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Imaging, Diagnosis, Prognosis |
Authors' Affiliations: 1 Gastroenterology Department, Germans Trias i Pujol Hospital, Universitat Autonòma de Barcelona; 2 Department of Gastroenterology, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona; 3 Department of Gastroenterology, Hospital del Mar, Barcelona, Spain; and Departments of 4 Pathology and 5 Gastroenterology, Hospital General Universitario de Alicante, Alicante, Spain
Requests for reprints: Xavier Llor, Gastroenterology Department, Germans Trias i Pujol Hospital, Carretera del Canyet s/n 08916 Badalona, Barcelona, Spain. Phone: 011-34-93-465-1200, ext. 3716; Fax: 011-34-93-497-8843; E-mail: xllor{at}comb.es.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionAppendix A: Study Organization...References |
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Experimental Design: This was a prospective, population-based, cohort that included 1,309 newly diagnosed colorectal cancer patients. Demographic, clinical, pathologic data and tumor DNA from probands as well as a detailed family history were collected. Microsatellite analysis and MLH1, MSH2, and MSH6 immunohistochemistry were done. Germ line MLH1 and MSH2 mutational analysis was done in all patients with evidence of MMR alterations.
Results: Twenty-five patients (1.9%) fulfilled Amsterdam criteria of HNPCC but 15 (60%) of them did not have microsatellite instability and showed normal expression of MMR proteins. These patients presented mostly left-sided tumors without lymphocytic infiltrate; they were older, had fewer family members affected with colorectal or endometrial cancers, and more often fulfilled Amsterdam II criteria than HNPCC patients with microsatellite instability. Like unstable HNPCC patients, this group without mutator pathway alterations had a significant percentage of synchronous and metachronous adenomatous polyps and cancers.
Conclusions: We define an important group of HNPCC families with specific features, no evidence of mismatch repair deficiency, and an autosomal dominant trait with a lesser penetrance than HNPCC with deficiency.
Genomic instability resulting in loss of heterozygosity is characterized by a sequential inactivation of oncosuppressor genes including APC, p53, DCC, SMAD2, and SMAD4. Tumors generated through this so-called suppressor pathway display chromosomal instability and frequent cytogenetic alterations and allelic losses. Much of what is known about this pathway has been learned from the study of familial adenomatous polyposis caused by germ line mutations in the APC gene. In fact, colorectal cancer with loss of heterozygosity has been considered the sporadic counterpart of the familial adenomatous polyposis syndrome.
The second and less common pathway of genomic instability is characterized by hypermutability and results in DNA MSI due to a failure to repair DNA mismatches after replication. This pathway was identified while searching for the gene responsible for hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome (2–4). The disruption of the DNA mismatch repair (MMR) system in HNPCC with MSI is mostly due to germ line mutations of the MMR genes MLH1, MSH2, and MSH6 whereas in sporadic high level instability (MSI-H) colorectal cancer, it is commonly due to somatic promoter hypermethylation of the MMR gene MLH1 (5). Nonfamilial MSI-H colorectal cancer has long been regarded as the sporadic counterpart of HNPCC. Recent data, based on molecular, pathologic, and clinical features, have questioned this view and suggest that the two groups may have distinct initiating mechanisms (6, 7). Thus, an important group of sporadic MSI-H would be associated with BRAF proto-oncogene mutations and gene promoter hypermethylation in the so-called "serrated pathway" of colorectal neoplasia (8).
HNPCC is the commonest form of hereditary colorectal cancer. It is an autosomal dominant disorder with a penetrance of around 80% and usually diagnosed at an early age. To unify the selection of these families for research studies, the Amsterdam criteria were drafted (9). Initial Amsterdam I criteria included presence of three family members with colorectal cancer, one of them being a first-degree relative of the other two; with at least two generations affected; and with at least one colorectal cancer diagnosed before age 50. This criteria turned out to be too strict, excluding small families or families that present with associated extracolonic tumors. Thus, the modified Amsterdam criteria and Amsterdam II criteria were proposed (10). Later on, the original (11) and revised (12) Bethesda guidelines, a set of clinicopathologic and familial features, have been validated (13) as a useful screening tool for the identification of HNPCC patients and eventually for distinguishing them from sporadic colorectal cancer tumors. Features commonly associated with HNPCC are predominance of right-sided colorectal cancer, excess of synchronous and metachronous colorectal cancer, and poorly differentiated histology with lymphocytic infiltration (14).
Whereas it has been suspected that MMR gene mutations are the underlying cause of HNPCC, an undetermined number of patients seem not to have these alterations. The heterogeneity of MMR gene mutations may be responsible for missing some of them while using conventional genomic DNA sequencing techniques. Other approaches, such as conversion analysis, could improve the yield in these cases (15). Nevertheless, it is yet unknown the effect of colorectal cancer that fulfills Amsterdam criteria but does not display any of the features commonly seen in colorectal cancer with alteration of the mutator pathway: MSI and lack of MMR protein expression or gene mutations. This could be due to the fact that the overwhelming majority of studies about HNPCC have been based on the retrospective evaluation of high-risk families or high-risk individuals. This situation resulted in national committees, such as the 2002 HNPCC National Cancer Institute workshop, recommending that HNPCC be studied from a population-based perspective (12). A recent report suggests that MMR gene mutation-negative tumors from clinically defined HNPCC patients have few alterations in the common pathways leading to colorectal carcinogenesis, suggesting that other unknown genes could be involved (16). Some distinctive clinicopathologic features of HNPCC without MSI had already been observed when Jass et al. (17) compared a group of families with hereditary colorectal cancer. In that study, microsatellite stable (MSS) HNPCC patients were older than MSI HNPCC patients; their tumors were less commonly on the right side of the colon, less often poorly differentiated and mucinous, and more often DNA aneuploid; and they did not present multiple cancers (17).
In this article, we report our results from a large, prospective, multicenter, nationwide cohort of 1,309 patients systematically recruited during a full year and from whom clinical and pathologic data, along with family history and tumor samples, were obtained. The main objectives of this study were to assess the relevance of clinically defined HNPCC patients without characteristic mutator pathway alterations and to identify their specific features.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionAppendix A: Study Organization...References |
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10% of all colorectal cancer diagnosed nationwide during 1 year (18). Nonconsenting patients (1.6%), patients with unavailable tumor DNA, as well as patients with adenomatous polyposis, a personal history of inflammatory bowel disease, or an incomplete family history were excluded. Participating centers collected demographic and clinical data, tumor-related variables from probands, and a detailed family history using a unified data base questionnaire. Cancer pedigrees were traced backward and laterally at least up to second-degree relatives. The Institutional Ethics Committee of each participating hospital approved the study and written informed consent was obtained from all patients. Every type of analysis (MSI testing, immunohistochemistry, and MMR gene sequencing) was done in a single center. Researchers working on specific procedures were blinded to the results obtained elsewhere.
Microsatellite instability analysis. The inactivation of the main MMR genes results in size changes of repetitive sequences that are scattered throughout the genome, a phenomenon called microsatellite instability (19). We obtained tumor DNA from the 1,309 patients included in this series. In 753 of them, samples were obtained fresh and DNA was also extracted from noninvolved colonic mucosa. In the rest, DNA was only extracted from formalin-fixed, paraffin-embedded tumor tissue. When tumor and uninvolved mucosa DNA were available, MSI analysis was done using the five markers recommended at the Bethesda conference of the National Cancer Institute (20): BAT-26, BAT-25, D5S346, D2S123, and D17S250. When only tumor DNA was available, the five quasimonomorphic mononucleotide repeats (BAT-26, BAT-25, NR21, NR22, and NR24) suggested by Suraweera et al. (21) and backed by the 2002 HNPCC workshop in Bethesda (12) were used. Tumors were classified as stable (MSS) if none of the markers showed instability. Tumors with >30% of unstable markers were classified as MSI-H and tumors with 
30% of unstable markers were classified as low-level MSI (MSI-L). All tumors evaluated using the Bethesda markers and found to be MSI-L were further studied with the additional set of NR mononucleotide markers to rule out MSI-H. MSI-H tumors with only altered dinucleotide markers were also evaluated with the additional set of NR markers according to the recommendations made in the mentioned workshop (12). Primers were labeled with fluorescence and analyzed on an ABI 3100 Avant Genetic Analyzer using GeneScan Analysis software (Applied Biosystems, Foster City, CA).
Tumor MLH1, MSH2, and MSH6 protein expressions. Pathogenic mutations in the MMR genes usually lead to an absence of protein product by immunohistochemistry staining (22). Immunohistochemistry for MLH1 and MSH2 was done in most tumors (93%). Immunohistochemistry for MSH6 was evaluated in HNPCC tumors (Amsterdam I and Amsterdam II), MSI-H tumors with normal MLH1 and MSH2 expression, and MSI-L tumors. Before immunostainning, antigen retrieval was done. Sections were then incubated with antibodies against MLH1 (clone G168-15, PharMingen, San Diego, CA), MSH2 (clone FE11, Oncogene Research Products, Boston, MA), and MSH6 (MSH6-GTBP, BD Biosciences, Erembodegem, Belgium). UltraVision streptavidin-biotin peroxidase detection kit (DAKO, Carpinteria, CA) was used as secondary detection system. Development was carried out with diaminobenzidine tetrachloride. Tumor cells were judged to be negative for protein expression only if they lacked staining in a sample in which normal colonocytes and stroma cells were stained.
MSH2/MLH1 germ line mutation analysis. Patients found to have tumors with MSI and/or lack of protein expression of either MSH2 or MLH1 underwent germ line genetic testing for MSH2 and MLH1 by both multiple ligation probe amplification analysis and sequencing, as described elsewhere (13).
Statistical analysis. Continuous variables are expressed as mean ± SD. All P values are two sided. For outcome analysis, patients were classified according to degree of MSI as MSI-H, MSI-L, and MSS. MSI-L data are not shown in the tables. For associations between clinicopathologic features and degree of MSI, statistical analysis was done using either 
2 test or Fisher's exact test. Variables included in the univariate analysis were sex, tumor location, mucin production, tumor differentiation, Dukes stage, family history, MMR immunohistochemistry results, and fulfillment of original Bethesda criteria. Continuous variables were analyzed by ANOVA test for comparisons of more than two groups and by Student's t test or Mann Whitney's U test for comparisons between two groups. Differences were considered significant if P < 0.05.
Variables achieving P < 0.1 in the univariate analysis were subsequently included in a stepwise forward logistic regression analysis to identify those variables independently associated with the presence of MSI-H. All calculations were done using the 12.0 SPSS software package (SPSS, Inc., Chicago, IL).
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Results |
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Specific features of hereditary nonpolyposis colorectal cancer patients (Amsterdam I and Amsterdam II) with and without characteristic mutator pathway alterations. A total of 25 patients fulfilled either Amsterdam I (17 patients) or Amsterdam II (8 patients) criteria of HNPCC. Therefore, the incidence of clinically defined HNPCC in this population-based study was 1.9%. Remarkably, in 15 (60%) of these patients, their tumors did not show MSI and expressed MLH1, MSH2, and MSH6 proteins. Comparing HNPCC patients with MSI tumors and HNPCC patients with MSS tumors (Table 1), the mean age at diagnosis of the probands was 64.8 for the former and 67.8 for the latter. Sex distribution was similar in both groups. The majority of the MSS HNPCC appeared on the left side of the colon (86.7%) whereas location was evenly distributed in the MSI HNPCC group. The latter group also showed a higher percentage of well-differentiated tumors (33.3%) than the former (0%). A low percentage of mucin production was seen in both groups. Whereas 50% of MSI HNPCC tumors had lymphocytic infiltrate, none of the MSS HNPCC tumors had it (0%). There were no significant differences between the two groups on the incidence of synchronous or metachronous colorectal adenomatous polyps. One MSI HNPCC patient had synchronous colorectal cancer. Two MSI HNPCC patients and one MSS HNPCC patient had metachronous colorectal cancer.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionAppendix A: Study Organization...References |
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Over the last few years, germ line mutations in the MMR genes MSH2 and MLH1 (23, 24), and to a lesser degree MSH6, PMS1, and PMS2, have been identified as the alterations responsible for this syndrome. In spite of that, these mutations are only identified in 50% to 70% of families meeting the stringent Amsterdam I criteria. This could be explained, at least in part, by the difficulty in identifying MMR gene mutations due to their heterogeneous nature (25). In fact, with the use of more sophisticated techniques, mutation detection can be significantly improved (15).
This would indeed be the case for tumors that show characteristic features of MMR gene mutations such as MSI or lack of MMR protein expression. Both types of alterations commonly coincide, showing an excellent correlation between them (13, 26, 27), and they almost invariably accompany deleterious MMR gene mutations (15, 27, 28).
On the other hand, little is known about the incidence, phenotype, and genetic alterations responsible for colorectal cancer in patients fulfilling Amsterdam criteria but not showing any evidence of mutator pathway abnormalities, such as MSI and absent MMR protein expression. The first report addressing this issue was based on the study of 50 families randomly chosen from a registry of hereditary colorectal cancer (17). After dividing them according to partial or total fulfillment of Amsterdam I criteria and MSI, they observed that MSS HNPCC patients were older than MSI HNPCC patients; their tumors were less commonly on the right side of the colon, less often poorly differentiated and mucinous, and more often DNA aneuploid; and they did not present multiple cancers (17). Later on, in a study that included a mix of families fulfilling Amsterdam I, Amsterdam II, or Bethesda criteria, Renkonen et al. (27) confirmed the older age at diagnosis of MMR gene mutation-negative patients and found a lower incidence of endometrial cancers in that group. Recently, a study geared to determine cancer risks in families fulfilling Amsterdam I criteria showed that HNPCC families without evidence of MMR defect had an increased incidence only of colorectal cancer, coinciding with the findings of previous studies, and had even smaller colorectal cancer risk than MMR-deficient families (29). Regarding the molecular mechanisms responsible for colorectal cancer development in these families, this group seems to have few of the molecular alterations seen in the common pathways leading to colorectal carcinogenesis, which suggests that other unknown genes might be involved (16).
The main purpose of this study was to assess the relevance of clinically defined HNPCC patients without characteristic mutator pathway alterations and to further define their specific features. A major strength of this study stems from the fact that this analysis was done in the context of a large, population-based cohort that included a very significant proportion of newly diagnosed colorectal cancer from an entire country over the course of a full year (13). A potential weakness of the study is that exclusion of familial adenomatous polyposis was decided solely on clinical grounds without systematic performance of APC and MYH mutation analysis. Therefore, it would be conceivable that some patients with attenuated forms of familial adenomatous polyposis could have ended up being included in the MSS HNPCC group of patients. We think this is unlikely because the number of adenomatous polyps found in that group averaged 0.4% per patient with a maximum of two polyps in two patients, which is way below the reported number of polyps for this syndrome. Finally, the pattern of inheritance of this group of MSS HNPCC patients is autosomal dominant and not recessive as seen in MYH causing attenuated familial adenomatous polyposis (30). Another potential limitation is that we did not perform immunohistochemistry or mutation analysis for PMS2, which was found to be the cause of almost 9% of MMR gene mutations in a recently published large series of colorectal cancer (31). In that study, all PMS2 mutations were found in MSI-H tumors; therefore, it is extremely unlikely that they could be the underlying cause of any of our MSS HNPCC patients.
We have been able to determine that this group of HNPCC patients (Amsterdam I or Amsterdam II), with none of the characteristic features of MMR deficiency, represents a very high percentage (
60%) of all HNPCC patients. As expected in an autosomal dominant pattern of inheritance, these patients have an equal gender distribution as observed in MSI HNPCC patients. Some important features set the MSS HNPCC group apart from the MSI HNPCC patients. In agreement with previous reports (17, 27), age at diagnosis is 6 years higher on average and most colorectal cancers appear on the left side of the colon. In addition, we have shown that these tumors neither have a lymphocytic infiltrate nor are well differentiated, and they present a similar percentage of synchronous and metachronous adenomatous polyps and colorectal cancer as MSI HNPCC. There were also significantly different findings from previous reports (17). We found a similar proportion (1/4) of undifferentiated tumors in both MSI HNPCC and MSS HNPCC patients. That percentage was similar to that of sporadic MSI tumors and much higher than that of nonfamilial forms of MSS tumors. Furthermore, mucin production was very low in all HNPCC patients (MSI and MSS) whereas it was strongly associated with sporadic MSI tumors.
We also found that this group of MSS HNPCC families had a lower percentage of members affected with colorectal cancer, which was in agreement with previous reports (17, 27, 29). On the other hand, contrary to previous findings, our series also showed a high incidence of endometrial cancer in these MSS HNPCC families. This could be due to differences in the studied populations. Thus, although we targeted all families fulfilling Amsterdam I and Amsterdam II criteria of HNPCC within a cohort of newly diagnosed colorectal cancer, the mentioned studies only included Amsterdam I families (17, 29). Amsterdam II criteria were precisely drafted to take into account extracolonic malignancies associated with this syndrome. In fact, in our series, MSS HNPCC families were more likely to satisfy Amsterdam II criteria and, within those families, there was a 2.7% incidence of endometrial cancer whereas among the MSS HNPCC fulfilling Amsterdam I criteria, only 0.6% of family members had endometrial cancers.
It is interesting to note that in our series, the mean age at cancer diagnosis of all family members with HNPCC was 10 to 15 years higher than what is usually reported. This is in agreement with the large series recently published by Lindor et al. (29) and it emphasizes the importance of studying colorectal cancer syndromes not only in highly selected referral populations but also in the context of a general colorectal cancer population.
Finally, a recent study has shown the existence of a different group of familial colorectal cancer with variable levels of MSI and BRAF mutations (32). None of the MSS HNPCC patients in our series presented such mutations.6
In summary, this large, prospective, multicenter, nationwide cohort allowed us to clarify important issues on the evaluation of colorectal cancer according to characteristic molecular features of the MMR deficiency pathway. We have also been able to study HNPCC from a general colorectal cancer population perspective and we have further defined an important group of HNPCC families with specific features, no evidence of MMR deficiency, and an autosomal dominant trait with a lesser penetrance than HNPCC with MMR deficiency. Future studies will have to address this group as a distinct entity. Furthermore, we will have to reconsider early diagnosis and management strategies for this group in light of the presented findings.
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Appendix A: Study Organization and Investigators from the Gastrointestinal Oncology Group of the Spanish Gastroenterological Association who Participated in the Study |
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TopAbstractMaterials and MethodsResultsDiscussionAppendix A: Study Organization...References |
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All participants listed below were fully involved in the study: Hospital 12 de Octubre, Madrid: Juan Diego Morillas (local coordinator), Raquel Muñoz, Marisa Manzano, Francisco Colina, Jose Díaz, Carolina Ibarrola, Guadalupe López, and Alberto Ibáñez; Hospital Clínic, Barcelona: Antoni Castells (local coordinator), Virgínia Piñol, Sergi Castellví-Bel, Francisco Rodríguez-Moranta, Francesc Balaguer, Antonio Soriano, Rosa Cuadrado, Maria Pellisé, Rosa Miquel, J. Ignasi Elizalde, and Josep M. Piqué; Hospital Clínico Universitario, Zaragoza: Ángel Lanas (local coordinator), Javier Alcedo, and Javier Ortego; Hospital Cristal-Piñor, Complexo Hospitalario de Ourense: Joaquin Cubiella (local coordinator), Ma. Soledad Díez, Mercedes Salgado, Eloy Sánchez, and Mariano Vega; Hospital del Mar, Barcelona: Montserrat Andreu (local coordinator), Xavier Bessa, Agustín Panadés, Asumpta Munné, Felipe Bory, Miguel Nieto, and Agustín Seoane; Hospital Donosti, San Sebastián: Luis Bujanda (local coordinator), Juan Ignacio Arenas, Isabel Montalvo, Julio Torrado, and Ángel Cosme; Hospital General Universitario de Alicante: Artemio Payá (local coordinator), Rodrigo Jover, Juan Carlos Penalva, and Cristina Alenda; Hospital General de Granollers: Joaquim Rigau (local coordinator), Ángel Serrano, and Anna Giménez; Hospital General de Vic: Joan Saló (local coordinator), Eduard Batiste-Alentorn, Josefina Autonell, and Ramon Barniol; Hospital General Universitario de Guadalajara: Ana María García (local coordinator), Fernando Carballo, Antonio Bienvenido, Eduardo Sanz, Fernando González, and Jaime Sánchez; Hospital General Universitario de Valencia: Enrique Medina (local coordinator), Jaime Cuquerella, Pilar Canelles, Miguel Martorell, José Ángel García, Francisco Quiles, and Elisa Orti; Hospital do Meixoeiro, Vigo: Juan Clofent (local coordinator), Jaime Seoane, Antoni Tardío, and Eugenia Sanchez; Hospital San Eloy, Baracaldo: Luis Bujanda (local coordinator), Carmen Muñoz, María del Mar Ramírez, and Araceli Sánchez; Hospital Universitari Germans Trias i Pujol, Badalona: Xavier Llor (local coordinator), Rosa M. Xicola, Marta Piñol, Mercè Rosinach, Anna Roca, Elisenda Pons, José M. Hernández, and Miquel A. Gassull; Hospital Universitari Mútua de Terrassa: Fernando Fernández-Bañares (local coordinator), Josep M. Viver, Antonio Salas, Jorge Espinós, Montserrat Forné, and Maria Esteve; Hospital Universitari Arnau de Vilanova, Lleida: Josep M. Reñé (local coordinator), Carmen Piñol, Juan Buenestado, and Joan Viñas; Hospital Universitario de Canarias: Enrique Quintero (local coordinator), David Nicolás, Adolfo Parra, and Antonio Martín; Hospital Universitario La Fe, Valencia: Lidia Argüello (local coordinator), Vicente Pons, Virginia Pertejo, and Teresa Sala; Hospital Universitario Reina Sofía, Córdoba: Antonio Naranjo (local coordinator), María del Valle García, Patricia López, Fernando López, Rosa Ortega, Javier Briceño, and Javier Padillo; Fundació Hospital Son Llatzer, Palma de Mallorca: Àngels Vilella (local coordinator), Carlos Dolz, and Hernan Andreu.
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 5/ 6/05; revised 7/10/05; accepted 7/21/05.
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TopAbstractMaterials and MethodsResultsDiscussionAppendix A: Study Organization...References |
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