TY - JOUR

T1 - No difference in penetrance between truncating and missense/aberrant splicing pathogenic variants in mlh1 and msh2

T2 - A prospective lynch syndrome database study

AU - Dominguez-Valentin, Mev

AU - Plazzer, John Paul

AU - Sampson, Julian R.

AU - Engel, Christoph

AU - Aretz, Stefan

AU - Jenkins, Mark A.

AU - Sunde, Lone

AU - Bernstein, Inge

AU - Capella, Gabriel

AU - Balaguer, Francesc

AU - Macrae, Finlay

AU - Winship, Ingrid M.

AU - Thomas, Huw

AU - Evans, Dafydd Gareth

AU - Burn, John

AU - Greenblatt, Marc

AU - de Vos tot Nederveen Cappel, Wouter H.

AU - Sijmons, Rolf H.

AU - Nielsen, Maartje

AU - Bertario, Lucio

AU - Bonanni, Bernardo

AU - Tibiletti, Maria Grazia

AU - Cavestro, Giulia Martina

AU - Lindblom, Annika

AU - Della Valle, Adriana

AU - Lopez-Kostner, Francisco

AU - Alvarez, Karin

AU - Gluck, Nathan

AU - Katz, Lior

AU - Heinimann, Karl

AU - Vaccaro, Carlos A.

AU - Nakken, Sigve

AU - Hovig, Eivind

AU - Green, Kate

AU - Lalloo, Fiona

AU - Hill, James

AU - Vasen, Hans F.A.

AU - Perne, Claudia

AU - Büttner, Reinhard

AU - Görgens, Heike

AU - Holinski-Feder, Elke

AU - Morak, Monika

AU - Holzapfel, Stefanie

AU - Hüneburg, Robert

AU - Doeberitz, Magnus von Knebel

AU - Loeffler, Markus

AU - Rahner, Nils

AU - Weitz, Jürgen

AU - Steinke-Lange, Verena

AU - Schmiegel, Wolff

AU - Vangala, Deepak

AU - Crosbie, Emma J.

AU - Pineda, Marta

AU - Navarro, Matilde

AU - Brunet, Joan

AU - Moreira, Leticia

AU - Sánchez, Ariadna

AU - Serra-Burriel, Miquel

AU - Mints, Miriam

AU - Kariv, Revital

AU - Rosner, Guy

AU - Piñero, Tamara Alejandra

AU - Pavicic, Walter Hernán

AU - Kalfayan, Pablo

AU - Ten Broeke, Sanne W.

AU - Mecklin, Jukka Pekka

AU - Pylvänäinen, Kirsi

AU - Renkonen-Sinisalo, Laura

AU - Lepistö, Anna

AU - Peltomäki, Päivi

AU - Hopper, John L.

AU - Win, Aung Ko

AU - Buchanan, Daniel D.

AU - Lindor, Noralane M.

AU - Gallinger, Steven

AU - Marchand, Loïc Le

AU - Newcomb, Polly A.

AU - Figueiredo, Jane C.

AU - Thibodeau, Stephen N.

AU - Therkildsen, Christina

AU - Hansen, Thomas V.O.

AU - Lindberg, Lars

AU - Rødland, Einar Andreas

AU - Neffa, Florencia

AU - Esperon, Patricia

AU - Tjandra, Douglas

AU - Möslein, Gabriela

AU - Seppälä, Toni T.

AU - Møller, Pål

N1 - Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021

Y1 - 2021

N2 - Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

AB - Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

KW - Aberrant splicing

KW - Cancer incidence

KW - Lynch syndrome

KW - Missense

KW - MLH1

KW - MSH2

KW - Penetrance

KW - Truncating

U2 - 10.3390/jcm10132856

DO - 10.3390/jcm10132856

M3 - Journal article

C2 - 34203177

AN - SCOPUS:85114073501

VL - 10

JO - Journal of Clinical Medicine

JF - Journal of Clinical Medicine

SN - 2077-0383

IS - 13

M1 - 2856

ER -