Prevalence of germline MUTYH mutations among Lynch-like syndrome patients

Adela Castillejo; Gardenia Vargas; María Isabel Castillejo; Matilde Navarro; Víctor Manuel Barberá; Sara González; Eva Hernández-Illán; Joan Brunet; Teresa Ramón Y Cajal; Judith Balmaña; Silvestre Oltra; Sílvia Iglesias; Àngela Velasco; Ares Solanes; Olga Campos; Ana Beatriz Sánchez Heras; Javier Gallego; Estela Carrasco; Dolors González Juan; Ángel Segura; Isabel Chirivella; María José Juan; Isabel Tena; Conxi Lázaro; Ignacio Blanco; Marta Pineda; Gabriel Capellá; José Luis Soto

doi:10.1016/j.ejca.2014.05.022

Prevalence of germline MUTYH mutations among Lynch-like syndrome patients

Adela Castillejo, Gardenia Vargas, María Isabel Castillejo, Matilde Navarro, Víctor Manuel Barberá, Sara González, Eva Hernández-Illán, Joan Brunet, Teresa Ramón Y Cajal, Judith Balmaña, Silvestre Oltra, Sílvia Iglesias, Àngela Velasco, Ares Solanes, Olga Campos, Ana Beatriz Sánchez Heras, Javier Gallego, Estela Carrasco, Dolors González Juan, Ángel SeguraIsabel Chirivella, María José Juan, Isabel Tena, Conxi Lázaro, Ignacio Blanco, Marta Pineda, Gabriel Capellá, José Luis Soto

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

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Abstract

Background and aims Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients. Methods Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed. Results We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P = 0.02) and wildtype patients (P < 0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P < 0.0001). Conclusions A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients.

Original language	English
Pages (from-to)	2241-2250
Number of pages	10
Journal	European Journal of Cancer
Volume	50
Issue number	13
DOIs	https://doi.org/10.1016/j.ejca.2014.05.022
State	Published - Sep 2014

Bibliographical note

Funding Information:
This work was funded by the Spanish Ministry of Economy and Competitiveness (grant SAF2012-33636 ); the Scientific Foundation Asociación Española Contra el Cáncer ; the Government of Catalonia (grant 2009SGR290 ), Fundación Mutua Madrileña (grant AP114252013 ), RTICC MINECO Network RD12/0036/0031 and RD12/0036/0008 , and the Biomedical Research Foundation from the Hospital of Elche (FIBElx-CO11/03). AC and M-IC are funded by Health and Biomedical Research Foundation from the Valencian Region ( FISABIO ). The Mexican National Council for Science and Technology (CONACyT) fellowship to GV. EH-I is recipient of a fellowship from the Fondo Investigación Sanitaria ISCIII (FI12/00233).

Keywords

KRAS mutations
Lynch syndrome
MAP syndrome
MUTYH

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10.1016/j.ejca.2014.05.022

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Castillejo, A., Vargas, G., Castillejo, M. I., Navarro, M., Barberá, V. M., González, S., Hernández-Illán, E., Brunet, J., Ramón Y Cajal, T., Balmaña, J., Oltra, S., Iglesias, S., Velasco, À., Solanes, A., Campos, O., Sánchez Heras, A. B., Gallego, J., Carrasco, E., González Juan, D., ... Soto, J. L. (2014). Prevalence of germline MUTYH mutations among Lynch-like syndrome patients. European Journal of Cancer, 50(13), 2241-2250. https://doi.org/10.1016/j.ejca.2014.05.022

@article{1fc4a364b8dd45dbac17d63db909db18,

title = "Prevalence of germline MUTYH mutations among Lynch-like syndrome patients",

abstract = "Background and aims Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients. Methods Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed. Results We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P = 0.02) and wildtype patients (P < 0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P < 0.0001). Conclusions A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients.",

keywords = "KRAS mutations, Lynch syndrome, MAP syndrome, MUTYH",

author = "Adela Castillejo and Gardenia Vargas and Castillejo, {Mar{\'i}a Isabel} and Matilde Navarro and Barber{\'a}, {V{\'i}ctor Manuel} and Sara Gonz{\'a}lez and Eva Hern{\'a}ndez-Ill{\'a}n and Joan Brunet and {Ram{\'o}n Y Cajal}, Teresa and Judith Balma{\~n}a and Silvestre Oltra and S{\'i}lvia Iglesias and {\`A}ngela Velasco and Ares Solanes and Olga Campos and {S{\'a}nchez Heras}, {Ana Beatriz} and Javier Gallego and Estela Carrasco and {Gonz{\'a}lez Juan}, Dolors and {\'A}ngel Segura and Isabel Chirivella and Juan, {Mar{\'i}a Jos{\'e}} and Isabel Tena and Conxi L{\'a}zaro and Ignacio Blanco and Marta Pineda and Gabriel Capell{\'a} and Soto, {Jos{\'e} Luis}",

note = "Funding Information: This work was funded by the Spanish Ministry of Economy and Competitiveness (grant SAF2012-33636 ); the Scientific Foundation Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer ; the Government of Catalonia (grant 2009SGR290 ), Fundaci{\'o}n Mutua Madrile{\~n}a (grant AP114252013 ), RTICC MINECO Network RD12/0036/0031 and RD12/0036/0008 , and the Biomedical Research Foundation from the Hospital of Elche (FIBElx-CO11/03). AC and M-IC are funded by Health and Biomedical Research Foundation from the Valencian Region ( FISABIO ). The Mexican National Council for Science and Technology (CONACyT) fellowship to GV. EH-I is recipient of a fellowship from the Fondo Investigaci{\'o}n Sanitaria ISCIII (FI12/00233). ",

year = "2014",

month = sep,

doi = "10.1016/j.ejca.2014.05.022",

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

volume = "50",

pages = "2241--2250",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "Elsevier Ltd.",

number = "13",

}

Castillejo, A, Vargas, G, Castillejo, MI, Navarro, M, Barberá, VM, González, S, Hernández-Illán, E, Brunet, J, Ramón Y Cajal, T, Balmaña, J, Oltra, S, Iglesias, S, Velasco, À, Solanes, A, Campos, O, Sánchez Heras, AB, Gallego, J, Carrasco, E, González Juan, D, Segura, Á, Chirivella, I, Juan, MJ, Tena, I, Lázaro, C, Blanco, I, Pineda, M, Capellá, G & Soto, JL 2014, 'Prevalence of germline MUTYH mutations among Lynch-like syndrome patients', European Journal of Cancer, vol. 50, no. 13, pp. 2241-2250. https://doi.org/10.1016/j.ejca.2014.05.022

TY - JOUR

T1 - Prevalence of germline MUTYH mutations among Lynch-like syndrome patients

AU - Castillejo, Adela

AU - Vargas, Gardenia

AU - Castillejo, María Isabel

AU - Navarro, Matilde

AU - Barberá, Víctor Manuel

AU - González, Sara

AU - Hernández-Illán, Eva

AU - Brunet, Joan

AU - Ramón Y Cajal, Teresa

AU - Balmaña, Judith

AU - Oltra, Silvestre

AU - Iglesias, Sílvia

AU - Velasco, Àngela

AU - Solanes, Ares

AU - Campos, Olga

AU - Sánchez Heras, Ana Beatriz

AU - Gallego, Javier

AU - Carrasco, Estela

AU - González Juan, Dolors

AU - Segura, Ángel

AU - Chirivella, Isabel

AU - Juan, María José

AU - Tena, Isabel

AU - Lázaro, Conxi

AU - Blanco, Ignacio

AU - Pineda, Marta

AU - Capellá, Gabriel

AU - Soto, José Luis

N1 - Funding Information: This work was funded by the Spanish Ministry of Economy and Competitiveness (grant SAF2012-33636 ); the Scientific Foundation Asociación Española Contra el Cáncer ; the Government of Catalonia (grant 2009SGR290 ), Fundación Mutua Madrileña (grant AP114252013 ), RTICC MINECO Network RD12/0036/0031 and RD12/0036/0008 , and the Biomedical Research Foundation from the Hospital of Elche (FIBElx-CO11/03). AC and M-IC are funded by Health and Biomedical Research Foundation from the Valencian Region ( FISABIO ). The Mexican National Council for Science and Technology (CONACyT) fellowship to GV. EH-I is recipient of a fellowship from the Fondo Investigación Sanitaria ISCIII (FI12/00233).

PY - 2014/9

Y1 - 2014/9

N2 - Background and aims Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients. Methods Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed. Results We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P = 0.02) and wildtype patients (P < 0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P < 0.0001). Conclusions A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients.

AB - Background and aims Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients. Methods Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed. Results We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P = 0.02) and wildtype patients (P < 0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P < 0.0001). Conclusions A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients.

KW - KRAS mutations

KW - Lynch syndrome

KW - MAP syndrome

KW - MUTYH

UR - http://www.scopus.com/inward/record.url?scp=84905126480&partnerID=8YFLogxK

U2 - 10.1016/j.ejca.2014.05.022

DO - 10.1016/j.ejca.2014.05.022

M3 - Artículo

C2 - 24953332

AN - SCOPUS:84905126480

SN - 0959-8049

VL - 50

SP - 2241

EP - 2250

JO - European Journal of Cancer

JF - European Journal of Cancer

IS - 13

ER -

Prevalence of germline MUTYH mutations among Lynch-like syndrome patients

Abstract

Bibliographical note

Keywords

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