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 journalArticlepeer-review

168 Scopus citations


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 languageEnglish
Pages (from-to)926-932.e1
Issue number5
StatePublished - May 2013

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.


  • Cancer Risk
  • Genetic Testing
  • Immunohistochemistry
  • Inherited Colon Cancer


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