Open Access

Recurrent APC gene mutations in Polish FAP families

  • Andrzej Pławski1,
  • Marta Podralska1 and
  • Ryszard Słomski1
Hereditary Cancer in Clinical Practice20075:195

https://doi.org/10.1186/1897-4287-5-4-195

Received: 13 August 2007

Accepted: 22 September 2007

Published: 15 December 2007

Abstract

The molecular diagnostics of genetically conditioned disorders is based on the identification of the mutations in the predisposing genes. Hereditary cancer disorders of the gastrointestinal tracts are caused by mutations of the tumour suppressor genes or the DNA repair genes. Occurrence of recurrent mutation allows improvement of molecular diagnostics. The mutation spectrum in the genes causing hereditary forms of colorectal cancers in the Polish population was previously described. In the present work an estimation of the frequency of the recurrent mutations of the APC gene was performed. Eight types of mutations occurred in 19.4% of our FAP families and these constitute 43% of all Polish diagnosed families.

Keywords

FAP APC gene mutations Polish population

Introduction

Molecular diagnostics of cancer predisposition is very important for the medical treatment of the patient and persons belonging to the high risk group. Molecular studies enable the detection of mutation carriers and release from unreasonable stress of persons from the group with increased risk of cancer occurrence. The mutation spectrums in the genes predisposing to colorectal cancer in the Polish population have been described [14]. In the present work we focused on recurrent mutations of the APC gene causing FAP [5].

Familial adenomatous polyposis (FAP) is characterized by the appearance of numerous polyps in the large intestine. Untreated polyps lead to the development of colorectal cancer before age of 50 years. FAP is a genetically determined disorder, inherited in an autosomal dominant manner. The correlation between mutations of the APC gene and the occurrence of familial adenomatous polyposis was described in 1991 [1, 2] and since then, mutations of the APC gene have been investigated in research centres leading to identification of various mutation types. APC gene mutations arise de novo in 1 per 10,000 newborns. The APC gene is localized on chromosome 5q21 and consists of 21 exons. Mutations of the APC gene, in most cases, are small deletions or insertions with the most frequent mutations, in the greater part of the described populations, being the AAAGA deletion at codon 1309 and the ACAAA deletion at codon 1061.

Patients

Clinical diagnoses of FAP patients were conducted in collaborating genetic centres or gastroenterology clinics in the place of residence of patients. So far, samples of DNA belonging to 280 Polish FAP families have been collected in the DNA bank of Polish FAP families established in 1997 at the Institute of Human Genetics, Polish Academy of Science in Poznan.

Molecular methods

DNA was extracted from peripheral blood cells by the classical phenol purification method and entire coding sequence of APC gene was screened for mutations by PCR-HD and SSCP methods in 280 probands. DNA fragments showing heteroduplex or additional pattern in SSCP analysis were sequenced by direct PCR product sequencing and analyzed using a MegaBace 500 sequencer according to the manufacturer's specifications.

Results and discussion

We identified 72 mutations in 124 of our 280 FAP families and observed eight types of recurrent mutations. The mutations and age of onset are presented in Table 1. Two of them were localized in exon 11 and the remaining six in the 3' part of exon 15. The most frequent mutation, 3927–3931delAAAGA, occurred in twenty-eight families (10%); the second one was 3183–3187delACAAA, occurring in eight families (2.8%); and the third most frequent mutation was 3202–3205delTCAA, detected in 5 families (1.7%). In our FAP patients Y500X occurred in four families (1.4%) while Q978X was detected in three families. Each of the remaining four types of mutation occurred in two families and the frequencies of these mutations were below one percent.
Table 1

Fifty-four recurrent mutations identified in APC gene and age of onset in a group of 124 diagnosed Polish FAP families

No.

Family

Clinical manifestation

Mutation

Exon

Age of onset

1.

9001

FAP

1490–1491insT

11

35

2.

9129

FAP

1490–1491insT

11

10

3.

9117

FAP

1500T>A

11

ND

4.

9141

FAP

1500T>A

11

ND

5.

9158

FAP

1500T>A

11

ND

6.

9182

FAP

1500T>A

11

ND

7.

9031

FAP

2626subC>T

15

ND

8.

9043

FAP

2626subC>T

15

30

9.

9099

FAP

2932C>T

15

ND

10.

9139

FAP

2932C>T

15

ND

11.

9152

FAP

2932C>T

15

ND

12.

9028

FAP

3183–3187delACAAA

15

28

13.

9067

FAP

3183–3187delACAAA

15

19

14.

9093

FAP

3183–3187delACAAA

15

17

15.

9108

FAP

3183–3187delACAAA

15

ND

16.

9111

FAP

3183–3187delACAAA

15

ND

17.

9192

FAP

3183–3187delACAAA

15

ND

18.

9262

FAP

3183–3187delACAAA

15

24

19.

9311

FAP

3183–3187delACAAA

15

ND

20.

9088

FAP

3202–3205delTCAA

15

30

21.

9106

FAP

3202–3205delTCAA

15

26

22.

9213

FAP

3202–3205delTCAA

15

28

23.

9226

FAP

3202–3205delTCAA

15

ND

24.

9342

FAP

3202–3205delTCAA

15

12

25.

9016

FAP

3927–3931delAAAGA

15

20

26.

9032

FAP

3927–3931delAAAGA

15

ND

27.

9036

FAP

3927–3931delAAAGA

15

13

28.

9059

FAP

3927–3931delAAAGA

15

18

29.

9065

FAP

3927–3931delAAAGA

15

36

30.

9069

FAP

3927–3931delAAAGA

15

ND

31.

9071

FAP

3927–3931delAAAGA

15

36

32.

9075

FAP

3927–3931delAAAGA

15

ND

33.

9084

FAP

3927–3931delAAAGA

15

ND

34.

9103

FAP

3927–3931delAAAGA

15

26

35.

9104

FAP

3927–3931delAAAGA

15

ND

36.

9105

FAP

3927–3931delAAAGA

15

20

37.

9118

FAP

3927–3931delAAAGA

15

ND

38.

9142

FAP

3927–3931delAAAGA

15

ND

39.

9147

FAP

3927–3931delAAAGA

15

29

40.

9149

FAP

3927–3931delAAAGA

15

16

41.

9162

FAP

3927–3931delAAAGA

15

ND

42.

9187

FAP

3927–3931delAAAGA

15

ND

43.

9193

FAP

3927–3931delAAAGA

15

ND

44.

9229

FAP

3927–3931delAAAGA

15

22

45.

9235

FAP

3927–3931delAAAGA

15

ND

46.

9237

FAP

3927–3931delAAAGA

15

21

47.

9244

FAP

3927–3931delAAAGA

15

16

48.

9292

FAP

3927–3931delAAAGA

15

19

49.

9300

FAP

3927–3931delAAAGA

15

17

50.

9312

FAP

3927–3931delAAAGA

15

ND

51.

9321

FAP

3927–3931delAAAGA

15

31

52.

9324

FAP

3927–3931delAAAGA

15

ND

53.

9070

Gardner syndrome

4129–4130delGT

15

ND

54.

9119

FAP

4129–4130delGT

15

ND

ND – no data available

In the Human Mutations Database at the Institute of Medical Genetics in Cardiff http://www.hgmd.cf.ac.uk/ac/gene.php?gene=APC, considered the most representative population in the world, seven hundred mutations are listed for the APC gene. The most important mutation of the APC gene is 3927–3931delAAAGA. The frequency of these mutations varies depending on populations. The mutation reports describe the frequency of this mutation from 0% in northwest Spain, 2.4% in the Australian population, 5% in Dutch, 7% in Israeli to 16% in the group of Italian FAP patients [69]. The second most frequent mutation, 3183–3187delACAAA, is reported with frequency ranging from 0% in northwest Spain, 1.5% in Israeli populations to 8.4% in Australia [69]. A study of over 100 Dutch families revealed equal frequency of those two most frequent mutations (3927–3931delAAAGA and 3183–3187delACAAA) [10]. The largest studies of APC gene mutations were performed on a German population [11, 12]. The latest published report in 2005 involved the analysis of over 1000 patients. In comparison to this study, the representative study of mutation frequency in the neighbouring population indicated two times higher frequency of 3927–3931delAAAGA, whereas a difference in frequency of 3183–3187del-ACAAA was not observed (Germany 3.8%, Poland 2.7%). The frequency of 3202–3205delTCAA was equal (1.7%) in both populations. In worldwide comparison differences in the frequency of mutations were observed. The Polish population of FAP patients belongs to the group where 3927–3931delAAAGA occurred with higher frequency, whereas the frequency of mutation 3183–3187del-ACAAA occurred with medium frequency in comparison with other populations. The two recurrent mutations localized on exon 11 were observed only in the Polish population. In our two unrelated families with 1490–1491insT brain tumours were observed. Additionally in one family desmoid tumours occurred [10, 13]. Another mutation (Q978X) did not occur with higher frequency as described for other populations [14]. In our FAP patient group Q283X, which occurs with frequency of 4.5% in UK FAP patients, was not observed [13]. Recurrent mutations occurred in 54 Polish FAP families. Screening for these mutations permitted us to diagnose 19% of all families in our population but eight types of mutations constitute 43.5% of all our diagnosed families. The mutation study in our population should involve these eight mutations to improve molecular diagnostics of the APC gene.

The study was financed by grant 2P05A10728 from the Ministry of Science and Higher Education.

Authors’ Affiliations

(1)
Institute of Human Genetics, Polish Academy of Sciences

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Copyright

© The Author(s) 2007

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