Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers

被引：101

作者：

Jansen, Anne M. L. ^{[1
,2
]}

van Wezel, Tom ^{[1
]}

van den Akker, Brendy E. W. M. ^{[1
]}

Garcia, Marina Ventayol ^{[1
]}

Ruano, Dina ^{[1
]}

Tops, Carli M. J. ^{[3
]}

Wagner, Anja ^{[4
]}

Letteboer, Tom G. W. ^{[5
]}

Gomez-Garcia, Encarna B. ^{[6
]}

Devilee, Peter ^{[2
]}

Wijnen, Juul T. ^{[2
,3
]}

Hes, Frederik J. ^{[3
]}

Morreau, Hans ^{[1
]}

机构：

[1] Leiden Univ, Med Ctr, Dept Pathol, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands

[2] Leiden Univ, Med Ctr, Dept Human Genet, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands

[3] Leiden Univ, Med Ctr, Dept Clin Genet, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands

[4] Erasmus Univ, Dept Clin Genet, Med Ctr, NL-3000 DR Rotterdam, Netherlands

[5] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands

[6] Univ Hosp Maastricht, Dept Clin Genet, Maastricht, Netherlands

来源：

EUROPEAN JOURNAL OF HUMAN GENETICS | 2016年 / 24卷 / 07期

关键词：

GERMLINE MUTATIONS; POLYMERASE-EPSILON; DNA-POLYMERASE; ENDOMETRIAL CANCERS; COLORECTAL ADENOMAS; POLE; DEFICIENCY; CARCINOMAS; GENES;

D O I：

10.1038/ejhg.2015.252

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Many suspected Lynch Syndrome (sLS) patients who lack mismatch repair (MMR) germline gene variants and MLH1 or MSH2 hypermethylation are currently explained by somatic MMR gene variants or, occasionally, by germline POLE variants. To further investigate unexplained sLS patients, we analyzed leukocyte and tumor DNA of 62 sLS patients using gene panel sequencing including the POLE, POLD1 and MMR genes. Forty tumors showed either one, two or more somatic MMR variants predicted to affect function. Nine sLS tumors showed a likely ultramutated phenotype and were found to carry germline (n=2) or somatic variants (n=7) in the POLE/POLD1 exonuclease domain (EDM). Six of these POLE/POLD1-EDM mutated tumors also carried somatic MMR variants. Our findings suggest that faulty proofreading may result in loss of MMR and thereby in microsatellite instability.

引用

页码：1089 / 1092

页数：4

共 21 条

[1] POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance [J].

Bellido, Fernando ;

Pineda, Marta ;

Aiza, Gemma ;

Valdes-Mas, Rafael ;

Navarro, Matilde ;

Puente, Diana A. ;

Pons, Tirso ;

Gonzalez, Sara ;

Iglesias, Silvia ;

Darder, Esther ;

Pinol, Virginia ;

Luis Soto, Jose ;

Valencia, Alfonso ;

Blanco, Ignacio ;

Urioste, Miguel ;

Brunet, Joan ;

Lazaro, Conxi ;

Capella, Gabriel ;

Puente, Xose S. ;

Valle, Laura .

GENETICS IN MEDICINE, 2016, 18 (04) :325-332

[2] Polymerase ε (POLE) Mutations in Endometrial Cancer: Clinical Outcomes and Implications for Lynch Syndrome Testing [J].

Billingsley, Caroline C. ;

Cohn, David E. ;

Mutch, David G. ;

Stephens, Julie A. ;

Suarez, Adrian A. ;

Goodfellow, Paul J. .

CANCER, 2015, 121 (03) :386-394

[3] Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers [J].

Briggs, Sarah ;

Tomlinson, Ian .

JOURNAL OF PATHOLOGY, 2013, 230 (02) :148-153

[4] Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome) [J].

Buchanan, Daniel D. ;

Rosty, Christophe ;

Clendenning, Mark ;

Spurdle, Amanda B. ;

Win, Aung Ko .

APPLICATION OF CLINICAL GENETICS, 2014, 7 :183-193

[5] DNA polymerase ? and exonuclease domain mutations in endometrial cancer [J].

Church, David N. ;

Briggs, Sarah E. W. ;

Palles, Claire ;

Domingo, Enric ;

Kearsey, Stephen J. ;

Grimes, Jonathon M. ;

Gorman, Maggie ;

Martin, Lynn ;

Howarth, Kimberley M. ;

Hodgson, Shirley V. ;

Kaur, Kulvinder ;

Taylor, Jenny ;

Tomlinson, Ian P. M. .

HUMAN MOLECULAR GENETICS, 2013, 22 (14) :2820-2828

[6] Lynch or Not Lynch? Is that Always a Question? [J].

Colas, Chrystelle ;

Coulet, Florence ;

Svrcek, Magali ;

Collura, Ada ;

Flejou, Jean-Francois ;

Duval, Alex ;

Hamelin, Richard .

ADVANCES IN CANCER RESEARCH, VOL 113, 2012, 113 :121-166

[7] Ever since Knudson [J].

Devilee, P ;

Cleton-Jansen, AM ;

Cornelisse, CJ .

TRENDS IN GENETICS, 2001, 17 (10) :569-573

[8] Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer [J].

Elsayed, Fadwa A. ;

Kets, C. Marleen ;

Ruano, Dina ;

van den Akker, Brendy ;

Mensenkamp, Arjen R. ;

Schrumpf, Melanie ;

Nielsen, Maartje ;

Wijnen, Juul T. ;

Tops, Carli M. ;

Ligtenberg, Marjolijn J. ;

Vasen, Hans F. A. ;

Hes, Frederik J. ;

Morreau, Hans ;

van Wezel, Tom .

EUROPEAN JOURNAL OF HUMAN GENETICS, 2015, 23 (08) :1080-1084

[9] Somatic aberrations of mismatch repair genes as a cause of microsatellite-unstable cancers [J].

Geurts-Giele, Willemina R. R. ;

Leenen, Celine H. M. ;

Dubbink, Hendrikus J. ;

Meijssen, Isabelle C. ;

Post, Edward ;

Sleddens, Hein F. B. M. ;

Kuipers, Ernst J. ;

Goverde, Anne ;

van den Ouweland, Ans M. W. ;

van Lier, Margot G. F. ;

Steyerberg, Ewout W. ;

van Leerdam, Monique E. ;

Wagner, Anja ;

Dinjens, Winand N. M. .

JOURNAL OF PATHOLOGY, 2014, 234 (04) :548-559

[10] Colon and Endometrial Cancers With Mismatch Repair Deficiency Can Arise From Somatic, Rather Than Germline, Mutations [J].

Haraldsdottir, Sigurdis ;

Hampel, Heather ;

Tomsic, Jerneja ;

Frankel, Wendy L. ;

Pearlman, Rachel ;

de la Chapelle, Albert ;

Pritchard, Colin C. .

GASTROENTEROLOGY, 2014, 147 (06) :1308-+

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