Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are infrequent in familial colorectal cancer and polyposis

Pilar Mur; Richarda M De Voer; Rubén Olivera-Salguero; Sandra Rodríguez-Perales; Tirso Pons; Fernando Setién; Gemma Aiza; Rafael Valdés-Mas; Angelo Bertini; Marta Pineda; Lilian Vreede; Matilde Navarro; Silvia Iglesias; Sara González; Joan Brunet; Alfonso Valencia; Manel Esteller; Conxi Lázaro; Geert J P L Kops; Miguel Urioste; Xose S Puente; Gabriel Capellá; Laura Valle

doi:10.1186/s12943-018-0762-8

Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are infrequent in familial colorectal cancer and polyposis

Pilar Mur, Richarda M De Voer, Rubén Olivera-Salguero, Sandra Rodríguez-Perales, Tirso Pons, Fernando Setién, Gemma Aiza, Rafael Valdés-Mas, Angelo Bertini, Marta Pineda, Lilian Vreede, Matilde Navarro, Silvia Iglesias, Sara González, Joan Brunet, Alfonso Valencia, Manel Esteller, Conxi Lázaro, Geert J P L Kops, Miguel UriosteXose S Puente, Gabriel Capellá, Laura Valle

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

Abstract

Germline mutations in BUB1 and BUB3 have been reported to increase the risk of developing colorectal cancer (CRC) at young age, in presence of variegated aneuploidy and reminiscent dysmorphic traits of mosaic variegated aneuploidy syndrome. We performed a mutational analysis of BUB1 and BUB3 in 456 uncharacterized mismatch repair-proficient hereditary non-polyposis CRC families and 88 polyposis cases. Four novel or rare germline variants, one splice-site and three missense, were identified in four families. Neither variegated aneuploidy nor dysmorphic traits were observed in carriers. Evident functional effects in the heterozygous form were observed for c.1965-1G>A, but not for c.2296G>A (p.E766K), in spite of the positive co-segregation in the family. BUB1 c.2473C>T (p.P825S) and BUB3 c.77C>T (p.T26I) remained as variants of uncertain significance. As of today, the rarity of functionally relevant mutations identified in familial and/or early onset series does not support the inclusion of BUB1 and BUB3 testing in routine genetic diagnostics of familial CRC.

Original language	English
Pages (from-to)	23
Journal	Molecular Cancer
Volume	17
Issue number	1
DOIs	https://doi.org/10.1186/s12943-018-0762-8
Publication status	Published - 15 Feb 2018

Keywords

Adenomatous Polyposis Coli/genetics
Cell Cycle Proteins/chemistry
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
Germ-Line Mutation
Humans
Models, Molecular
Pedigree
Poly-ADP-Ribose Binding Proteins/chemistry
Protein Conformation
Protein-Serine-Threonine Kinases/chemistry
Spindle Apparatus/genetics

Access to Document

10.1186/s12943-018-0762-8

Cite this

Mur, P., De Voer, R. M., Olivera-Salguero, R., Rodríguez-Perales, S., Pons, T., Setién, F., Aiza, G., Valdés-Mas, R., Bertini, A., Pineda, M., Vreede, L., Navarro, M., Iglesias, S., González, S., Brunet, J., Valencia, A., Esteller, M., Lázaro, C., Kops, G. J. P. L., ... Valle, L. (2018). Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are infrequent in familial colorectal cancer and polyposis. Molecular Cancer, 17(1), 23. https://doi.org/10.1186/s12943-018-0762-8

@article{76ecf25055e846e0904bce50d8757d9e,

title = "Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are infrequent in familial colorectal cancer and polyposis",

abstract = "Germline mutations in BUB1 and BUB3 have been reported to increase the risk of developing colorectal cancer (CRC) at young age, in presence of variegated aneuploidy and reminiscent dysmorphic traits of mosaic variegated aneuploidy syndrome. We performed a mutational analysis of BUB1 and BUB3 in 456 uncharacterized mismatch repair-proficient hereditary non-polyposis CRC families and 88 polyposis cases. Four novel or rare germline variants, one splice-site and three missense, were identified in four families. Neither variegated aneuploidy nor dysmorphic traits were observed in carriers. Evident functional effects in the heterozygous form were observed for c.1965-1G>A, but not for c.2296G>A (p.E766K), in spite of the positive co-segregation in the family. BUB1 c.2473C>T (p.P825S) and BUB3 c.77C>T (p.T26I) remained as variants of uncertain significance. As of today, the rarity of functionally relevant mutations identified in familial and/or early onset series does not support the inclusion of BUB1 and BUB3 testing in routine genetic diagnostics of familial CRC.",

keywords = "Adenomatous Polyposis Coli/genetics, Cell Cycle Proteins/chemistry, Colorectal Neoplasms, Hereditary Nonpolyposis/genetics, Germ-Line Mutation, Humans, Models, Molecular, Pedigree, Poly-ADP-Ribose Binding Proteins/chemistry, Protein Conformation, Protein-Serine-Threonine Kinases/chemistry, Spindle Apparatus/genetics",

author = "Pilar Mur and {De Voer}, {Richarda M} and Rub{\'e}n Olivera-Salguero and Sandra Rodr{\'i}guez-Perales and Tirso Pons and Fernando Seti{\'e}n and Gemma Aiza and Rafael Vald{\'e}s-Mas and Angelo Bertini and Marta Pineda and Lilian Vreede and Matilde Navarro and Silvia Iglesias and Sara Gonz{\'a}lez and Joan Brunet and Alfonso Valencia and Manel Esteller and Conxi L{\'a}zaro and Kops, {Geert J P L} and Miguel Urioste and Puente, {Xose S} and Gabriel Capell{\'a} and Laura Valle",

year = "2018",

month = feb,

day = "15",

doi = "10.1186/s12943-018-0762-8",

language = "English",

volume = "17",

pages = "23",

journal = "Molecular Cancer",

issn = "1476-4598",

publisher = "BioMed Central",

number = "1",

}

Mur, P, De Voer, RM, Olivera-Salguero, R, Rodríguez-Perales, S, Pons, T, Setién, F, Aiza, G, Valdés-Mas, R, Bertini, A, Pineda, M, Vreede, L, Navarro, M, Iglesias, S, González, S, Brunet, J, Valencia, A, Esteller, M, Lázaro, C, Kops, GJPL, Urioste, M, Puente, XS, Capellá, G & Valle, L 2018, 'Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are infrequent in familial colorectal cancer and polyposis', Molecular Cancer, vol. 17, no. 1, pp. 23. https://doi.org/10.1186/s12943-018-0762-8

TY - JOUR

T1 - Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are infrequent in familial colorectal cancer and polyposis

AU - Mur, Pilar

AU - De Voer, Richarda M

AU - Olivera-Salguero, Rubén

AU - Rodríguez-Perales, Sandra

AU - Pons, Tirso

AU - Setién, Fernando

AU - Aiza, Gemma

AU - Valdés-Mas, Rafael

AU - Bertini, Angelo

AU - Pineda, Marta

AU - Vreede, Lilian

AU - Navarro, Matilde

AU - Iglesias, Silvia

AU - González, Sara

AU - Brunet, Joan

AU - Valencia, Alfonso

AU - Esteller, Manel

AU - Lázaro, Conxi

AU - Kops, Geert J P L

AU - Urioste, Miguel

AU - Puente, Xose S

AU - Capellá, Gabriel

AU - Valle, Laura

PY - 2018/2/15

Y1 - 2018/2/15

N2 - Germline mutations in BUB1 and BUB3 have been reported to increase the risk of developing colorectal cancer (CRC) at young age, in presence of variegated aneuploidy and reminiscent dysmorphic traits of mosaic variegated aneuploidy syndrome. We performed a mutational analysis of BUB1 and BUB3 in 456 uncharacterized mismatch repair-proficient hereditary non-polyposis CRC families and 88 polyposis cases. Four novel or rare germline variants, one splice-site and three missense, were identified in four families. Neither variegated aneuploidy nor dysmorphic traits were observed in carriers. Evident functional effects in the heterozygous form were observed for c.1965-1G>A, but not for c.2296G>A (p.E766K), in spite of the positive co-segregation in the family. BUB1 c.2473C>T (p.P825S) and BUB3 c.77C>T (p.T26I) remained as variants of uncertain significance. As of today, the rarity of functionally relevant mutations identified in familial and/or early onset series does not support the inclusion of BUB1 and BUB3 testing in routine genetic diagnostics of familial CRC.

AB - Germline mutations in BUB1 and BUB3 have been reported to increase the risk of developing colorectal cancer (CRC) at young age, in presence of variegated aneuploidy and reminiscent dysmorphic traits of mosaic variegated aneuploidy syndrome. We performed a mutational analysis of BUB1 and BUB3 in 456 uncharacterized mismatch repair-proficient hereditary non-polyposis CRC families and 88 polyposis cases. Four novel or rare germline variants, one splice-site and three missense, were identified in four families. Neither variegated aneuploidy nor dysmorphic traits were observed in carriers. Evident functional effects in the heterozygous form were observed for c.1965-1G>A, but not for c.2296G>A (p.E766K), in spite of the positive co-segregation in the family. BUB1 c.2473C>T (p.P825S) and BUB3 c.77C>T (p.T26I) remained as variants of uncertain significance. As of today, the rarity of functionally relevant mutations identified in familial and/or early onset series does not support the inclusion of BUB1 and BUB3 testing in routine genetic diagnostics of familial CRC.

KW - Adenomatous Polyposis Coli/genetics

KW - Cell Cycle Proteins/chemistry

KW - Colorectal Neoplasms, Hereditary Nonpolyposis/genetics

KW - Germ-Line Mutation

KW - Humans

KW - Models, Molecular

KW - Pedigree

KW - Poly-ADP-Ribose Binding Proteins/chemistry

KW - Protein Conformation

KW - Protein-Serine-Threonine Kinases/chemistry

KW - Spindle Apparatus/genetics

U2 - 10.1186/s12943-018-0762-8

DO - 10.1186/s12943-018-0762-8

M3 - Article

C2 - 29448935

SN - 1476-4598

VL - 17

SP - 23

JO - Molecular Cancer

JF - Molecular Cancer

IS - 1

ER -

Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are infrequent in familial colorectal cancer and polyposis

Abstract

Keywords

Access to Document

Fingerprint

Cite this