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Multiple Approach to the Exploration of Genotype-Phenotype Correlations in Familial Adenomatous Polyposis

L. Bertario, A. Russo, P. Sala, L. Varesco, M. Giarola, P. Mondini, M. Pierotti, P. Spinelli, P. Radice for the Hereditary Colorectal Tumor Registry

From the Division of Predictive and Preventive Medicine, Department of Experimental Oncology, and Endoscopy Division, National Cancer Institute; Epidemiology Unit, Local Health Authority of Milan, Milan; and Division of Experimental Oncology, National Cancer Institute, Genoa, Italy.

Address reprint requests to Lucio Bertario, MD, National Cancer Institute, Via Venezian 1 20133 Milan, Italy; email: bertario{at}istitutotumori.mi.it.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Purpose: Familial adenomatous polyposis (FAP), caused by a mutation in the APC gene, is a colorectal cancer predisposition syndrome associated with several other clinical conditions. The severity of the FAP is related to the position of the inherited mutation in the APC gene. We analyzed a large series of FAP patients to identify associations among major clinical manifestations and to correlate the mutation site with specific disease manifestations.

Materials and Methods: APC mutations were identified in 953 FAP patients from 187 families. We used unconditional logistic regression models and a method involving generalized estimating equations to investigate the association between genotype and phenotype. We used multiple correspondence analysis to represent the interrelationships of a multiway contingency table of the considered variables.

Results: APC germline mutations were located between codons 156 and 2011 of the APC gene. Mutations spanning the region between codons 543 and 1309 were variable, but strongly associated with congenital hypertrophy of retinal pigment epithelium. Mutations between codons 1310 and 2011 were associated with a six-fold risk of desmoid tumors relative to the low-risk reference region (159 to 495). Mutations at codon 1309 were associated with early development of colorectal cancer. Mutations between codons 976 and 1067 were associated with a three- to four-fold increased risk of duodenal adenomas. The cumulative frequency of extracolonic manifestations was highest for mutations between codons 976 and 1067, followed by mutations between 1310 and 2011.

Conclusion: Analysis of the relation between APC mutation site and phenotype identifies subgroups of FAP patients at high risk for major extracolonic disease, which is useful for surveillance and prevention.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
FAMILIAL ADENOMATOUS polyposis (FAP) (OMIM 175100) is a dominantly inherited tumor predisposition syndrome, the incidence of which varies in different populations. In Italy, the annual incidence is estimated at 1 per 7,300 to 19,000 births.¹ The condition is caused by mutations in the adenomatous polyposis coli (APC) gene at 5q21, which encodes a protein of 2,843 amino acids. The APC protein may be regarded as a tumor suppressor; its major known functions include regulation of cell growth and migration, signal transduction, and control of chromosome stability.^2,3

The APC gene consists of 8,535 base pairs organized into 21 exons. Exon 10A, downstream of exon 10, is subject to alternative splicing and, when transcribed, adds an extra 18 amino acids to the APC protein. Exon 15 contributes 70% to the open reading frame, including the region that binds to (and downregulates) Beta-catenin (ß-catenin). ß-catenin is believed to be the main partner of APC in its tumor suppression function. The majority of germline and somatic APC mutations occur in exon 15, and more than 50% occur between codons 1286 and 1513—known as the mutation cluster region (MCR).⁴

The vast majority of functionally relevant germline mutations in the APC gene result in a truncated nonfunctional protein.^2,3 The contribution of missense mutations to the inherited risk of colorectal cancer (CRC) is unclear. Somatic APC mutations may result in protein truncation, loss of heterozygosity, or, less frequently, promoter hypermethylation. Recent work indicates that the type of APC germline mutation can determine the nature of the second hit. If a germline mutation is present between codons 1194 and 1392, then there is strong selection for loss of heterozygosity as the second hit in the development of colorectal adenoma. If the germline mutation is outside this region, the second hit is likely to be a truncating mutation in the MCR.^2,3

In addition to causing large numbers of colonic adenomas, which have a 100% lifetime risk of progressing to CRC, FAP is associated with extracolonic conditions including osteomas, epidermoid cyst, congenital hypertrophy of the retinal pigment epithelium (CHRPE), upper gastrointestinal (UGI) polyps or adenomas, desmoid tumors, and other malignancies at sites including brain, thyroid, and biliary tract.^5,6 Each extracolonic manifestation affects only a proportion of FAP patients, and genotype-phenotype correlation studies have shown that their occurrence is related to the position of the inherited mutation of the APC gene.^7–23

In this study, we examined a large number of genetically characterized Italian FAP patients to identify associations between major disease-related manifestations, and identify associations between these manifestations and mutations in specific regions of the APC gene. Such information may be useful in treatment and surveillance programs for FAP, and can also be used to narrow the search for APC mutations to specific regions in new APC patients, rather than screening the whole of the very large gene.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patients
We examined the records of 1,548 patients with classic FAP belonging to 275 unrelated families diagnosed during the period from 1980 to 2000. These patient cases were archived in the Hereditary Colorectal Tumor Registry at the National Cancer Institute of Milan and had been initially identified by the presence of more than 100 colorectal polyps on endoscopic examination. Patients without the classic phenotype, as attenuated FAP, were not excluded from the analysis^21,22 Before inclusion in the registry, information on the occurrence of CRC and on the extracolonic manifestations in the patients included in the study were verified from medical records and family history.

We analyzed 953 FAP patients (60% of total) from 187 (65% of total) unrelated families for whom the presence of an APC gene mutation had been ascertained in at least one family member. In the remaining 88 families (35%), an APC mutation was not found despite extensive testing.

Genetic Testing
The presence and type of APC mutations were determined by various methods, including single-strand conformation polymorphism assay, blue/white assay, and protein truncation test followed by sequence analysis. Once a mutation was identified in a proband, its presence was tested in all affected relatives for whom a DNA sample was available and informed consent for the analysis had been given.^21,22

Colorectal Cancer and Extracolonic Manifestations
Information on the occurrence of CRC and extracolonic conditions was extracted from medical records and family histories archived in the Hereditary Colorectal Tumor Registry. All institutions contributing to the Hereditary Colorectal Tumor Registry followed a standardized protocol of management. Where necessary, data were checked by reviewing the original laboratory, surgical, or pathologic reports.

Epidermoid cysts and osteomas were identified by physical examination. Mandibular osteomas and dental or jaw abnormalities were identified from panoramic radiographs of the maxilla and mandible.

CHRPE was diagnosed by funduscopic examination. Patients were considered positive when at least one large lesion (larger than the diameter of one optic disc) was evident.⁸

Desmoid tumors, verified by reviewing clinical, surgical, and pathologic records, were classified according to localization: abdominal for mesenteric or retroperitoneal sites, and extra-abdominal for tumors elsewhere, including the abdominal wall. Multiple localizations (abdominal and extra-abdominal) were classified as abdominal.

The presence of gastroduodenal adenomas was assessed by upper (frontal or side viewing) endoscopy and histologic diagnosis.

Classification of APC Mutations
To analyze mutations, we divided them into groups of approximately equal number using a reiterative ranking procedure, introduced using two stopping rules: mutations at codon 1309 were retained as a separate category, and the reiterative procedure was stopped when 70% of the groups consisted of at least 100 cases.

We also used the four mutation classifications proposed in correlation studies by Caspari et al,¹⁴ Vasen et al,²⁴ Wallis et al,²⁵ and Lamlum et al.²⁶ These classifications are as follows: (1) two groups, including mutations up to and including codon 1444 and mutations beyond codon 1444;¹⁴ (2) three groups, including mutations up to and including codon 1249, mutations from codons 1250 to 1464 inclusive, and mutations beyond codon 1464;²⁴ (3) four groups, including mutations up to and including codon 456, mutations from codons 457 to 1309 inclusive, mutations from codons 1310 to 1493 inclusive, and mutations beyond codon 1493;²⁵ and (4) three groups, including mutations before, at, and beyond codon 1309, on the basis of the observation that mutations at codon 1309 are associated with an aggressive phenotype characterized by an exceptionally large number of polyps and development of CRC at an early age.²⁶

It has been shown that the level of expression of the truncated APC protein may vary greatly,^2–5 possibly influencing the biologic consequences of the germline mutation. However, the level of mutant protein could not be used as a criterion for mutation classification because of a lack of data for numerous specific mutations.

Statistical Methods
Crude odds ratio (ORs) and corresponding 95% confidence intervals (CIs) were calculated to assess associations between different clinical manifestations. To determine associations between clinical manifestations and mutations (classified in the five ways described above) we used unconditional multiple logistic regression and the generalized estimating equation (GEE) method for analyzing correlated data with a binary response, using the exchangeable working correlation structure.²⁷ The multiple regression approach does not take clustering of manifestations within families into account, whereas the GEE method does.

For all five mutation classifications, ORs and 95% CIs were calculated for each mutation group by both the individual approach (multiple regression) and considering families (GEE method). Both types of analysis included terms for age, sex, family size, and mean age of FAP diagnosis in the family.

To relate age of FAP and CRC diagnosis to mutation category, we used analysis of covariance with the Scheffé test for subsequent multiple comparisons.

To further explore the relation between phenotype and genotype, we used correspondence analysis. Correspondence analysis is a weighted principal component analysis of a multiway table that gives a low-dimensional graphical representation of all the levels of each categorical variable.²⁸ Each level is represented by a point in the Euclidean space in such a way that the distance between any two points may be interpreted in terms of the strength of the association between the corresponding categories. In addition, the points corresponding to different levels of the same variable are plotted at distances from the origin that are inversely related to their weight (ie, the number of subjects in the corresponding level). All analyses were performed using SAS version 8.02 (SAS Institute, Cary, NC).

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
All mutations were found to occur between codons 159 to 2011 inclusive (Fig 1). Each specific mutation was generally confined to a single family. However, mutations at codon 1309 were found in 33 of the 187 families (17.6%); mutations at codon 1061 occurred in 16 families (8.6%); mutations at codons 213, 935, and 1068 each affected three families (4.8%); and mutations at codons 564, 1112, 1539, and 1556 each affected two families (4.3%).

View larger version (12K): [in this window] [in a new window]   Fig 1. Distribution of mutations in the present series compared with the distribution in mutations in the APC mutation database (http://perso.curie.fr/Thierry.Soussi/APC.html).

Cancers
Of 953 mutation carriers, 401 (42%) had CRC at FAP diagnosis and 70 of 401 (17%) had multiple synchronous CRCs. Age at CRC diagnosis was 41 years (range, 16 to 79 years). Twenty-five mutation carriers developed 26 extracolonic cancers within the FAP spectrum, comprising eight stomach cancers, six of the papilla of Vater, two of the biliary tract, one of the pancreas, five thyroid cancers, and three medulloblastomas. One patient developed cancers of the stomach and of the papilla of Vater. Twelve other mutation carriers developed additional cancers: three ovarian cancer, three uterine cancer, two respiratory tract cancer, two renal cancer, one breast cancer, and one soft tissue sarcoma.

Extracolonic Manifestations
The Hereditary Colorectal Tumor Registry began in 1975, and the frequency and sensitivity of diagnostic procedures have improved markedly over the quarter century since then. For this reason, all or most FAP-related extracolonic manifestations had been extensively investigated in only 212 mutation carriers, and the number of patients for whom information on a clinical manifestation was available varied with the manifestation.

At least one extracolonic manifestation was observed in 698 (73.2%) of the 953 carriers from 171 (91.4%) of the 187 families.

CHRPE was the most common extracolonic manifestation and was present in 74% of patient cases investigated, followed by osteomas (43%), epidermoid cyst (25%), UGI adenoma (51%; duodenal 30%, gastric 21%), dental abnormalities (22%), intra-abdominal desmoid tumor (16%), and extra-abdominal desmoid tumor (12%). Table 1 shows relations between colonic and extracolonic manifestations in individuals with APC mutation (above the diagonal) and according to family (below the diagonal), with crude ORs and 95% CIs for the associations. A family was considered positive for a given manifestation when it was present in at least one member.

Genotype-Phenotype Correlations
Table 2 shows the genotype-phenotype correlations found when we divided APC mutations into eight groups by the automatic ranking procedure. ORs with CIs that are highlighted by shading and bold type in Table 2 are significant. It was found that mutations spanning a considerable portion of the gene (between codons 543 and 1309) were associated with a variable but generally high risk of CHRPE. Mutations downstream of codon 1309 were associated with about a six-fold increase in risk for desmoid tumors relative to the reference category (mutations between 159 and 495). Mutations from codon 976 to 1067 were associated with a three- to four-fold increase of risk for duodenal adenomas. The highest cumulative frequencies of extracolonic manifestations were associated with mutations between codons 976 and 1067 and between codons 1310 and 2011.

The results of multiple correspondence analysis are shown in Fig 2, for which the mutations were grouped according to the classification of Table 2. Correlations are indicated graphically by the proximity of the conditions and mutations to each other. Thus, desmoid tumors (extra- and intra-abdominal) were related to mutations between codons 1310 and 2011. UGI adenomas (particularly duodenal adenomas) correlated with mutations between codons 976 and 1067, whereas dental abnormalities were strongly associated with osteomas, and both conditions were associated with mutations between codons 1256 and 1303. Finally, the three major categories—mutation at codon 1309, CRC, and CHRPE—aggregated close to the origin of the graph because a large proportion of FAP patients exhibited all three features. When we placed mutation 1309 at the origin of the axes, the closest phenotypic manifestations were CRC and CHRPE. However, when we placed CHRPE at the origin, three groups of mutations were close to each other: codon 1309, codons 543 to 713, and codons 721 to 972. These codon categories were also associated with high risk for CHRPE in the multivariate analyses (Table 2). The reference category, codons 159 to 495 (farthest on the left in Fig 2), and other neoplasms (bottom right) were independent of all other variables.

View larger version (12K): [in this window] [in a new window]   Fig 2. Two-dimensional graphical representation of correspondence analysis. Each point was identified in Euclidean space by coordinates derived from the correspondence analysis. Abbreviations: CRC, colorectal cancer; CHRPE, congenital hypertrophy of the retinal pigment epithelium.

Using the classification of Vasen et al,²⁴ developed to investigate the association of mutation position with large bowel cancer, we found that mutations between codons 1250 and 1464 had a significantly increased risk of early CRC, mutations after codon 1464 were associated with a significantly increased risk of intra-abdominal desmoids, and mutations after codon 1250 were associated with increased risk of extra-abdominal desmoid tumors.

With the classification of Wallis et al,²⁵ mutations between codons 457 and 1309 had a high risk (ORs, 9.1 and 6.9) of CHRPE, mutations beyond codon 1493 were associated with increased risk of desmoid tumors, and mutations beyond codon 1493 were associated with a high risk of desmoid tumors (10-fold increase for intra-abdominal desmoids and 20-fold increase for extra-abdominal desmoids). The risk of CRC was increased for mutations from between codons 457 and 1309.

With the Lamlum et al²⁶ classification, which identified mutations at codon 1309 as related to early age at onset of CRC, a similar pattern of risks to that obtained by division at 1444 emerged. For all four classifications investigated, mutations at codon 1309 were associated with the greatest risk of early-onset CRC.

Finally, comparison of the mutational spectrum in our series with that of the APC mutation database of the Pasteur Institute (Fig 1) showed few differences, indicating little variation in the spectrum of APC mutations throughout Europe.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The discovery of the APC gene and its tumor suppressor role led to major advances in our understanding of the role of DNA alterations in the development of CRC.^2–4 The FAP syndrome is a good example of the one gene–one disease paradigm: numerous mutations are found, but most produce the well-defined phenotype of a hundred to thousands of large bowel adenomas (which invariably progress to CRC) and are associated with a large spectrum of extracolonic manifestations.

Numerous studies have established that specific phenotypic characteristics correlate with the position of the APC mutation.^{11,12,17,19,21,22} In this series of APC mutation carriers with classic FAP, at least one extracolonic lesion was found in 75% of patient cases (a result that is similar to previously described proportions^7–23), and a similarly wide spectrum of extracolonic manifestations was revealed.

Our study consisted of all the patients registered prospectively with the Hereditary Colorectal Tumor Registry whose mutational status had been characterized. The Registry was established in 1975 and in the time elapsed since then, the follow-up protocols applied to FAP patients and their families have become more intensive and have been accompanied by improvements in diagnostic procedures, including the introduction of new modalities (computed tomography or magnetic resonance imaging to identify desmoid tumors and random biopsies to identify UGI polyps). As a result, the numbers of patients investigated for each extracolonic manifestation varied markedly. In the register, a total of 377 patients underwent endoscopic examinations, resulting in the detection of UGI adenomas in 51% of the patients. Published detection rates for UGI adenomas vary between 20% and 100% and are influenced by the experience of the endoscopist, the type of endoscope used (side-viewing instruments are more sensitive), and the use of random biopsies when macroscopic lesions are not found.²⁹

We found that mutations between codons 976 and 1067 were associated with significant (four-fold) increase in the risk of duodenal adenomas. A recent article reported that a mutation downstream of exon 9 may be associated with reduced development of duodenal adenomatosis and a strikingly high prevalence of duodenal adenomas in patients with mutations at codons 479 to 1700,³⁰ whereas another study indicated that mutations downstream of codon 1051 may be associated with severe periampullary lesions.³¹

The presence of CHRPE in our patients was strongly associated with mutations anywhere in the large portion of the gene spanning exons 9 to 15. In contrast, CHRPE was not significantly associated with mutations beyond codon 1309, whereas the risk of desmoid tumor was greatly increased (> six-fold) for mutations beyond codon 1309. Previous studies reported that CHRPE is associated with mutations between codons 463 and 1444^14,32 (ie, including the sequence beyond codon 1309), whereas most classic FAP families with desmoids but without CHRPE generally have germline mutations between codons 1445 and 1578.^14,33 Three studies, including one on our series of desmoid tumor patients, found that carriers of mutations between codons 1445 and 1578 develop desmoid tumors more frequently than those with mutations in other regions of the APC gene.^14,15,22

With regard to CRC, we found a risk pattern for early onset that differed from that produced by other mutation classifications. Most studies indicate that mutations beyond codon 1250 are associated with a more aggressive CRC phenotype, manifesting as early-onset disease. We also found that mutations between codons 1256 and 1303 were associated with a significantly increased risk of early CRC (as well as those at codon 1309, as expected). However, we also found a significantly increased risk associated with two areas before codon 1250: 543 to 713 and 976 to 1067.

Findings for FAP phenotype are similar to those described above for age of CRC onset in that a sparse phenotype (1,000 to 2,000 polyps) is associated with germline mutations between codons 213 and 1597,⁷ whereas a profuse phenotype (> 5,000 polyps) is associated with mutations from codons 1250 to 1464.^11,12 The most frequent APC germline mutation, at codon 1309, is associated with severe FAP characterized by thousands of colorectal adenomas and early-onset CRC.^11,13 CRC can now be prevented by screening and early colectomy, so this specific mutation is less important in this respect. However, the increase in survival achieved by prophylactic colectomy is balanced by the increased lifetime risk for extracolonic diseases and consequent change in the natural history of FAP.³⁴

We used correspondence analysis to identify multiple associations between specific manifestations. Using this technique, we found a relation between mutations beyond codon 1256 and epidermoid cysts, desmoid tumors, osteomas, and dental abnormalities. This association of clinical features corresponds to the well-known Gardner syndrome variant of classic FAP.

The phenotypic heterogeneity among patients carrying the same APC mutation, reported by previous studies,^35–37 supports the view that APC-modifying genes or epigenetic and environmental factors may influence the expression of the disease, and various hypotheses have been advanced in this respect. In particular, the severity and progression of duodenal adenomatosis may not be determined by the APC gene alone,^6,38,39 and a modifier gene located on chromosome 1p35–36 may be involved.^40,41 Although the precise functions of the APC gene product have not been fully elucidated,³ it is known to be involved in the regulation of beta-catenin, cell adhesion, and cytoskeleton organization at the transcriptional level (possibly also in neurons).^2,3 It also seems that environmental factors such as diet play an important role in animal models of FAP.⁴² Furthermore, stochastic, genetic, or environmental factors are essential for the development of certain manifestations, thereby reducing the direct influence of the APC gene mutation site on the phenotype.^2,3

In conclusion, this study on a large number of FAP patients, who were extensively characterized both clinically and genetically, found several specific and highly significant phenotype-phenotype and phenotype-genotype associations. This indicates that the clinical attitude toward APC gene mutation carriers should depend on the specific mutation carried, inasmuch as the risk of several major colonic or extracolonic manifestations depends markedly on the mutation site. Age of CRC onset correlated with mutations at several sites, but early onset was particularly associated with mutation at codon 1309 (average age, 35 years); desmoid tumors were highly associated with mutations beyond codon 1310; duodenal adenomas were significantly associated with mutations between codons 967 and 1067. These findings are fully consistent with previously published findings and contribute to the definition of more detailed risk profiles for individual FAP patients on the basis of a genotype assessment. The findings also contribute to modulate follow-up strategies and introduce ad hoc chemopreventive programs, which are expected to help further improve the outcome for individuals affected with FAP.

	APPENDIX

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following institutions and investigators are part of the Hereditary Colorectal Tumors Registry:M.P. Baldacci, L. Grossano, L. Maculotti, G. Sansonetti, P. Setti Carraro, G. Toti, Milano; F. Barberani, Terni; T. Bruni, Mantova; L. Bucci, A. Tempesta, G.P. Ferulano, A. Renda, Napoli; G. Carassale, Firenze; M. Cataldi, Como; S. Civitelli, M. Messina, Siena; L. Dall’Oglio, A. Lorenzotti, M. Malerba, M. Pescatori, G. Ribotta, P. Fracasso, S. Valabrega, Roma; R. Gentilini, G. Roggia, S. Piffer, Trento; M. Grazia, Verona; C. Marchese, M. Pinna Pintor, Torino; C. Massazza, Varese; M. Moretti, Perugia; A. Paterlini, Brescia; M. Pisani, Piacenza; M. Ponz De Leon, Modena; E. Scarcello, Pisa; P. Tansini, Piacenza; and F. Tricarico, Foggia, Italy.

The following databases can be found online: OMIM (available at http://www.ncbi.nlm.nih.gov/Omim) and the APC database (available at http://perso.curie.fr/Thierry.Soussi/APC.html).

	ACKNOWLEDGMENTS

 
We thank all study participants and collaborators, Patrizia Di Benedetto for editorial assistance, Professor Adriano Decarli for a critical reading of the manuscript, and D.C. Ward for help with the English.

	NOTES

 
Supported by the Italian Association for Cancer Research.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted September 23, 2002; accepted January 30, 2003.

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