Risk of cancer in cases of suspected lynch syndrome without germline mutation

María Rodríguez-Soler; Lucía Pérez-Carbonell; Carla Guarinos; Pedro Zapater; Adela Castillejo; Victor M. Barberá; Miriam Juárez; Xavier Bessa; Rosa M. Xicola; Juan Clofent; Luis Bujanda; Francesc Balaguer; Josep Maria Reñé; Luisa De-Castro; José C. Marín-Gabriel; Angel Lanas; Joaquín Cubiella; David Nicolás-Pérez; Alejandro Brea-Fernández; Sergi Castellví-Bel; Cristina Alenda; Clara Ruiz-Ponte; Angel Carracedo; Antoni Castells; Montserrat Andreu; Xavier Llor; José L. Soto; Artemio Payá; Rodrigo Jover

doi:10.1053/j.gastro.2013.01.044

Risk of cancer in cases of suspected lynch syndrome without germline mutation

María Rodríguez-Soler, Lucía Pérez-Carbonell, Carla Guarinos, Pedro Zapater, Adela Castillejo, Victor M. Barberá, Miriam Juárez, Xavier Bessa, Rosa M. Xicola, Juan Clofent, Luis Bujanda, Francesc Balaguer, Josep Maria Reñé, Luisa De-Castro, José C. Marín-Gabriel, Angel Lanas, Joaquín Cubiella, David Nicolás-Pérez, Alejandro Brea-Fernández, Sergi Castellví-BelCristina Alenda, Clara Ruiz-Ponte, Angel Carracedo, Antoni Castells, Montserrat Andreu, Xavier Llor, José L. Soto, Artemio Payá, Rodrigo Jover

Research output: Contribution to journal › Article › peer-review

179 Scopus citations

Abstract

Background & Aims: Colorectal cancers (CRCs) with microsatellite instability (MSI) and a mismatch repair (MMR) immunohistochemical deficit without hypermethylation of the MLH1 promoter are likely to be caused by Lynch syndrome. Some patients with these cancers have not been found to have pathogenic germline mutations and are considered to have Lynch-like syndrome (LLS). The aim of this study was to determine the risk of cancer in families of patients with LLS. Methods: We studied a population-based cohort of 1705 consecutive patients, performing MSI tests and immunohistochemical analyses of MMR proteins. Patients were diagnosed with Lynch syndrome when they were found to have pathogenic germline mutations. Patients with MSI and loss of MSH2 and/or MSH6 expression, isolated loss of PMS2 or loss of MLH1 without MLH1 promoter hypermethylation, and no pathogenic mutation were considered to have LLS. The clinical characteristics of patients and the age- and sex-adjusted standardized incidence ratios (SIRs) of cancer in families were compared between groups. Results: The incidence of CRC was significantly lower in families of patients with LLS than in families with confirmed cases of Lynch syndrome (SIR for Lynch syndrome, 6.04; 95% confidence interval [CI], 3.58-9.54; SIR for LLS, 2.12; 95% CI, 1.16-3.56; P <.001). However, the incidence of CRC was higher in families of patients with LLS than in families with sporadic CRC (SIR for sporadic CRC, 0.48; 95% CI, 0.27-0.79; P <.001). Conclusions: The risk of cancer in families with LLS is lower that of families with Lynch syndrome but higher than that of families with sporadic CRC. These results confirm the need for special screening and surveillance strategies for these patients and their relatives.

Original language	English
Pages (from-to)	926-932.e1
Journal	Gastroenterology
Volume	144
Issue number	5
DOIs	https://doi.org/10.1053/j.gastro.2013.01.044
State	Published - May 2013
Externally published	Yes

Bibliographical note

Funding Information:
Writing assistance was provided by SF edits and supported by the Instituto de Salud Carlos III (PI08/0726).

Funding Information:
Funding Supported by grants from Instituto de Salud Carlos III ( PI-080726 , INT-09/208 , and PI11/026030 ), the Fondo de Investigación Sanitaria/FEDER ( PS09/02368 , 10/00384 , 10/00918 , 11/00219 , and 11/00681 ), Fundació Olga Torres (to C.R.-P.) and FP7 CHIBCHA Consortium (S.C.-B. and A. Carracedo), the Ministerio de Economía y Competitividad ( SAF2010-19273 ), and Agència de Gestió d'Ajuts Universitaris i de Recerca ( 2009 SGR 849 ). S.C.-B. was supported by a contract from the Fondo de Investigación Sanitaria ( CP03-0070 ). CIBERER and CIBERehd are funded by the Instituto de Salud Carlos III.

Keywords

Cancer Risk
Genetic Testing
Immunohistochemistry
Inherited Colon Cancer

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10.1053/j.gastro.2013.01.044

Cite this

Rodríguez-Soler, M., Pérez-Carbonell, L., Guarinos, C., Zapater, P., Castillejo, A., Barberá, V. M., Juárez, M., Bessa, X., Xicola, R. M., Clofent, J., Bujanda, L., Balaguer, F., Reñé, J. M., De-Castro, L., Marín-Gabriel, J. C., Lanas, A., Cubiella, J., Nicolás-Pérez, D., Brea-Fernández, A., ... Jover, R. (2013). Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology, 144(5), 926-932.e1. https://doi.org/10.1053/j.gastro.2013.01.044

@article{450b909b5ac0469d966cb7cc573e2e2d,

title = "Risk of cancer in cases of suspected lynch syndrome without germline mutation",

abstract = "Background & Aims: Colorectal cancers (CRCs) with microsatellite instability (MSI) and a mismatch repair (MMR) immunohistochemical deficit without hypermethylation of the MLH1 promoter are likely to be caused by Lynch syndrome. Some patients with these cancers have not been found to have pathogenic germline mutations and are considered to have Lynch-like syndrome (LLS). The aim of this study was to determine the risk of cancer in families of patients with LLS. Methods: We studied a population-based cohort of 1705 consecutive patients, performing MSI tests and immunohistochemical analyses of MMR proteins. Patients were diagnosed with Lynch syndrome when they were found to have pathogenic germline mutations. Patients with MSI and loss of MSH2 and/or MSH6 expression, isolated loss of PMS2 or loss of MLH1 without MLH1 promoter hypermethylation, and no pathogenic mutation were considered to have LLS. The clinical characteristics of patients and the age- and sex-adjusted standardized incidence ratios (SIRs) of cancer in families were compared between groups. Results: The incidence of CRC was significantly lower in families of patients with LLS than in families with confirmed cases of Lynch syndrome (SIR for Lynch syndrome, 6.04; 95% confidence interval [CI], 3.58-9.54; SIR for LLS, 2.12; 95% CI, 1.16-3.56; P <.001). However, the incidence of CRC was higher in families of patients with LLS than in families with sporadic CRC (SIR for sporadic CRC, 0.48; 95% CI, 0.27-0.79; P <.001). Conclusions: The risk of cancer in families with LLS is lower that of families with Lynch syndrome but higher than that of families with sporadic CRC. These results confirm the need for special screening and surveillance strategies for these patients and their relatives.",

keywords = "Cancer Risk, Genetic Testing, Immunohistochemistry, Inherited Colon Cancer",

author = "Mar{\'i}a Rodr{\'i}guez-Soler and Luc{\'i}a P{\'e}rez-Carbonell and Carla Guarinos and Pedro Zapater and Adela Castillejo and Barber{\'a}, {Victor M.} and Miriam Ju{\'a}rez and Xavier Bessa and Xicola, {Rosa M.} and Juan Clofent and Luis Bujanda and Francesc Balaguer and Re{\~n}{\'e}, {Josep Maria} and Luisa De-Castro and Mar{\'i}n-Gabriel, {Jos{\'e} C.} and Angel Lanas and Joaqu{\'i}n Cubiella and David Nicol{\'a}s-P{\'e}rez and Alejandro Brea-Fern{\'a}ndez and Sergi Castellv{\'i}-Bel and Cristina Alenda and Clara Ruiz-Ponte and Angel Carracedo and Antoni Castells and Montserrat Andreu and Xavier Llor and Soto, {Jos{\'e} L.} and Artemio Pay{\'a} and Rodrigo Jover",

note = "Funding Information: Writing assistance was provided by SF edits and supported by the Instituto de Salud Carlos III (PI08/0726). Funding Information: Funding Supported by grants from Instituto de Salud Carlos III ( PI-080726 , INT-09/208 , and PI11/026030 ), the Fondo de Investigaci{\'o}n Sanitaria/FEDER ( PS09/02368 , 10/00384 , 10/00918 , 11/00219 , and 11/00681 ), Fundaci{\'o} Olga Torres (to C.R.-P.) and FP7 CHIBCHA Consortium (S.C.-B. and A. Carracedo), the Ministerio de Econom{\'i}a y Competitividad ( SAF2010-19273 ), and Ag{\`e}ncia de Gesti{\'o} d'Ajuts Universitaris i de Recerca ( 2009 SGR 849 ). S.C.-B. was supported by a contract from the Fondo de Investigaci{\'o}n Sanitaria ( CP03-0070 ). CIBERER and CIBERehd are funded by the Instituto de Salud Carlos III. ",

year = "2013",

month = may,

doi = "10.1053/j.gastro.2013.01.044",

language = "Ingl{\'e}s",

volume = "144",

pages = "926--932.e1",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "5",

}

Rodríguez-Soler, M, Pérez-Carbonell, L, Guarinos, C, Zapater, P, Castillejo, A, Barberá, VM, Juárez, M, Bessa, X, Xicola, RM, Clofent, J, Bujanda, L, Balaguer, F, Reñé, JM, De-Castro, L, Marín-Gabriel, JC, Lanas, A, Cubiella, J, Nicolás-Pérez, D, Brea-Fernández, A, Castellví-Bel, S, Alenda, C, Ruiz-Ponte, C, Carracedo, A, Castells, A, Andreu, M, Llor, X, Soto, JL, Payá, A & Jover, R 2013, 'Risk of cancer in cases of suspected lynch syndrome without germline mutation', Gastroenterology, vol. 144, no. 5, pp. 926-932.e1. https://doi.org/10.1053/j.gastro.2013.01.044

TY - JOUR

T1 - Risk of cancer in cases of suspected lynch syndrome without germline mutation

AU - Rodríguez-Soler, María

AU - Pérez-Carbonell, Lucía

AU - Guarinos, Carla

AU - Zapater, Pedro

AU - Castillejo, Adela

AU - Barberá, Victor M.

AU - Juárez, Miriam

AU - Bessa, Xavier

AU - Xicola, Rosa M.

AU - Clofent, Juan

AU - Bujanda, Luis

AU - Balaguer, Francesc

AU - Reñé, Josep Maria

AU - De-Castro, Luisa

AU - Marín-Gabriel, José C.

AU - Lanas, Angel

AU - Cubiella, Joaquín

AU - Nicolás-Pérez, David

AU - Brea-Fernández, Alejandro

AU - Castellví-Bel, Sergi

AU - Alenda, Cristina

AU - Ruiz-Ponte, Clara

AU - Carracedo, Angel

AU - Castells, Antoni

AU - Andreu, Montserrat

AU - Llor, Xavier

AU - Soto, José L.

AU - Payá, Artemio

AU - Jover, Rodrigo

N1 - Funding Information: Writing assistance was provided by SF edits and supported by the Instituto de Salud Carlos III (PI08/0726). Funding Information: Funding Supported by grants from Instituto de Salud Carlos III ( PI-080726 , INT-09/208 , and PI11/026030 ), the Fondo de Investigación Sanitaria/FEDER ( PS09/02368 , 10/00384 , 10/00918 , 11/00219 , and 11/00681 ), Fundació Olga Torres (to C.R.-P.) and FP7 CHIBCHA Consortium (S.C.-B. and A. Carracedo), the Ministerio de Economía y Competitividad ( SAF2010-19273 ), and Agència de Gestió d'Ajuts Universitaris i de Recerca ( 2009 SGR 849 ). S.C.-B. was supported by a contract from the Fondo de Investigación Sanitaria ( CP03-0070 ). CIBERER and CIBERehd are funded by the Instituto de Salud Carlos III.

PY - 2013/5

Y1 - 2013/5

N2 - Background & Aims: Colorectal cancers (CRCs) with microsatellite instability (MSI) and a mismatch repair (MMR) immunohistochemical deficit without hypermethylation of the MLH1 promoter are likely to be caused by Lynch syndrome. Some patients with these cancers have not been found to have pathogenic germline mutations and are considered to have Lynch-like syndrome (LLS). The aim of this study was to determine the risk of cancer in families of patients with LLS. Methods: We studied a population-based cohort of 1705 consecutive patients, performing MSI tests and immunohistochemical analyses of MMR proteins. Patients were diagnosed with Lynch syndrome when they were found to have pathogenic germline mutations. Patients with MSI and loss of MSH2 and/or MSH6 expression, isolated loss of PMS2 or loss of MLH1 without MLH1 promoter hypermethylation, and no pathogenic mutation were considered to have LLS. The clinical characteristics of patients and the age- and sex-adjusted standardized incidence ratios (SIRs) of cancer in families were compared between groups. Results: The incidence of CRC was significantly lower in families of patients with LLS than in families with confirmed cases of Lynch syndrome (SIR for Lynch syndrome, 6.04; 95% confidence interval [CI], 3.58-9.54; SIR for LLS, 2.12; 95% CI, 1.16-3.56; P <.001). However, the incidence of CRC was higher in families of patients with LLS than in families with sporadic CRC (SIR for sporadic CRC, 0.48; 95% CI, 0.27-0.79; P <.001). Conclusions: The risk of cancer in families with LLS is lower that of families with Lynch syndrome but higher than that of families with sporadic CRC. These results confirm the need for special screening and surveillance strategies for these patients and their relatives.

AB - Background & Aims: Colorectal cancers (CRCs) with microsatellite instability (MSI) and a mismatch repair (MMR) immunohistochemical deficit without hypermethylation of the MLH1 promoter are likely to be caused by Lynch syndrome. Some patients with these cancers have not been found to have pathogenic germline mutations and are considered to have Lynch-like syndrome (LLS). The aim of this study was to determine the risk of cancer in families of patients with LLS. Methods: We studied a population-based cohort of 1705 consecutive patients, performing MSI tests and immunohistochemical analyses of MMR proteins. Patients were diagnosed with Lynch syndrome when they were found to have pathogenic germline mutations. Patients with MSI and loss of MSH2 and/or MSH6 expression, isolated loss of PMS2 or loss of MLH1 without MLH1 promoter hypermethylation, and no pathogenic mutation were considered to have LLS. The clinical characteristics of patients and the age- and sex-adjusted standardized incidence ratios (SIRs) of cancer in families were compared between groups. Results: The incidence of CRC was significantly lower in families of patients with LLS than in families with confirmed cases of Lynch syndrome (SIR for Lynch syndrome, 6.04; 95% confidence interval [CI], 3.58-9.54; SIR for LLS, 2.12; 95% CI, 1.16-3.56; P <.001). However, the incidence of CRC was higher in families of patients with LLS than in families with sporadic CRC (SIR for sporadic CRC, 0.48; 95% CI, 0.27-0.79; P <.001). Conclusions: The risk of cancer in families with LLS is lower that of families with Lynch syndrome but higher than that of families with sporadic CRC. These results confirm the need for special screening and surveillance strategies for these patients and their relatives.

KW - Cancer Risk

KW - Genetic Testing

KW - Immunohistochemistry

KW - Inherited Colon Cancer

UR - http://www.scopus.com/inward/record.url?scp=84876492979&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2013.01.044

DO - 10.1053/j.gastro.2013.01.044

M3 - Artículo

AN - SCOPUS:84876492979

SN - 0016-5085

VL - 144

SP - 926-932.e1

JO - Gastroenterology

JF - Gastroenterology

IS - 5

ER -

Risk of cancer in cases of suspected lynch syndrome without germline mutation

Abstract

Bibliographical note

Keywords

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