Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases

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Human Molecular Genetics Pages 1907-1912

Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases
Introduction
Results
Discussion
Materials And Methods
   Patient selection
   Linkage analysis
   Mutation screen
Acknowledgements
References

Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases

Richard Houlston, Stephen Bevan, Andrew Williams¹, Joanne Young², Malcolm Dunlop³, Paul Rozen⁴, Charis Eng⁵, David Markie⁶, Kelly Woodford-Richens⁷, Miguel A. Rodriguez-Bigas⁸, Barbara Leggett², Kay Neale⁹, Robin Phillips⁹, Eamon Sheridan¹⁰, Shirley Hodgson¹¹, Takeo Iwama¹², Diana Eccles¹³, Walter Bodmer¹⁴ and Ian Tomlinson^7,*

Cancer Genetics, Haddow Laboratories, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK, ¹Department of Gastroenterology, St John's Hospital, Livingston EH54 6PP, UK, ²Queensland Institute of Medical Research, Royal Brisbane Hospital, Herston, Brisbane, Australia, ³MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK, ⁴Department of Gastroenterology, Tel Aviv Medical Center and Medical School, IL-64239 Tel Aviv, Israel, ⁵Translational Research Laboratory, Dana-Farber Cancer Institute, Boston, MA 02115-6084, USA, ⁶Molecular Genetics Laboratory, Pathology Department, Dunedin School of Medicine, Dunedin, New Zealand, ⁷Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, PO Box 123, 44 Lincoln's Inn Fields, London WC2A 3PX, UK, ⁸Roswell Park Cancer Institute, Buffalo, NY 14263, USA, ⁹Polyposis Registry, St Mark's Hospital, Watford Road, Harrow HA1 3UJ, UK, ¹⁰Department of Clinical Genetics, Royal Hospital for Children, St Michael's Hill, Bristol, UK, ¹¹Department of Clinical Genetics, Guy's Hospital, St Thomas's Street, London SE1 9RT, UK, ¹²Department of Surgery, Kyoundo Hospital, Sasaki Institute, 101-0062, Tokyo, Japan, ¹³Wessex Regional Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK and ¹⁴Cancer Immunogenetics Laboratory, ICRF, Institute of Molecular Medicine, Oxford OX3 9DS, UK

Received June 13, 1998; Revised and Accepted August 7, 1998

Juvenile polyps are present in a number of Mendelian disorders, sometimes in association only with gastrointestinal cancer [juvenile polyposis syndrome (JPS)] and sometimes as part of known syndromes (Cowden, Gorlin and Banayan-Zonana) in association with developmental abnormalities, dysmorphic features or extra-intestinal tumours. Recently, a gene for JPS was mapped to 18q21.1 and the candidate gene DPC4 (SMAD4) was shown to carry frameshift mutations in some JPS families. We have analysed eight JPS families for linkage to DPC4. Overall, there was no evidence for linkage to DPC4; linkage could be excluded in two of the eight pedigrees and was unlikely in two others. We then tested these eight families and a further 13 familial and sporadic JPS cases for germline mutations in DPC4. Just one germline DPC4 mutation was found (in a familial JPS patient from a pedigree unsuitable for linkage analysis). Like all three previously reported germline mutations, this variant occurred towards the C-terminus of the DPC4 protein. However, our patient's mutation is a missense change (R361C); somatic missense mutations in DPC4 have been reported previously in tumours. We therefore confirm DPC4 as a cause of JPS, but show that there is considerable remaining, uncharacterized genetic heterogeneity in this disease.

INTRODUCTION

   MD

   BRIS
   HWK

   YAD
   I1

   CORD
   C1

   NE

Figure 1. Pedigrees of families studied by linkage analysis and haplotypes close to DPC4. Closed symbols, affected individuals; ?, `unknown' individuals; open symbols, unaffected individuals. Marker genotypes are shown in the order given in Materials and Methods [D18S57 (top), D18S1118, D18S1099 and D18S487]. DPC4 lies between D18S1118 and D18S1099. Genetic distances are given in the legend to Table 1. Four pedigrees (MD, BRIS, HWK and YAD) provide good evidence against linkage to DPC4. It can readily be seen that affected individuals do not share haplotypes in pedigree MD. In BRIS, 2.10 must carry the haplotype 11-11-8-7, which is allelic to the 11-1-10-6 or 11-1-10-7 haplotype shared by the other affected individuals, thus, affected individuals do not share a haplotype close to DPC4 in this family. In HWK, linkage to DPC4 cannot be disproven, but is unlikely: 3.2 carries the 11-1-6-? haplotype, which is probably inherited from his affected mother 2.2 (given the presence of this haplotype in aunts 2.4 and 2.5), but affected sibs 4.1 and 4.2 have inherited the 13-15-10-6 haplotype from 3.2. In YAD, there is weak evidence against linkage to DPC4, provided by failure of 402 and 403 to share an allele at D18S57 and the poor information at D18S1118.

Juvenile polyps are hamartomatous lesions which occur in the gastrointestinal tract. They are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as juvenile polyposis syndrome (JPS; MIM 174900); here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers (1,2). A variant of JPS, termed hereditary mixed polyposis syndrome (HMPS; MIM 601228), is characterized by atypical juvenile polyps, with mixed features of hamartomas and adenomas (3). The HMPS locus has been mapped to 6q16, although the gene responsible has not been identified (4).

Juvenile polyps can also occur as part of known syndromes (Cowden, Gorlin and Bannayan-Zonana) in association with developmental abnormalities, dysmorphic features or other tumours. The juvenile polyps in these syndromes probably have a much weaker association with colon and other gastrointestinal cancers, although they may be associated with cancers at other sites. Cowden syndrome (CS; MIM 158350) is known as multiple hamartoma syndrome and individuals develop characteristic features such as cobblestone papules of the mouth, trichilemmomas, macrocephaly and meningiomas. CS predisposes to cancers of the thyroid and breast, as well as the colorectum in some reported cases (5). The CS gene is PTEN/MMAC1/TEP1 (10q22-q23) (6), a dual specificity phosphatase which acts as a tumour suppressor and is mutated in several sporadic tumour types, including glioblastomas, prostate carcinoma, thyroid cancers and a small proportion of breast cancers (7-15). A very small proportion of colon cancers have PTEN mutations (16). Inherited PTEN mutations are also responsible for Bannayan-Zonana syndrome (BZS; MIM 153480) (10,17); its features include macrocephaly, lipomas, speckled penis, haemangiomas and juvenile polyps. There is conflicting evidence concerning the suggestion that germline PTEN mutations can cause JPS in the absence of the other features of CS or BZS (18,19). Gorlin syndrome (GS; MIM 109400) is characterized by the development of basal cell naevi, basal cell carcinoma and palmar/plantar pitting. It results from germline mutations in the PTCH gene (the homologue of Drosophila patched) on chromosome 9q22.1 (20). Juvenile polyps comprise a relatively minor and infrequent component of this disease.

Apart from the possibility that a small number of JPS patients results from germline PTEN mutations, the genetic cause of the great majority of JPS cases has been unknown. Recently, however, a gene for JPS was mapped to 18q21.1 in a single large family (21). The minimal region, although as large as 9-11 cM between D18S1118 and D18S487, contained the candidate gene DPC4 (SMAD4), which is frequently mutated in gastrointestinal cancers. Howe et al. (22) subsequently showed that germline DPC4 mutations were indeed the cause of some cases of JPS.

We have previously tested a set of families with JPS for genetic linkage to and germline mutations in PTEN (18). There was no evidence for PTEN linkage in these families and no PTEN mutations were found. Here, we present the results of linkage analysis to the DPC4 region in eight JPS families. These families and 13 other unrelated JPS patients (either sporadic cases or from families unsuitable for linkage analysis) were then tested for germline mutations in the DPC4 gene.

RESULTS

The family haplotypes defined by D18S57, D18S1118, D18S1099 and D18S487 are shown in Figure 1. Haplotype inspection showed that four of the eight JPS families (MD, BRIS, HWK and to a lesser extent YAD) provide good evidence against linkage to this region, based on failure of affected individuals to share a common `disease-associated' haplotype (Fig. 1). Table 1 shows the two-point, multipoint and heterogeneity LOD scores for the families. Overall, there was no evidence for genetic linkage of JPS to the region studied, excluding DPC4 as the only locus responsible for JPS in our set of families.

Table 1. . LOD scores in the eight JPS families at markers D18S57, D18S1118, D18S1099 and D18S487

Locus Distance
from D8S57 (cM) LOD scores [alpha]

Two-point Multipoint HLOD

D18S57 0 -8.86 -9.50 0.00 0

D18S1118 6.1 1.80 -2.92 0.12 0.26

D18S1099 8.5 -1.15 -3.29 0.08 0.22

D18S487 13.4 -5.53 -6.54 0.00 0

Two-point and multipoint LOD scores at [thetas] = 0 are shown for each marker, together with the maximum heterogeneity LOD and the estimated proportion of families linked ([alpha]).

The mutation screen of DPC4 by conformation-specific gel electrophoresis (CSGE) and sequencing revealed a single JPS patient (AF) with a variant band in exon 8 on CSGE analysis. Sequencing (Fig. 2) showed this to result from a missense mutation in codon 361 of DPC4 (CGC->TGC, Arg->Cys). This change is predicted to abolish an MboI restriction site and the absence of this site in one of the patient's DPC4 alleles was used to confirm existence of the mutation (Fig. 2). Although this patient had a family history of JPS (affected parent), samples were not available to enable the presence of the mutation to be confirmed in other family members. None of 50 control individuals and none of the other JPS patients showed this variant. The amino acid change has potentially profound effects on protein function through, for example, disulphide bridge formation or disruption. No particular clinical features distinguished this patient from the others.

a

b

Figure 2. Germline DPC4 mutation in patient AF. (a) Part of the forward sequence of exon 8 is shown and the mutation (C->T) originally demonstrated by CSGE analysis is arrowed. A wild-type control sequence is shown above. Although the sequence change is relatively subtle, it is convincing. Note: (i) absence of the underlying T at the mutation site in the wild-type; (ii) the reduced height of the C peak in the heterozygote mutant; (iii) the sequentially reduced heights of `T' peaks in poly(T) tracts in this sequence, explaining why the mutant `T' is less strong than the wild-type `C' in the heterozygote mutant; and (iv) the absence of spurious `T' peaks underlying `C' in the sequence. The mutation was also shown in the reverse sequence (data not shown). (b) The gel shows confirmation of the mutation using differential restriction digests of the exon 8 PCR product with MboI. MboI restricts the wild-type PCR product of 232 bp to produce fragments of 154 and 68 bp; the latter of these is too small to visualize easily on agarose mini-gels. Lane 1, 100 bp ladder; lane 2, uncut wild-type (232 bp); lane 3, deliberately blank; lane 4, cut wild-type (154 bp fragment, smaller 68 bp not clearly visible); lanes 5 and 6, replicates of cut mutant (full-length 232 bp from mutant allele and 154 bp from wild-type allele visible, 68 bp not visible).

DISCUSSION

The tendency to develop juvenile polyps is undoubtedly a genetically heterogeneous trait. Clinical classification is of some help in distinguishing patients with germline mutations in the PTEN and PTCH genes from other patients with juvenile polyps. Recent work has identified germline mutations in the DPC4 (SMAD4) gene on 18q21.1 as a cause of JPS (juvenile polyposis associated only with colon carcinoma). We have found no evidence for linkage of JPS to DPC4 in a set of eight JPS families; two pedigrees were incompatible with DPC4 linkage and a further two families provided evidence against linkage. No DPC4 mutations were found in these eight families, but a germline DPC4 mutation was found in another familial case of JPS (out of a total of 21 familial and sporadic patients screened).

We conclude that mutations in the DPC4 gene are responsible for some cases of JPS, as reported by Howe et al. (22). Like the results of Howe et al., the mutation in our patient affects the C-terminus of the protein, but our variant is missense, whereas all the mutations of Howe et al. were frameshifts. Somatic missense mutations in DPC4 have been reported previously in colorectal cancers (24,25) and some of these changes may be refractory to detection by SSCP analysis (22). Just 5% of our JPS cases had a detectable DPC4 mutation, compared with five of nine patients (56%) in the study of Howe et al. One reason for this difference is that three patients studied by Howe et al. carried the same DPC4 mutation [del(ACAG), codons 414-416, exon 9], a variant which is easily detectable using SSCP or CSGE and which was certainly absent from our patient sample (22). The families studied by Howe et al. were not known to have a common ancestry, but they were generally larger than those in this study and it may be that the 4 bp deletion mutation is of high penetrance and/or leads to a severe phenotype. Both the study of Howe et al. and this study may underestimate the true frequency of DPC4 mutations in JPS families, because neither analysis searched for mutations involving the UTRs or promoter region of DPC4 or used methods which would have detected large deletions involving all or part of the DPC4 locus.

We have shown that there remains residual, unexplained genetic heterogeneity in JPS. Of our four families which provided good evidence against linkage to 18q21.1, two have disease which is unlinked to the PTEN locus (Young et al., unpublished data), one is compatible with PTEN linkage but no PTEN mutation was detected using DGGE (18) and one has not been tested for PTEN mutations. None of the families has notable features of CS, BZS or GS. It is extremely unlikely, moreover, that the failure to find DPC4 mutations in >90% of our cases resulted entirely from problems of methods or from an unusual mutation spectrum, given the presence of frameshift mutations (which should be easily detected using CSGE) in all the patients of Howe et al. (22). The extent of uncharacterized genetic heterogeneity in JPS is difficult to quantify until the spectrum of germline DPC4 mutations in this disease is established in both familial and sporadic cases. Certainly, our data suggest that DPC4 is a relatively infrequent cause of JPS. Identification of further JPS loci will be problematical, given the small size of most JPS families and the involvement of at least five genes in predisposition to juvenile polyps.

MATERIALS AND METHODS

Patient selection

JPS patients were identified from sources in the UK, Australia, Israel, USA and Japan. No patient had clinical features indicative of CS, GS or BZS. All affected individuals had more than one typical juvenile polyp as confirmed by histology. Sixteen patients had a known family history of JPS and eight of these pedigrees were suitable for linkage analysis. Five patients had no known relative affected with juvenile polyps, although in some cases relatives had developed colon carcinoma. DNA was extracted from blood samples from appropriate individuals using a standard sucrose lysis method.

Linkage analysis

Families were included in the linkage analysis if DNA was available from two or more affected individuals who were not parent and child. The linkage search was performed using fluorescent dye-labelled primers for polymorphic microsatellite markers mapping to 18q21. The following markers were studied: D18S57, D18S1118, D18S1099 and D18S487. DPC4 maps approximately equidistant between D18S1118 and D18S1099. Dye-labelled PCR products were detected on ABI 377 DNA sequencers and analysed using Genescan and Genotyper software.

Table 2. Oligonucleotides used for exon-by-exon amplification of DPC4 in the PCR

Exon Sequence Product size (bp)

1.F TTG CTT CAG AAA TTG GAG ACA 385

1.R GCT TGA AAG GAA ACG TAG CAA

2.F TGT ATG ACA TGG CCA AGT TAG 530

2.R CAA TAC TCG GTT TTA GCA GTC

3.F CTG AAT TGA AAT GGT TCA TGA AC 308

3.R GCC CCT AAC CTC AAA ATC TAC

4.F TTT TGC TGG TAA AGT AGT ATG C 509

4.R CTA TGA AAG ATA GTA CAG TTA C

5/6.F CAT CTT TAT AGT TGT GCA TTA TC 557

5/6.R TAA TGA AAC AAA ATC ACA GGA TG

7.F TGA AAG TTT TAG CAT TAG ACA AC 224

7.R TGT ACT CAT CTG AGA AGT GAC

8.F GGA TGT TCT TTC CCA TTT AT 224

8.R ACA ATC AAT ACC TTG CTC TC

9.F TAT TAA GCA TGC TAT ACA ATC TG 332

9.R CTT CCA CCC AGA TTT CAA TTC

10.F AGG CAT TGG TTT TTA ATG TAT G 293

10.R CTG CTC AAA GAA ACT AAT CAA C

11.F CCA AAA GTG TGC AGC TTG TTG 570

11.R ATT GTA TTT TGT AGT CCA CC

Some of these have been described by Moskaluk et al. (26).

The disease was modelled as a dominant trait (q = 0.001) with a penetrance of 0.7 and phenocopy rate of 0.001. The moderate penetrance value was used because there are reasons to suspect incomplete penetrance of genes for JPS [for example, owing to auto-amputation of polyps (1)] and because the age-dependent penetrance of juvenile polyposis is largely unknown. Individuals were classed as: `affected' if they had developed one or more histologically proven juvenile polyps; `unknown' if they had developed colorectal adenomas or colon or other gastrointestinal carcinoma without proven juvenile polyps; `unknown' if they were at risk and had not been screened by colonoscopy as an adult; and `unaffected' otherwise. Two-point and multipoint linkage analyses were performed using the GENEHUNTER program. Marker allele frequencies were estimated from the set of individuals studied. The family set studied provides a theoretical maximum LOD score of 4.64 (under genetic homogeneity).

Mutation screen

The search for germline mutations in the DPC4 gene was performed using CSGE. A combination of published and newly designed oligonucleotides was used to amplify each exon of DPC4 (including splice sites) specifically in the PCR (Table 2). CSGE was performed as described by Ganguly et al. (23). For each of the linkage families, two affected individuals were screened for mutations. All samples with bandshifts were sequenced in duplicate and in forward and reverse orientations after reamplification of the appropriate exon from genomic DNA in the PCR. Purified PCR products were sequenced using the ABI Ready Reaction Dye Terminator Cycle Sequencing kit and the 377 Prism sequencer. Mutations were confirmed, if appropriate, using wild-type- or mutant-specific restriction endonuclease digestion of the PCR product in question.

ACKNOWLEDGEMENTS

We thank the ICRF, CRC and Coeliac Society for support and James Howe for information on DPC4.

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*To whom correspondence should be addressed. Tel: +44 171 269 2884; Fax: +44 171 269 2885; Email: i.tomlinson@icrf.icnet.uk

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S ROTH, M JOHANSSON, A LOUKOLA, P PELTOMÄKI, H JÄRVINEN, J-P MECKLIN, and L A AALTONEN
Mutation analysis of SMAD2, SMAD3, and SMAD4 genes in hereditary non-polyposis colorectal cancer
J. Med. Genet., April 1, 2000; 37(4): 298 - 301.
[Full Text]

K. Takaku, H. Miyoshi, A. Matsunaga, M. Oshima, N. Sasaki, and M. M. Taketo
Gastric and Duodenal Polyps in Smad4 (Dpc4) Knockout Mice
Cancer Res., December 1, 1999; 59(24): 6113 - 6117.
[Abstract] [Full Text] [PDF]

S Bevan, K Woodford-Richens, P Rozen, C Eng, J Young, M Dunlop, K Neale, R Phillips, D Markie, M Rodriguez-Bigas, et al.
Screening SMAD1, SMAD2, SMAD3, and SMAD5 for germline mutations in juvenile polyposis syndrome
Gut, September 1, 1999; 45(3): 406 - 408.
[Abstract] [Full Text] [PDF]

K. L. Woodford-Richens, A. J. Rowan, P. Gorman, S. Halford, D. C. Bicknell, H. S. Wasan, R. R. Roylance, W. F. Bodmer, and I. P. M. Tomlinson
SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway
PNAS, August 14, 2001; 98(17): 9719 - 9723.
[Abstract] [Full Text] [PDF]

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Locus	Distance from D8S57 (cM)	LOD scores			[alpha]
Locus	Distance from D8S57 (cM)	Two-point	Multipoint	HLOD	[alpha]
D18S57	0	-8.86	-9.50	0.00	0
D18S1118	6.1	1.80	-2.92	0.12	0.26
D18S1099	8.5	-1.15	-3.29	0.08	0.22
D18S487	13.4	-5.53	-6.54	0.00	0

Exon	Sequence	Product size (bp)
1.F	TTG CTT CAG AAA TTG GAG ACA	385
1.R	GCT TGA AAG GAA ACG TAG CAA	385
2.F	TGT ATG ACA TGG CCA AGT TAG	530
2.R	CAA TAC TCG GTT TTA GCA GTC	530
3.F	CTG AAT TGA AAT GGT TCA TGA AC	308
3.R	GCC CCT AAC CTC AAA ATC TAC	308
4.F	TTT TGC TGG TAA AGT AGT ATG C	509
4.R	CTA TGA AAG ATA GTA CAG TTA C	509
5/6.F	CAT CTT TAT AGT TGT GCA TTA TC	557
5/6.R	TAA TGA AAC AAA ATC ACA GGA TG	557
7.F	TGA AAG TTT TAG CAT TAG ACA AC	224
7.R	TGT ACT CAT CTG AGA AGT GAC	224
8.F	GGA TGT TCT TTC CCA TTT AT	224
8.R	ACA ATC AAT ACC TTG CTC TC	224
9.F	TAT TAA GCA TGC TAT ACA ATC TG	332
9.R	CTT CCA CCC AGA TTT CAA TTC	332
10.F	AGG CAT TGG TTT TTA ATG TAT G	293
10.R	CTG CTC AAA GAA ACT AAT CAA C	293
11.F	CCA AAA GTG TGC AGC TTG TTG	570
11.R	ATT GTA TTT TGT AGT CCA CC	570

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				S ROTH, M JOHANSSON, A LOUKOLA, P PELTOMÄKI, H JÄRVINEN, J-P MECKLIN, and L A AALTONEN Mutation analysis of SMAD2, SMAD3, and SMAD4 genes in hereditary non-polyposis colorectal cancer J. Med. Genet., April 1, 2000; 37(4): 298 - 301. [Full Text]

				K. Takaku, H. Miyoshi, A. Matsunaga, M. Oshima, N. Sasaki, and M. M. Taketo Gastric and Duodenal Polyps in Smad4 (Dpc4) Knockout Mice Cancer Res., December 1, 1999; 59(24): 6113 - 6117. [Abstract] [Full Text] [PDF]

				S Bevan, K Woodford-Richens, P Rozen, C Eng, J Young, M Dunlop, K Neale, R Phillips, D Markie, M Rodriguez-Bigas, et al. Screening SMAD1, SMAD2, SMAD3, and SMAD5 for germline mutations in juvenile polyposis syndrome Gut, September 1, 1999; 45(3): 406 - 408. [Abstract] [Full Text] [PDF]