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Arquivos de Gastroenterologia

Print version ISSN 0004-2803

Arq. Gastroenterol. vol.49 no.4 São Paulo Oct./Dec. 2012 



CHEK2 1100DELC germline mutation: a frequency study in hereditary breast and colon cancer Brazilian families


Mutação germinativa 1100delC no gene CHEK2: estudo da frequência em famílias brasileiras com câncer de mama e cólon hereditários



Jamile AbudI,II; Patrícia Koehler-SantosII; Patricia Ashton-ProllaII, III, IV, V, VI João Carlos ProllaI, VII And The Study Group On Hereditary Breast And Colorectal Cancer*

I Programa de Pós-Graduação em Medicina: Ciências Gastroenterológicas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brasil
II Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brasil
III Serviço de Genética Médica, HCPA
IV Departamento de Genética, UFRGS
V Programa de Pós-Graduação em Genética e Biologia Molecular, UFRGS
VI Instituto Nacional de Genética Médica Populacional (INAGEMP), Brasil
VII Departamento de Medicina Interna, UFRGS





CONTEXT: CHEK2 encodes a cell cycle checkpoint kinase that plays an important role in the DNA damage repair pathway, activated mainly by ATM (Ataxia Telangiectasia Mutated) in response to double-stranded DNA breaks. A germline mutation in CHEK2, 1100delC, has been described as a low penetrance allele in a significant number of families with breast and colorectal cancer in certain countries and is also associated with increased risk of contralateral breast cancer in women previously affected by the disease. About 5%-10% of all breast and colorectal cancers are associated with hereditary predisposition and its recognition is of great importance for genetic counseling and cancer risk management.
OBJECTIVES: Here, we have assessed the frequency of the CHEK2 1100delC mutation in the germline of 59 unrelated Brazilian individuals with clinical criteria for the hereditary breast and colorectal cancer syndrome.
METHODS: A long-range PCR strategy followed by gene sequencing was used.
RESULTS: The 1100delC mutation was encountered in the germline of one (1.7%) individual in this high risk cohort. This indicates that the CHEK2 1100delC is not commonly encountered in Brazilian families with multiple diagnoses of breast and colorectal cancer.
CONCLUSION: These results should be confirmed in a larger series of families and further testing should be undertaken to investigate the molecular mechanisms underlying the hereditary breast and colorectal cancer phenotype.

Headings: Breast neoplasms, genetics. Colonic neoplasms, genetics. Protein-serine-threonine-kinase, genetics. Genetic predisposition to disease.


INTRODUÇÃO: CHEK2 codifica uma proteína quinase envolvida em um ponto de checagem do ciclo celular que desempenha um papel importante na via de reparação do DNA, danos ativados principalmente por ATM (Ataxia Telangiectasia Mutado) em resposta a danos na dupla hélice do DNA. A mutação germinativa 1100delC no gene CHEK2 tem sido descrita como um alelo de baixa penetrância em um número significativo de famílias com câncer de mama e cólon em certos países e também está associada com risco aumentado de câncer de mama contralateral em mulheres previamente afetadas pela doença. Cerca de 5%-10% de todos os cânceres de mama e colorretais estão associados a predisposição hereditária e o seu reconhecimento é de grande importância para o aconselhamento genético e gestão do risco de câncer.
OBJETIVOS: Neste estudo foi avaliada a frequência da mutação germinativa 1100delC no gene CHEK2 em 59 diferentes indivíduos brasileiros com critérios clínicos para a síndrome de câncer de mama e cólon hereditários.
MÉTODO: Utilizamos como estratégia a realização do PCR de longo alcance seguido de sequenciamento.
RESULTADOS: A mutação 1100delC foi encontrada em um indivíduo (1,7%), indicando que esta mutação germinativa não é comumente encontrada em famílias brasileiras com múltiplos diagnósticos de câncer de mama e câncer colorretal.
CONCLUSÃO: Estes resultados devem ser confirmados em uma série maior de famílias, e estudos adicionais devem ser realizados para investigar a patologia molecular do fenótipo HBCC.

Descritores: Neoplasias da mama, genética Neoplasias do colo, genética. Proteínas serina-treonina quinases. Predisposição genética para doença.




The CHEK2 gene (OMIM#604373, also known as CHK2) is the mammalian homologue of the Saccharomyces cerevisiae RAD53 and Schizosaccharomyces pombe Cds1 genes. In humans, it is located in 22q12.1, and encodes a cell cycle checkpoint kinase that is implicated in DNA damage responses(9, 19). Following the occurrence of double-stranded DNA breaks, CHEK2 is activated through phosphorylation by ATM. Activated CHEK2 then phosphorylates critical cell-cycle proteins, including Cdc25A and Cdc25C phosphatases, P1K3 kinase and the E2F1 transcription factor, as well as proteins involved in DNA repair (such as brca1) and in regulation of cell death (such as p53-mdm2 and pml-1). This reflects the wide mediator role of CHEK2 in the signaling pathways in response to DNA damage, with direct impact on downstream effectors within the cell cycle checkpoints, DNA repair and apoptosis machineries. These findings have been well documented in cells with a functional deficiency of CHEK2(28, 32).

CHEK2 has been considered a candidate tumor suppressor gene, and germline mutations in this gene seem to predispose to familial breast cancer (BC) and other malignancies(2, 6). In 1999, germline mutations in CHEK2 were associated with the Li-Fraumeni syndrome (LFS) phenotype(3). However, a strong association with the syndrome and this variant has never been confirmed(30). Also in 1999, Bell et al.(3) described for the first time the 1100delC mutation in exon 10 of CHEK2 in families with breast and/or colorectal cancer, and association with an intermediate relative risk for the occurrence of these tumors has been confirmed in subsequent reports(1, 24, 42). Meijers-Heijboer et al.(24) in the Netherlands investigated the frequency of CHEK2 1100delC in 55 families with multiple breast and colo-rectal cancer diagnoses and encountered the mutation in 18.2% of the families studied. Considering these results, the authors proposed a new phenotype associated to the CHEK2 1100delC mutation called hereditary breast and colon cancer syndrome (HBCC, OMIM#604373) (Figure 1). The majority of reports that associate germline CHEK2 mutations with HBCC syndrome, describe the 1100delC mutation. However, definition of CHEK2 1100delC as a high penetrance mutation is still controversial and the existence of HBCC as a true syndromic entity has been questioned by some authors(22, 26). In fact, limited data are available in the literature on true associations of germline CHEK2 mutations with the HBCC phenotype, and recent reports suggest that there may be significant geographic differences in mutation frequency. In this study, we describe the frequency of CHEK2 1100delC in Brazilian families with multiple cases of breast and colorectal cancer.




Patient recruitment

A total of 112 families with multiple diagnoses of breast and colorectal cancer fulfilling HBCC criteria(24, 26) were recruited from cancer genetics clinics located in three Brazi-lian capitals: Rio de Janeiro (Instituto Nacional do Câncer, INCA), São Paulo (Hospital A. C. Camargo, HCACC) and Porto Alegre (Hospital de Clínicas de Porto Alegre, HCPA) between March 2007 and October 2008. In addition, families with multiple diagnoses of breast and colorectal cancer (at least three diagnosis and at least one patient under the age of 50 years), but not fulfilling the HBCC criteria described above, were also included (Figure 2). Of the 112 families interviewed, 59 unrelated index cases had their personal and family histories of cancer confirmed by medical records, pathology reports and/or death certificates, and agreed to participate in the study, providing clinical data and biological samples after informed consent. Clinical data were obtained from review of medical records and from patient interviews by a clinical geneticist. Medical and family histories (FH) were recorded in detailed pedigrees with information traced as far backwards and laterally as possible, by extending through both maternal and paternal lines and including a minimum of three generations. Confirmation of cancer in the FH was attempted in all cases and pathology reports, medical records and/or death certificates were obtained whenever possible for relatives. Detailed information on tumor type, diagnosis and treatment were obtained for all index cases. All pedigrees were classified according to the clinical phenotypes that were observed. In addition to previously described criteria for the diagnosis of HBCC(24, 26), families were also reviewed for the presence of criteria for other cancer predisposition syndromes: HBOC (ASCO, NCCN), LFS/LFL (Classic, Birch, Eeles and Chompret)(4, 7, 8, 11, 14, 21, 27, 29, 35, 36) and Lynch Syndrome (Amsterdam criteria and Bethesda guideli-nes)(5, 39). All pedigrees and phenotypic criteria attributions were reviewed independently by two clinical geneticists. The study was approved by the local ethics committees in all three participating institutions.




DNA was extracted from peripheral blood using the Ilustra blood genomicPrep Mini Spin kit (GE Healthcare, Buckinghamshire, UK). Samples were submitted to PCR amplification using a long-range PCR methodology as des-cribed by Sodha et al.(34). Amplified products were submitted to sequencing in an ABI 3730 automated sequencer using the Big Dye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, USA) as described by the manufacturer. All analyses were performed in duplicates.

Statistical analysis

SPSS version 16.0 was used for data handling and statistical analyses. For descriptive analysis, categorical variables were described by their absolute and/or relative frequencies and quantitative variables were expressed as mean and standard deviation (SD).



Clinical data of the 59 unrelated patients included are summarized in Table 1. The mean age at recruitment was 48.5 years and the majority of probands were affected with breast cancer (69.6%). The average prior probability of being a carrier of a BRCA mutation in the overall sample was 16.0% and 16.4% using the mutation prevalence tables (Myriad) and the Penn II model (Penn II), respectively. The overall probability of carrying a BRCA mutation among breast cancer-affected probands (n = 41) was 20% and 18.2% using these two models, respectively. The prior probability of being a germline MMR mutation carrier (MLH1 and MSH2 genes) using the Premm 1.2 Model (Premm 1.2) was 7.3% in the overall sample and 13.8% among CRC affected probands.

CHEK2 1100delC mutation was identified in one of the 59 (1.7%) individuals studied. At recruitment, the patient was a 61 year-old woman diagnosed with breast cancer at the age of 52 years, and her family matched clinical criteria for HBCC according to Meijers-Heijboer et al.(24) and Naseem et al.(26) and none of the other criteria for hereditary breast and colorectal cancer syndromes that were considered in this study (Figure 3). The proband's breast tumor was an invasive ductal carcinoma, showing HER-2/neu oncoprotein overexpression, positive staining for progesterone receptor and negative staining for estrogen receptor.



A recurrent mutation in the CHEK2 gene (1100delC) was first reported to be an important cause of breast cancer by Meijers-Heijboer et al.(23). Since then, numerous studies have documented the prevalence of this single mutation in breast cancer-affected women from different countries. In a recent meta-analysis study, Weischer et al.(42) conclude that CHEK2 1100delC is an important breast cancer-predisposing mutation, which increases cancer risk by three-to five-fold in its carriers. In 2008, Wasielewski et al.(41), found a frequency of 4.2% of CHEK2 1100delC mutation in 237 patients diagnosed with Lynch syndrome, compared with a frequency of 1.0% in population controls, suggesting a strong association of this specific mutation with familial colorectal cancer (P = 0.002).

In the present study, we assessed the CHEK2 1100delC mutation among families with multiple breast and colorectal cancer diagnoses, and we encountered only one carrier proband, which is significantly less than expected from the original report by Meijers-Heijboer et al.(24) in families with similar cancer histories. However, other mutation prevalence studies among HBCC families in different countries point to a frequency of CHEK2 1100delC below 5% among HBCC families, including studies in Sweden, Spain and the United Kingdom(15, 26, 31). Thus, in the Netherlands, the CHEK2 1100delC mutation appears to be unusually frequent, and this is reflected in the finding that 4% of women with early onset breast cancer (irrespective of CRC history in the family) carry CHEK2 1100delC in that country. In other Northern European countries, the frequency of the mutation among early-onset BC patients appears to be lower (2.3% in Germany and 2.5% in Finland). Finally, in other countries, such as Spain and Australia, the mutation has been reported at a very low frequency(25). Based on these data, the worldwide distribution of the CHEK2 1100delC mutation is clearly heterogeneous and its frequency in different countries should be known before mutation screening initiatives are considered. We conclude that in Brazilian families, recruited from the Southern and Southeastern regions of the country and with a strong family history of breast and colorectal cancer, CHEK2 1100delC is not frequent. Further investigations of other CHEK2 mutations and/or mutations in other cancer predisposition genes are being undertaken in these families.



We are indebted to the patients and their family members who agreed to participate in this study and to Fundação de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPe-HCPA) and Programa de Pós-Graduação em Ciências Gastroenterológicas (UFRGS) who provided funding for this study. We thank Amanda de Nobrega, RN for help with patient recruitment.



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Dr. Jamile Abud
Laboratório de Medicina Genômica - Centro de Pesquisa Experimental - Hospital de Clínicas de Porto Alegre
Rua Ramiro Barcelos, 2350
90035-903 - Porto Alegre, RS, Brazil

Received 16/8/2012.
Accepted 12/9/2012.
Declared conflict of interest of all authors: none



* Grupo de Estudos de Câncer de Mama e Câncer Colorretal. Hereditários: Jamile Abud1,2; Patrícia Koehler-Santos2; Patricia Ashton-Prolla2, 3, 4, 5, 6; João Carlos Prolla1, 7; Cristina Rossi2, 8; Edenir Inez Palmero9; Fernando Regla Vargas10; Luciana Neves Nunes11; Maria Izabel Achatz12; Miguel Ângelo Moreira10; Patrícia Izetti2, 13; Silvia Liliana Cossio2, 6.
1 Programa de Pós-Graduação em Medicina: Ciências Gastroenterológicas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brasil; 2 Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brasil; 3 Serviço de Genética Médica, HCPA; 4 Departamento de Genética, UFRGS; 5 Programa de Pós-Graduação em Genética e Biologia Molecular, UFRGS; 6 Instituto Nacional de Genética Médica Populacional (INAGEMP), Brasil; 7 Departamento de Medicina Interna, UFRGS; 8 Faculdade de Medicina, UFRGS; 9 Laboratório de Oncologia Molecular, Hospital de Câncer de Barretos, SP, Brasil; 10 Instituto Nacional do Câncer (INCA), Rio de Janeiro, RJ, Brasil; 11 Departamento de Estatística, UFRGS; 12 Hospital do Câncer A.C. Camargo, São Paulo, SP, Brasil; 13 Unidade de Análises Moleculares e de Proteínas, HCPA.




In article "CHEK2 1100DELC germline mutation: a frequency study in hereditary breast and colon cancer Brazilian families" published in journal Arquivos de Gastroenterologia, v.49(4):273-8, on page 273 which was read:

Jamile ABUD1, João Carlos PROLLA1,2 and The Study Group on Hereditary Breast and Colorectal Cancer*
Jamile ABUD1,2, Patrícia KOEHLER-SANTOS2, Patricia ASHTON-PROLLA2, 3, 4, 5, 6, João Carlos PROLLA1, 7 and The Study Group on Hereditary Breast and Colorectal Cancer*

which was read:
* Grupo de Estudos de Câncer de Mama e Câncer Colorretal Hereditários: Jamile Abud1; João Carlos Prolla1, 2; Cristina Rossi3, 4; Edenir Inez Palmero5; Fernando Regla Vargas6; Luciana Neves Nunes7; Maria Izabel Achatz8; Miguel Ângelo Moreira6; Patricia Ashton-Prolla4, 9, 10, 11, 12; Patrícia Izetti4, 13; Silvia Liliana Cossio4, 12.
* Grupo de Estudos de Câncer de Mama e Câncer Colorretal. Hereditários: Jamile Abud1,2; Patrícia Koehler-Santos2; Patricia Ashton-Prolla2, 3, 4, 5, 6; João Carlos Prolla1, 7; Cristina Rossi2, 8; Edenir Inez Palmero9; Fernando Regla Vargas10; Luciana Neves Nunes11; Maria Izabel Achatz12; Miguel Ângelo Moreira10; Patrícia Izetti2, 13; Silvia Liliana Cossio2, 6.

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