Polish FAP patients, 42 were novel mutations, 16 mutations were first described by our research team in the Polish population previously (Plawski et al. 2004; Plawski et al. 2007a; Plawski et al. 2007b), and 22 mutations were earlier described in other populations. In total, 58 mutations were first observed in the Polish population. Fifty-four mutations that occurred in 102 families were ORF mutations, from which 40 deletions ranged from 1 to 11 bp. One mutation (deletion of 3 adenines from codons 793 and 794) caused a change of glutamine and serine to arginine. Other mutations led to a change in the ORF and to the development of the Stop codon in close proximity to the site of mutation. The remaining 14 mutations were insertions or duplications ranging from 1 to 8 bp. All insertions and duplications led to ORF alterations and premature termination of the translation of APC protein. In 33 families, 26 substitutions were observed, of which 12 led to

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Stop codons. One of them was an Ashkenazi variant. In 8 cases, a change in amino acids was observed, which did not appear in the control group . Six substitutions occurred at splice sites. APC gene rearrangements

A total of 165 unrelated patients were studied, in which no small sequence mutations were previously found but 17 large changes in 29 FAP families were observed (Table 2). Eight large rearrangements occurred more frequently than in one family. The most common deletion occurred within promoter sequence 2. It was identified in 4 cases. The deletion of the whole APC gene was detected in 3 families. Each deletion of exons 3, 4, 12, and 15M occurred in 2 families. Amplifications were identified in 6 families, including the amplification of exon 11 in 3 families. The largest deletions concerned the whole APC gene, exon 14 and whole exon 15, or exons from 10 to 14 and from 11 to 13. Large rearrangements occurred in 9.6% of the studied families.

Discussion The analysis was performed for 300 Polish families with FAP, and 97 mutations were found in 164 families. Most of the detected mutations were small. Six mutations occurring in introns close to the exon–intron border were identified. Two of them were described previously, and the remaining 4 did not occur in the studied control group. The IVS3-14T>G substitution, which is 14 nucleotides away from the exon–intron border, is novel. No studies were performed on the mRNA level but the absence of the substitution IVS3-14T>G in the control group and its cosegregation with the phenotype of this disorder in the family indicates the pathogenic character of IVS3-14T>G. The most common mutation in our population studied was c.3927_3931delAAAGA. The frequency of c.3927_3931delAAAGA varied depending on the population and it was the most common mutation in the Polish FAP patients. Its frequency was more than 10% and was one of the highest in the studied groups (Gavert et al. 2002; Plawski et al. 2007b; Ruiz-Ponte et al. 2001; Schnitzler et al. 1998; Varesco et al. 1993b). The frequency of the second most common mutation (c.3183_3187delACAAA) in the Polish patients reached 4% . The high heterogeneity of the APC gene mutation is noteworthy. Out of the 80 small mutations that were found in the Polish FAP

410 Table 1. Characteristics of the sequence alterations in the APC gene detected in Polish FAP patients Mutation

Exon/ intron

1

2

Consequence of mutation

Affected families

3

4

IVS3-14T>G IVS3-1G>C c.517_521delCCTT c.601delG c.636delA c.646C>T c.892_893delCA IVS9-1G>C IVS9+5G>C c.1111_1112delGG c.1288_1291delGGCA c.1297C>T c.1429G>T c.1490_1491insT c.1500T>A IVS13-3T>G IVS13 +1 G>A c.1744G>T c.1817delG c.1816_1817InsA c.1829delA c.1873delC c.1875_1878delGACA c.2292_2293insA c.2365_2366insC c.2377_2379delAAA c.2413C>T c.2482A>G c.2527_2530delAGTT c.2609delC C.2626C>T

3 3 4 5 5 6 8 9 9 9 9 9 11 11 11 13 13 14 14 14 14 14 14 15 15 15 15 15 15 15 15

splice site splice site p.Pro173fs p.Glu201fs p.Lys212fs p.Arg216X p.Ser294fs splice site splice site p.Gly371fs p.Gly430fs p.Pro433X p.Glu477X p.Leu497fs p.Tyr500X splice site splice site p.Glu582X p.Ile606fs p.Ile606fs p.Asp610fs p.Gln625fs p.Gln625fs p.Phe764fs p.Gln789fs p.Gln793fs p.Arg805X p.Thr828Ala p.Ser843fs p.Pro870fs P.Arg876X

1 1 1 1 1 1 1 1 1 1 1 1 2 2 4 1 1 1 1 1 2 1 1 1 1 1 1 1 1 1 2

c.2645_2649delCCACT c.2797_2800dAACA c.2802_2805delTTAC c.2805C>A c.2815_2816delAA c.2853T>G c.2922_2923insG c.2932C>T c.3090_3091insA c.3093T>G c.3109_3110delAA c.3118_3119dupCTCTGGAA c.3164_3168delTAATA c.3183_3184insA C.3183_3187delACAAA

15 15 15 15 15 15 15 15 15 15 15 15 15 15 15

p.Thr882fs p.Asn933fs p.Thr934fs p.Tyr935X p.Lys939fs p.Tyr951X p.Gly974fs p.Gly978X p.Asn1031fs p.Asn1031X p.Asn1037fs p.Arg1040fs p.Ile1055fs p.Gln1062fs P.Lys1061fs

1 1 1 1 1 1 1 3 1 1 1 1 1 1 12

c.3183delA c.3184_3187delCAAA c.3202_3205delTCAA c.3225T>A c.3371delA c.3473_3474delGA

15 15 15 15 15 15

p.Lys1061fs p.Gln1062fs p.Ser1068fs p.Tyr1075X p.Asn1124fs p.Arg1158fs

1 1 5 1 1 1

Source 5 novel (Brozek et al. 2008; Hutter et al. 2001) (Plawski et al. 2007a; Stekrova et al. 2007) (Plawski et al. 2004) (Plawski et al. 2004) (Lamlum et al. 1999) (Plawski et al. 2004) novel (Mihalatos et al. 2005) novel novel (Friedl et al. 2001) novel (Plawski et al. 2004) novel novel novel novel novel novel novel novel novel novel novel novel (Dobbie et al. 1996) novel (Chen et al. 2006) (Plawski et al. 2004) (Ficari et al. 2000; Furuuchi et al. 2000; Nordling et al. 1997; Prosser et al. 1994; Valanzano et al. 1996) novel novel (Truta et al. 2005) (Groden et al. 1993) novel novel (Plawski et al. 2004) (Kim et al. 2001) novel (Homfray et al. 1998) novel (Plawski et al. 2004) (Mandl et al. 1994b; Miyoshi et al. 1992) novel (Groden et al. 1991; Miyoshi et al. 1992; Wakatsuki et al. 1998) novel (Mandl et al. 1994a) (Paul et al. 1993) (Palmirotta et al. 1995) (Plawski et al. 2004) (Plawski et al. 2004)

APC mutations in Polish FAP patients

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Table 1 continue. 1

2

c.3515delA c.3538delA c.3577_3580delCAGT c.3580delT c.3613delA c.3645T>G c.3685T>C c.3807_3808delAT c.3919T>A c.3921_3924DelAAAA c.3923A>G c.3927_3931delAAAGA c.3929delA c.3930_3931insG c.3933delT c.3949G>C c.3977_3978insC c.3977_3978insT c.4129_4130delGT c.4144C>T c.4266_4276delTCTTCCAGATA c.4394_4395dupGA c.4394_4395insAG c.4588delG c.4609delA c.4650_4651delGA c.4666_4667insA c.5465t>a

15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15

3 p.Ser1171fs p.Val1173fs p.Gln1193fs p.Ser1194fs p.Ser1205fs p.Ser1215Arg p.Leu1129Ser p.Ile1269fs p.Ile1307Leu p.Ile1307fs p.Glu1308Arg p.Glu1309fs p.Glu1309fs p.Lys1310fs p.Ile1311fs p.Glu1317Gln p.Val1326fs p.Val1326fs p.Val1377fs p.Ser1382Phe p.Asp1422fs p.Ser1465fs p.Ser1465fs p.Thr1530fs p.Thr1537fs p.Glu1550fs p.Thr1556fs p.Asp1822Val

4 1 1 1 1 1 1 1 1 1 1 1 31 1 1 1 1 1 1 2 1 1 1 1 1 1 1 1 1

5 (Plawski et al. 2004) novel novel (Plawski et al. 2004) (Plawski et al. 2004) novel novel novel (Laken et al. 1997) (Walon et al. 1997) novel (Groden et al. 1991) novel novel novel (Frayling et al. 1998; van Puijenbroek et al. 2008) novel novel (Plawski et al. 2007b) novel (Plawski et al. 2004) (Plawski et al. 2004) novel novel novel novel (Bjork et al. 2001; Shitoh et al. 2000) (Wallis et al. 1999)

Novel: mutations absent in The Human Mutation Database at the Institute of Medical Genetics in Cardiff http://www.hgmd.cf.ac.uk/ac/index.php and in reviewed literature. Mutations described in the Polish population for the first time are marked as “novel” (42), or the remaining ones (16) were described earlier by P³awski The cDNA numbering is based on reference sequence (GenBank NM_000038); +1 corresponds to the A of the ATG translation initiation codon.

Table 2. Characteristics of the large rearrangements of the APC gene detected in Polish FAP patients No.

Mutation

Exons

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

deletion deletion deletion deletion deletion deletion deletion deletion deletion deletion deletion deletion deletion amplification amplification amplification amplification

whole APC gene promoter 1 promoter 2 3 4 10 10–14 11–13 12 14 14-15M 14-15 15M 3 7 11 15M

Affected families 3 2 4 2 2 1 1 1 2 1 1 1 2 1 1 3 1

patients, 58 were identified for the first time and, out of them, only one mutation (c.517_521delCCT) was later found in the Czech population (Plawski et al. 2007a; Stekrova et al. 2007). Most of the detected mutations (72.5%) are characteristic for our Polish populations. These mutations were found in 58 families diagnosed with a small mutation (43% of all diagnosed families). Mutations characteristic for Polish patients do not occur with increased frequencies. One of the newly identified mutations was c.1500T>A, which was detected in 4 families. Three other mutations were found in 2 families. The contribution of these mutations to the process of determining the risk of the disorder was lower in the diagnosed families in spite of the fact that those mutations constituted more than 70% of all detected mutations. We observed 10 small mutations that occurred in more than one family. These mutations augmented the risk of the disorder in 65 families. No small mutations at exons 1, 2, 3, 7, 10, 12, and 13 were identified in our studies. Most

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of the diagnosed small mutations were detected at exon 15 of the APC gene. These mutations conditioned the risk of the disorder in 106 diagnosed families. Mostly, the mutations occurred at the 5’ end of exon 15. A considerable rearrangement in the APC gene was found in 10% of the studied families. Seventeen mutations occurred in 29 families, of which 8 were repeated mutations determining the occurrence of the disorder in 20 families. Frequent changes were found within the promoter, although the deletion of the entire APC gene was by no means infrequent. Studies of the occurrence of the large APC gene rearrangements in FAP patients without small mutations were already described in other populations. The largest described group was that of 174 unrelated patients from Germany. The large APC gene rearrangements were identified in 26 patients, and 12 of them were deletions of the whole APC gene (Aretz et al. 2005). In Greek patients, only one large rearrangement in 25 studied families was detected (Mihalatos et al. 2005), while in another study in Belgium, 4 large rearrangements were revealed in 27 examined FAP families, and 3 of them were deletions of the whole APC gene (Michils et al. 2005). In the German and Belgian groups, the percentage of large rearrangements was almost equal (15%), but in the Greek group it was 4%. The frequency of the large APC gene rearrangement in Polish FAP patients was lower in comparison with that described in Germany and in Belgium. Additionally, the frequency of the deletion of the whole APC gene was much lower than in West European populations. Detection of large rearrangements in the APC gene can be easily performed with the MLPA test. This test can be used to screen large numbers of copies of individual exons. Moreover, the kit contains probes that detect changes within the studied gene. As for the APC gene, the kit contains probes for c.3927_3931delAAAGA and c.3183_3187del ACAAA mutations, which constitute a significant percentage of mutations determining FAP in the majority of populations. In the case of Polish patients, the use of the MLPA test allowed detecting mutations in 72 families of Polish FAP patients. The heterogeneous character of mutations in the APC gene hinders the development of a rapid diagnostic test for a majority of affected people. In this particular case the employment of the MLPA test allowed diagnosing a higher number of affected people (72 families) than the developed test for 10 mutations (65 families) that appeared in more than one family. After the detection of 2 of

the most common mutations, the remaining repeat mutations determined the occurrence of the disorder only in 21 families. Thus, for the optimization of molecular diagnostics of the APC gene in the Polish population, the most useful way will be to apply the MLPA test and next study the 5’ end part at exon 15 of the APC gene (codons 784–1556) and then successively exons 14, 9, 11, 13, 5, and 3. Acknowledgements. This study was supported by the Ministry of Education and Science Poland (grant number 2PO5A10728). REFERENCES Aretz S, Stienen D, Uhlhaas S, Pagenstecher C, Mangold E, Caspari R, et al. 2005. Large submicroscopic genomic APC deletions are a common cause of typical familial adenomatous polyposis. J Med Genet 42: 185–192. Bjork J, Akerbrant H, Iselius L, Bergman A, Engwall Y, Wahlstrom J, et al. 2001. Periampullary adenomas and adenocarcinomas in familial adenomatous polyposis: cumulative risks and APC gene mutations. Gastroenterology 121: 1127–1135. Brozek I, Plawski A, Podralska M, Kanka C, Slomski R, Limon J, 2008. Thyroid cancer in two siblings with FAP syndrome and APC mutation. Int J Colorectal Dis 23: 331–332. Cetta F, Dhamo A, 2007. Inherited multitumoral syndromes including colorectal carcinoma. Surg Oncol 16 Suppl 1: S17–23. Chen CS, Phillips KD, Grist S, Bennet G, Craig JE, Muecke JS, Suthers GK, 2006. Congenital hypertrophy of the retinal pigment epithelium, CHRPE. in familial colorectal cancer. Fam Cancer 5: 397–404. Chetty R, Salahshor S, Bapat B, Berk T, Croitoru M, Gallinger S, 2005. Intraductal papillary mucinous neoplasm of the pancreas in a patient with attenuated familial adenomatous polyposis. J Clin Pathol 58: 97–101. Cruz-Correa M, Giardiello FM, 2003. Familial adenomatous polyposis. Gastrointest Endosc 58: 885–894. Dobbie Z, Spycher M, Mary JL, Haner M, Guldenschuh I, Hurliman R, et al. 1996. Correlation between the development of extracolonic manifestations in FAP patients and mutations beyond codon 1403 in the APC gene. J Med Genet 33: 274–280. Ficari F, Cama A, Valanzano R, Curia MC, Palmirotta R, Aceto G, et al. 2000. APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis. Br J Cancer 82: 348–353. Frayling IM, Beck NE, Ilyas M, Dove-Edwin I, Goodman P, Pack K, et al. 1998. The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history. Proc Natl Acad Sci U S A 95: 10722–10727.

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