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1. Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database (Genetics in Medicine, (2020), 22, 1, (15-25), 10.1038/s41436-019-0596-9)

Author

Dominguez-Valentin M., Sampson J. R., Seppala T. T., ten Broeke S. W., Plazzer J. -P., Nakken S., Engel C., Aretz S., Jenkins M. A., Sunde L., Bernstein I., Capella G., Balaguer F., Thomas H., Evans D. G., Burn J., Greenblatt M., Hovig E., de Vos tot Nederveen Cappel W. H., Sijmons R. H., Bertario L., Tibiletti M. G., Cavestro G. M., Lindblom A., Della Valle A., Lopez-Kostner F., Gluck N., Katz L. H., Heinimann K., Vaccaro C. A., Buttner R., Gorgens H., Holinski-Feder E., Morak M., Holzapfel S., Huneburg R., Knebel Doeberitz M., Loeffler M., Rahner N., Schackert H. K., Steinke-Lange V., Schmiegel W., Vangala D., Pylvanainen K., Renkonen-Sinisalo L., Hopper J. L., Win A. K., Haile R. W., Lindor N. M., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J. C., Thibodeau S. N., Wadt K., Therkildsen C., Okkels H., Ketabi Z., Moreira L., Sanchez A., Serra-Burriel M., Pineda M., Navarro M., Blanco I., Green K., Lalloo F., Crosbie E. J., Hill J., Denton O. G., Frayling I. M., Rodland E. A., Vasen H., Mints M., Neffa F., Esperon P., Alvarez K., Kariv R., Rosner G., Pinero T. A., Gonzalez M. L., Kalfayan P., Tjandra D., Winship I. M., Macrae F., Moslein G., Mecklin J. -P., Nielsen M., Moller P., Dominguez-Valentin, M., Sampson, J. R., Seppala, T. T., ten Broeke, S. W., Plazzer, J. -P., Nakken, S., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., Hovig, E., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Bertario, L., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Della Valle, A., Lopez-Kostner, F., Gluck, N., Katz, L. H., Heinimann, K., Vaccaro, C. A., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., Knebel Doeberitz, M., Loeffler, M., Rahner, N., Schackert, H. K., Steinke-Lange, V., Schmiegel, W., Vangala, D., Pylvanainen, K., Renkonen-Sinisalo, L., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Wadt, K., Therkildsen, C., Okkels, H., Ketabi, Z., Moreira, L., Sanchez, A., Serra-Burriel, M., Pineda, M., Navarro, M., Blanco, I., Green, K., Lalloo, F., Crosbie, E. J., Hill, J., Denton, O. G., Frayling, I. M., Rodland, E. A., Vasen, H., Mints, M., Neffa, F., Esperon, P., Alvarez, K., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Tjandra, D., Winship, I. M., Macrae, F., Moslein, G., Mecklin, J. -P., Nielsen, M., and Moller, P.

Abstract

The original version of this Article did not contain details of Dutch Cancer Society (DCS) funding (grant number UL 2017-8223) in the Acknowledgements section. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2020

2. Analysis in the Prospective Lynch Syndrome Database identifies sarcoma as part of the Lynch syndrome tumor spectrum

Author

Dominguez-Valentin M., Sampson J. R., Moller P., Seppala T. T., Plazzer J. -P., Nakken S., Engel C., Aretz S., Jenkins M. A., Sunde L., Bernstein I., Capella G., Balaguer F., Thomas H., Evans D. G., Burn J., Greenblatt M., Hovig E., Nielsen M., de Vos tot Nederveen Cappel W. H., Sijmons R. H., Bertario L., Tibiletti M. G., Cavestro G. M., Lindblom A., Valle A. D., Lopez-Kostner F., Gluck N., Katz L. H., Heinimann K., Vaccaro C. A., Buttner R., Gorgens H., Holinski-Feder E., Morak M., Holzapfel S., Huneburg R., von Knebel Doeberitz M., Loeffler M., Rahner N., Weitz J., Steinke-Lange V., ten Broeke S. W., Schmiegel W., Vangala D., Pylvanainen K., Renkonen-Sinisalo L., Hopper J. L., Win A. K., Haile R. W., Lindor N. M., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J. C., Thibodeau S. N., Jensen L. H., Madsen M. B., Kroldrup L., Nilbert M., Moreira L., Sanchez A., Serra-Burriel M., Pineda M., Navarro M., Vidal J. B., Blanco I., Green K., Lalloo F., Crosbie E. J., Hill J., Denton O. G., Rodland E. A., Vasen H., Mints M., Neffa F., Esperon P., Alvarez K., Kariv R., Rosner G., Pinero T. A., Gonzalez M. L., Kalfayan P., Tjandra D., Winship I. M., Macrae F., Moslein G., Mecklin J. -P., Dominguez-Valentin, M., Sampson, J. R., Moller, P., Seppala, T. T., Plazzer, J. -P., Nakken, S., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., Hovig, E., Nielsen, M., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Bertario, L., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Valle, A. D., Lopez-Kostner, F., Gluck, N., Katz, L. H., Heinimann, K., Vaccaro, C. A., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., von Knebel Doeberitz, M., Loeffler, M., Rahner, N., Weitz, J., Steinke-Lange, V., ten Broeke, S. W., Schmiegel, W., Vangala, D., Pylvanainen, K., Renkonen-Sinisalo, L., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Jensen, L. H., Madsen, M. B., Kroldrup, L., Nilbert, M., Moreira, L., Sanchez, A., Serra-Burriel, M., Pineda, M., Navarro, M., Vidal, J. B., Blanco, I., Green, K., Lalloo, F., Crosbie, E. J., Hill, J., Denton, O. G., Rodland, E. A., Vasen, H., Mints, M., Neffa, F., Esperon, P., Alvarez, K., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Tjandra, D., Winship, I. M., Macrae, F., Moslein, G., and Mecklin, J. -P.

Subjects
Male, Adult, Oncology, Cancer Research, 2019-20 coronavirus outbreak, medicine.medical_specialty, sarcoma, Databases, Factual, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Sarcoma/diagnosis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Humans, Medicine, Aged, business.industry, Sarcoma, Syndrome, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, MSH2, 030220 oncology & carcinogenesis, Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis, Female, 030211 gastroenterology & hepatology, business
Published
2020

3. Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Author

Kho, P-F, Amant, F, Annibali, D, Ashton, K, Attia, J, Auer, PL, Beckmann, MW, Black, A, Brinton, L, Buchanan, DD, Chen, C, Chen, MM, Cheng, THT, Cook, LS, Crous-Bous, M, Czene, K, De Vivo, I, Dennis, J, Dörk, T, Dowdy, SC, Dunning, AM, Dürst, M, Easton, DF, Ekici, AB, Fasching, PA, Fridley, BL, Friedenreich, CM, García-Closas, M, Gaudet, MM, Giles, GG, Goode, EL, Gorman, M, Haiman, CA, Hall, P, Hankison, SE, Hein, A, Hillemanns, P, Hodgson, S, Hoivik, EA, Holliday, EG, Hunter, DJ, Jones, A, Kraft, P, Krakstad, C, Lambrechts, D, Le Marchand, L, Liang, X, Lindblom, A, Lissowska, J, Long, J, Lu, L, Magliocco, AM, Martin, L, McEvoy, M, Milne, RL, Mints, M, Nassir, R, Otton, G, Palles, C, Pooler, L, Proietto, T, Rebbeck, TR, Renner, SP, Risch, HA, Rübner, M, Runnebaum, I, Sacerdote, C, Sarto, GE, Schumacher, F, Scott, RJ, Setiawan, VW, Shah, M, Sheng, X, Shu, X-O, Southey, MC, Tham, E, Tomlinson, I, Trovik, J, Turman, C, Tyrer, JP, Van Den Berg, D, Wang, Z, Wentzensen, N, Xia, L, Xiang, Y-B, Yang, HP, Yu, H, Zheng, W, Webb, PM, Thompson, DJ, Spurdle, AB, Glubb, DM, and O'Mara, TA

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two‐sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low‐density lipoprotein [LDL] and high‐density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P

Published
2020

4. Identification of nine new susceptibility loci for endometrial cancer

Author

O'Mara, T, Glubb, D, Amant, F, Annibali, D, Ashton, K, Attia, J, Auer, P, Beckmann, M, Black, A, Humphreys, M, Brauch, H, Brenner, H, Brinton, L, Buchanan, D, Burwinkel, B, Chang-Claude, J, Chanock, S, Chen, C, Chen, M, Cheng, T, Clarke, C, Clendenning, M, Cook, L, Couch, F, Cox, A, Crous-Bou, M, Czene, K, Day, F, Dennis, J, Depreeuw, J, Doherty, JA, Dork, T, Dowdy, S, Dürst, M, Ekici, A, Fasching, P, Fridley, B, Friedenreich, C, Fritschi, L, Fung, J, Garcia-Closas, M, Gaudet, M, Giles, G, Goode, E, Gorman, M, Haiman, C, Hall, P, Hankinson, S, Healey, C, Hein, A, Hillemanns, P, Hodgson, S, Hoivik, E, Holliday, E, Hopper, J, Hunter, D, Jones, A, Krakstad, C, Kristensen, V, Lambrechts, D, Le Marchand, L, Liang, X, Lindblom, A, Lissowska, J, Long, J, Lu, L, Magliocco, A, Martin, L, McEvoy, M, Meindl, A, Michailidou, K, Milne, R, Mints, M, Montgomery, G, Nassir, R, Olsson, H, Orlow, I, Sacerdote, G, Sarto, G, Schumacher, F, Scott, R, Setiawan, VW, Shah, M, Sheng, M, Shu, X-O, Southey, M, Swerdlow, A, Tham, E, Trovik, J, Wolk, A, Xia, L, Xiang, YB, Yang, H, Yu, H, Zheng, W, Pharoah, P, Dunning, A, Kraft, P, De Vivo, I, Tomlinson, I, Easton, D, Spurdle, A, and Thompson, D

Abstract

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

Published
2018

5. PKN1 modulates TGFß and EGF signaling in HEC-1-A endometrial cancer cell line

Author

Attarha S, Saini RK, Andersson S, Mints M, and Souchelnytskyi S

Subjects
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282
Abstract

Sanaz Attarha,1,2 Ravi Kanth Rao Saini,3 Sonia Andersson,2 Miriam Mints,2 Serhiy Souchelnytskyi1,4,5 1Department of Oncology–Pathology, 2Department of Women's and Children's Health, Karolinska Institutet, Stockholm, 3Department of Biomedicine, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden; 4OCD-AB, Uppsala, Sweden; 5Neurocentrum, Karolinska University Hospital, Solna, Sweden Background: The response of cells to TGFβ and EGF is mediated by a network of various intracellular regulators. The signaling crosstalk between different regulators is of key importance for tumorigenesis. The crosstalk may explain the modulation of cellular responses to the same regulator by another signaling molecule. As PKN1 – a serine/threonine kinase implicated in tumorigenesis – was identified as potential crosstalk node for TGFβ and EGF signaling, the cellular functions that may be affected by PKN1 in a crosstalk of TGFβ and EGF were explored. Methods: To investigate the contribution of PKN1 to TGFβ and EGF signaling, transiently PKN1-transfected HEC-1-A endometrial cancer cells were generated and subjected to treatment with TGFβ1, EGF, and their combination. Proliferation, apoptosis, invasion, wound healing, and migration assays were performed. The impact of PKN1 on the expression and phosphorylation of intracellular proteins was monitored by immunoblotting. Results: It was demonstrated that PKN1 modulated the responses of HEC-A-1 endometrial cancer cells to TGFβ1 and EGF. PKN1 had an inhibitory effect on the stimulation of cell migration, and PKN1 kinase activity was required for the inhibitory effect of TGFβ and EGF on cell proliferation and invasiveness. It was observed that phosphorylation of Smad2, FAK, and Erk1/2 correlated with responses of the cells to TGFβ1 and EGF. Conclusion: PKN1 modulates TGFβ- and EGF-dependent regulation of cell proliferation, migration, and invasiveness, and therefore is a component of the network signaling downstream of TGFβ and EGF. Keywords: PKN1 kinase, TGFβ, EGF, cell migration, proliferation, invasiveness

Published
2014

6. Five endometrial cancer risk loci identified through genome-wide association analysis

Author

Cheng, THT, Thompson, DJ, O'Mara, TA, Painter, JN, Glubb, DM, Flach, S, Lewis, A, French, JD, Freeman-Mills, L, Church, D, Gorman, M, Martin, L, National Study of Endometrial Cancer Genetics Group (NSECG), Hodgson, S, Webb, PM, Australian National Endometrial Cancer Study Group (ANECS), Attia, J, Holliday, EG, McEvoy, M, Scott, RJ, Henders, AK, Martin, NG, Montgomery, GW, Nyholt, DR, Ahmed, S, Healey, CS, Shah, M, Dennis, J, Fasching, PA, Beckmann, MW, Hein, A, Ekici, AB, Hall, P, Czene, K, Darabi, H, Li, J, Dörk, T, Dürst, M, Hillemanns, P, Runnebaum, I, Amant, F, Schrauwen, S, Zhao, H, Lambrechts, D, Depreeuw, J, Dowdy, SC, Goode, EL, Fridley, BL, Winham, SJ, Njølstad, TS, Salvesen, HB, Trovik, J, Werner, HMJ, Ashton, K, Otton, G, Proietto, T, Liu, T, Mints, M, Tham, E, RENDOCAS, CHIBCHA Consortium, Li, MJ, Yip, SH, Wang, J, Bolla, MK, Michailidou, K, Wang, Q, Tyrer, JP, Dunlop, M, Houlston, R, Palles, C, Hopper, JL, AOCS Group, Peto, J, Swerdlow, AJ, Burwinkel, B, Brenner, H, Meindl, A, Brauch, H, Lindblom, A, Chang-Claude, J, Couch, FJ, Giles, GG, Kristensen, VN, Cox, A, Cunningham, JM, Pharoah, PDP, Dunning, AM, Edwards, SL, Easton, DF, Tomlinson, I, Spurdle, AB, Thompson, Deborah [0000-0003-1465-5799], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Humans, Female, Genetic Predisposition to Disease, Promoter Regions, Genetic, Polymorphism, Single Nucleotide, Chromosomes, Human, Pair 8, Endometrial Neoplasms, Genome-Wide Association Study
Abstract

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

Published
2016

7. Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

Author

Painter, J.N., O'Mara, T.A., Batra, J., Cheng, T., Lose, F.A., Dennis, J., Michailidou, K., Tyrer, J.P., Ahmed, S., Ferguson, K., Healey, C.S., Kaufmann, S., Hillman, K.M., Walpole, C., Moya, L., Pollock, P., Jones, A., Howarth, K., Martin, L., Gorman, M., Hodgson, S., Magdalena Echeverry De Polanco, M., Sans, M., Carracedo, A., Castellvi-Bel, S., Rojas-Martinez, A., Santos, E., Teixeira, M.R., Carvajal-Carmona, L., Shu, X-O., Long, J., Zheng, W., Xiang, Y-B., Montgomery, G.W., Webb, P.M., Scott, R.J., McEvoy, M., Attia, J., Holliday, E., Martin, N.G., Nyholt, D.R., Henders, A.K., Fasching, P.A., Hein, A., Beckmann, M.W., Renner, S.P., Doerk, T., Hillemanns, P., Duerst, M., Runnebaum, I., Lambrechts, D., Coenegrachts, L., Schrauwen, S., Amant, F., Winterhoff, B., Dowdy, S.C., Goode, E.L., Teoman, A., Salvesen, H.B., Trovik, J., Njolstad, T.S., Werner, H.M.J., Ashton, K., Proietto, T., Otton, G., Tzortzatos, G., Mints, M., Tham, E., Hall, P., Czene, K., Liu, J., Li, J., Hopper, J.L., Southey, M.C., Ekici, A.B., Ruebner, M., Johnson, N., Peto, J., Burwinkel, B., Marme, F., Brenner, H., Dieffenbach, A.K., Meindl, A., Brauch, H., Lindblom, A., Depreeuw, J., Moisse, M., Chang-Claude, J., Rudolph, A., Couch, F.J., Olson, J.E., Giles, G.G., Bruinsma, F., Cunningham, J.M., Fridley, B.L., Borresen-Dale, A-L., Kristensen, V.N., Cox, A., Swerdlow, A.J., Orr, N., Bolla, M.K., Wang, Q., Weber, R.P., Chen, Z., Shah, M., French, J.D., Pharoah, P.D.P., Dunning, A.M., Tomlinson, I., Easton, D.F., Edwards, S.L., Thompson, D.J., Spurdle, A.B., Canc, N.S.E., Consortium, CHIBCHA, Canc, ANE, RENDOCAS, AOCS, Network, GENICA, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Thompson, Deborah [0000-0003-1465-5799], and Apollo - University of Cambridge Repository

Subjects
Genotype, Chromosome Mapping, Computational Biology, Genetic Variation, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, Endometrial Neoplasms, Epigenesis, Genetic, Haplotypes, Genetic Loci, Risk Factors, Case-Control Studies, Cell Line, Tumor, Databases, Genetic, Humans, Female, RNA, Messenger, Promoter Regions, Genetic, Alleles, Genome-Wide Association Study, Hepatocyte Nuclear Factor 1-beta
Abstract

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1,184 genotyped and imputed SNPs in 6,608 Caucasian cases and 37,925 controls, and 895 Asian cases and 1,968 controls, revealed the best signal of association for SNP rs11263763 (P=8.4×10(-14), OR=0.86, 95% CI=0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumour samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high to moderate LD as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression. ispartof: Human Molecular Genetics vol:24 issue:5 pages:1478-92 ispartof: location:England status: published

Published
2015

8. Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk

Author

Carvajal-Carmona, L.G., O'Mara, T.A., Painter, J.N.., Lose, F.A., Dennis, J., Michailidou, K., Tyrer, J.P., Ahmed, S., Ferguson, K., Healey, C.S., Pooley, K., Beesley, J., Cheng, T., Jones, A., Howarth, K., Martin, L., Gorman, M., Hodgson, S., Wentzensen, N., Fasching, P.A., Hein, A., Beckmann, M.W., Renner, S.P., Doerk, T., Hillemanns, P., Duerst, M., Runnebaum, I., Lambrechts, D., Coenegrachts, L., Schrauwen, S., Amant, F., Winterhoff, B., Dowdy, S.C., Goode, E.L., Teoman, A., Salvesen, H.B., Trovik, J., Njolstad, T.S., Werner, H.M.J., Scott, R.J., Ashton, K., Proietto, T., Otton, G., Wersaell, O., Mints, M., Tham, E., Hall, P., Czene, K., Liu, J., Li, J., Hopper, J.L., Southey, M.C., Ekici, A.B., Ruebner, M., Johnson, N., Peto, J., Burwinkel, B., Marme, F., Brenner, H., Dieffenbach, A.K., Meindl, A., Brauch, H., Lindblom, A., Depreeuw, J., Moisse, M., Chang-Claude, J., Rudolph, A., Couch, F.J., Olson, J.E., Giles, G.G., Bruinsma, F., Cunningham, J.M., Fridley, B.L., Borresen-Dale, A.-L., Kristensen, V.N., Cox, A., Swerdlow, A.J., Orr, N., Bolla, M.K., Wang, Q., Weber, R.P., Chen, Z., Shah, M., Pharoah, P.D.P., Dunning, A.M., Tomlinson, I., Easton, D.F., Spurdle, A.B., Thompson, D.J., NSECG, ANECS, RENDOCAS, AOCS, Network, GENICA, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan [0000-0003-3724-4757], Pooley, Karen [0000-0002-1274-9460], Wang, Jean [0000-0002-9139-0627], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
National Study of Endometrial Cancer Genetics Group, Australian Ovarian Cancer Study, Polymorphism, Single Nucleotide, Chromosomes, Promoter Regions, Paediatrics and Reproductive Medicine, Databases, Uterine Cancer, Genetic, Complementary and Alternative Medicine, Risk Factors, Models, Australian National Endometrial Cancer Study Group, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Testing, Aetiology, Polymorphism, Promoter Regions, Genetic, Telomerase, Cancer, Genetics & Heredity, Neoplastic, Models, Genetic, Nucleic Acid, RENDOCAS, Prevention, Human Genome, Membrane Proteins, Single Nucleotide, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Gene Expression Regulation, Haplotypes, Genetic Loci, Chromosomes, Human, Pair 5, Female, GENICA Network, Pair 5, Databases, Nucleic Acid, Human
Abstract

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility. ispartof: Human Genetics vol:134 issue:2 pages:231-45 ispartof: location:Germany status: published

Published
2015

9. Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

Author

Cheng, T.H.T., Thompson, D., Painter, J., O'Mara, T., Gorman, M., Martin, L., Palles, C., Jones, A., Buchanan, D.D., Win, A.K., Hopper, J., Jenkins, M., Lindor, N.M., Newcomb, P.A., Gallinger, S., Conti, D., Schumacher, F., Casey, G., Giles, G.G., Pharoah, P., Peto, J., Cox, A., Swerdlow, A., Couch, F., Cunningham, J.M., Goode, E.L., Winham, S.J., Lambrechts, D., Fasching, P., Burwinkel, B., Brenner, H., Brauch, H., Chang-Claude, J., Salvesen, H.B., Kristensen, V., Darabi, H., Li, J., Liu, T., Lindblom, A., Hall, P., Echeverry de Polanco, M., Sans, M., Carracedo, A., Castellvi-Bel, S., Rojas-Martinez, A., Jr, A.S., Teixeira, M.R., Dunning, A.M., Dennis, J., Otton, G., Proietto, T., Holliday, E., Attia, J., Ashton, K., Scott, R.J., McEvoy, M., Dowdy, S.C., Fridley, B.L., Werner, H.M.J., Trovik, J., Njolstad, T.S., Tham, E., Mints, M., Runnebaum, I., Hillemanns, P., Doerk, T., Amant, F., Schrauwen, S., Hein, A., Beckmann, M.W., Ekici, A., Czene, K., Meindl, A., Bolla, M.K., Michailidou, K., Tyrer, J.P., Wang, Q., Ahmed, S., Healey, C.S., Shah, M., Annibali, D., Depreeuw, J., Al-Tassan, N.A., Harris, R., Meyer, B.F., Whiffin, N., Hosking, F.J., Kinnersley, B., Farrington, S.M., Timofeeva, M., Tenesa, A., Campbell, H., Haile, R.W., Hodgson, S., Carvajal-Carmona, L., Cheadle, J.P., Easton, D., Dunlop, M., Houlston, R., Spurdle, A., Tomlinson, I., and Other departments

Subjects
Male, CARCINOMA, MICROSATELLITE INSTABILITY, DNA-POLYMERASE, LOCI, MTHFR C677T, VARIANTS, LYNCH-SYNDROME, Article, BREAST-CANCER, Humans, Genetic Predisposition to Disease, Alleles, Adaptor Proteins, Signal Transducing, RISK, Homeodomain Proteins, Science & Technology, Polymorphism, Genetic, MUTATIONS, Intracellular Signaling Peptides and Proteins, Proteins, Endometrial Neoplasms, Neoplasm Proteins, Multidisciplinary Sciences, Repressor Proteins, Science & Technology - Other Topics, Female, Colorectal Neoplasms, Genome-Wide Association Study
Abstract

High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers. ispartof: Scientific Reports vol:5 pages:17369- ispartof: location:England status: published

Published
2015

10. Impact of combinations of EGF, TGFβ, 17β-oestradiol, and inhibitors of corresponding pathways on proliferation of breast cancer cell lines

Author

Mints, M. and Serhiy Souchelnytskyi

Subjects
Epidermal Growth Factor, Estradiol, Original contributions, Antineoplastic Agents, Breast Neoplasms, Drug Combinations, Transforming Growth Factor beta, Cell Line, Tumor, Humans, Female, skin and connective tissue diseases, hormones, hormone substitutes, and hormone antagonists, Cell Proliferation, Signal Transduction
Abstract

Aim: The impact of combinations of anti-cancer drugs and growth factors on tumour cells may differ from the assumed sum of the effects of each factor separately. Therefore it is important to study the effects of different combinations of various drugs and treatments. Our aim was to study the effects on breast cancer cell proliferation of EGF, TGFβ and 17β-oestradiol, three important regulators of breast tumourigenesis, and their respective inhibitors in different combinations. Materials and Methods: We screened the effects on proliferation of MCF7 and MDA-MB-231 cells of ninety different combinations of EGF, TGFβ and 17β-oestradiol, Iressa, SB431542 and Tamoxifen. Meta-data analysis of available clinical data was performed to validate observed proliferation data. Results: In MDA-MB-231 cells, TGFβ1 was found inhibitory when cells were simultaneously treated with EGF and 17β-oestradiol, with the effect potentiated by addition of all inhibitors combined. In the same cells, Iressa when combined with EGF was paradoxically stimulatory. Tamoxifen inhibited MCF7 cells co-treated with EGF or oestrogen, and enhanced the inhibitory effect of TGFβ in MDA-MB-231 cells. Meta-analysis of clinical gene expression studies confirmed several of these points, showing enhanced TGFβ and EGF expression in Tamoxifen-treated patients to correlate with decreased tumour size and grade respectively, and combined TGFβ-EGF expression to decrease the risk of metastasis. Conclusion: Our study shows significant differences in proliferation response to drugs and growth factors between MCF7 cells which do not have propensity to form metastases in animal models and MDA-MB-231 cells which may form metastases upon inoculation into animals. Several of these differences are unexpected and confirmed by clinical observations. Key Words: breast cancer, combinatorial treatment, EGF, oestrogen, TGFβ.

Published
2014

18. Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment:a report from the prospective Lynch syndrome database

Author

Mev Dominguez-Valentin, Saskia Haupt, Toni T. Seppälä, Julian R. Sampson, Lone Sunde, Inge Bernstein, Mark A. Jenkins, Christoph Engel, Stefan Aretz, Maartje Nielsen, Gabriel Capella, Francesc Balaguer, Dafydd Gareth Evans, John Burn, Elke Holinski-Feder, Lucio Bertario, Bernardo Bonanni, Annika Lindblom, Zohar Levi, Finlay Macrae, Ingrid Winship, John-Paul Plazzer, Rolf Sijmons, Luigi Laghi, Adriana Della Valle, Karl Heinimann, Tadeusz Dębniak, Robert Fruscio, Francisco Lopez-Koestner, Karin Alvarez-Valenzuela, Lior H. Katz, Ido Laish, Elez Vainer, Carlos Vaccaro, Dirce Maria Carraro, Kevin Monahan, Elizabeth Half, Aine Stakelum, Des Winter, Rory Kennelly, Nathan Gluck, Harsh Sheth, Naim Abu-Freha, Marc Greenblatt, Benedito Mauro Rossi, Mabel Bohorquez, Giulia Martina Cavestro, Leonardo S. Lino-Silva, Karoline Horisberger, Maria Grazia Tibiletti, Ivana do Nascimento, Huw Thomas, Norma Teresa Rossi, Leandro Apolinário da Silva, Attila Zaránd, Juan Ruiz-Bañobre, Vincent Heuveline, Jukka-Pekka Mecklin, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo, Anna Lepistö, Päivi Peltomäki, Christina Therkildsen, Mia Gebauer Madsen, Stefan Kobbelgaard Burgdorf, John L. Hopper, Aung Ko Win, Robert W. Haile, Noralane Lindor, Steven Gallinger, Loïc Le Marchand, Polly A. Newcomb, Jane Figueiredo, Daniel D. Buchanan, Stephen N. Thibodeau, Magnus von Knebel Doeberitz, Markus Loeffler, Nils Rahner, Evelin Schröck, Verena Steinke-Lange, Wolff Schmiegel, Deepak Vangala, Claudia Perne, Robert Hüneburg, Silke Redler, Reinhard Büttner, Jürgen Weitz, Marta Pineda, Nuria Duenas, Joan Brunet Vidal, Leticia Moreira, Ariadna Sánchez, Eivind Hovig, Sigve Nakken, Kate Green, Fiona Lalloo, James Hill, Emma Crosbie, Miriam Mints, Yael Goldberg, Douglas Tjandra, Sanne W. ten Broeke, Revital Kariv, Guy Rosner, Suresh H. Advani, Lidiya Thomas, Pankaj Shah, Mithun Shah, Florencia Neffa, Patricia Esperon, Walter Pavicic, Giovana Tardin Torrezan, Thiago Bassaneze, Claudia Alejandra Martin, Gabriela Moslein, Pål Moller, Dominguez-Valentin, M, Haupt, S, Seppälä, T, Sampson, J, Sunde, L, Bernstein, I, Jenkins, M, Engel, C, Aretz, S, Nielsen, M, Capella, G, Balaguer, F, Evans, D, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Dębniak, T, Fruscio, R, Lopez-Koestner, F, Alvarez-Valenzuela, K, Katz, L, Laish, I, Vainer, E, Vaccaro, C, Carraro, D, Monahan, K, Half, E, Stakelum, A, Winter, D, Kennelly, R, Gluck, N, Sheth, H, Abu-Freha, N, Greenblatt, M, Rossi, B, Bohorquez, M, Cavestro, G, Lino-Silva, L, Horisberger, K, Tibiletti, M, Nascimento, I, Thomas, H, Rossi, N, Apolinário da Silva, L, Zaránd, A, Ruiz-Bañobre, J, Heuveline, V, Mecklin, J, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Peltomäki, P, Therkildsen, C, Madsen, M, Burgdorf, S, Hopper, J, Win, A, Haile, R, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, P, Figueiredo, J, Buchanan, D, Thibodeau, S, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schröck, E, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hüneburg, R, Redler, S, Büttner, R, Weitz, J, Pineda, M, Duenas, N, Vidal, J, Moreira, L, Sánchez, A, Hovig, E, Nakken, S, Green, K, Lalloo, F, Hill, J, Crosbie, E, Mints, M, and Goldberg, Y

Subjects
kuolleisuus, perinnölliset taudit, Survival, MLH1, riskitekijät, General Medicine, MSH6, sukupuoli, MSH2, Cancer risk, Lynch syndrome, PMS2, syöpägeenit, syöpätaudit, Lynchin oireyhtymä, Mortality, Prospective study, ilmaantuvuus, ikä, henkiinjääminen, kohorttitutkimus
Abstract

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time.Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender.Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers.Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

Published
2023

19. No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

Author

Guy Rosner, Walter Hernán Pavicic, Claudia Perne, Carlos A. Vaccaro, Elke Holinski-Feder, Leticia Moreira, Wouter H. de Vos tot Nederveen Cappel, Stefan Aretz, Einar Andreas Rødland, Polly A. Newcomb, Karin Alvarez, Ariadna Sánchez, Lone Sunde, Wolff Schmiegel, Joan Brunet, Marc S. Greenblatt, Christina Therkildsen, Karl Heinimann, Lior H. Katz, Fiona Lalloo, Jürgen Weitz, Anna Lepistö, Rolf H. Sijmons, Maartje Nielsen, Hans F. A. Vasen, Deepak Vangala, Monika Morak, Jukka-Pekka Mecklin, Toni T. Seppälä, Sigve Nakken, Stefanie Holzapfel, Douglas Tjandra, Finlay A. Macrae, Päivi Peltomäki, Daniel D. Buchanan, Stephen N. Thibodeau, Adriana Della Valle, James Hill, Annika Lindblom, Bernardo Bonanni, Reinhard Büttner, Francisco López-Köstner, Giulia Martina Cavestro, John Burn, Emma J Crosbie, Lucio Bertario, Sanne W. ten Broeke, D. G. R. Evans, Kate Green, Verena Steinke-Lange, Eivind Hovig, Miquel Serra-Burriel, Francesc Balaguer, Kirsi Pylvänäinen, Gabriela Möslein, Revital Kariv, Thomas Hansen, Maria Grazia Tibiletti, Tamara Alejandra Piñero, Nils Rahner, Magnus von Knebel Doeberitz, Ingrid Winship, Nathan Gluck, Lars Joachim Lindberg, Christoph Engel, Mev Dominguez-Valentin, John-Paul Plazzer, Julian R. Sampson, Marta Pineda, John L. Hopper, Pablo Kalfayan, Heike Görgens, Aung Ko Win, Steven Gallinger, Loic Le Marchand, Mark A. Jenkins, Markus Loeffler, Noralane M. Lindor, Inge Bernstein, Pål Møller, Laura Renkonen-Sinisalo, Florencia Neffa, Huw Thomas, Gabriel Capellá, Jane C. Figueiredo, Miriam Mints, Patricia Esperon, Matilde Navarro, Robert Hüneburg, Guided Treatment in Optimal Selected Cancer Patients (GUTS), HUS Abdominal Center, Department of Surgery, Genome-Scale Biology (GSB) Research Program, II kirurgian klinikka, ATG - Applied Tumor Genomics, Research Programs Unit, Clinicum, Department of Medical and Clinical Genetics, Dominguez-Valentin, M., Plazzer, J. -P., Sampson, J. R., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Macrae, F., Winship, I. M., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Nielsen, M., Bertario, L., Bonanni, B., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Della Valle, A., Lopez-Kostner, F., Alvarez, K., Gluck, N., Katz, L., Heinimann, K., Vaccaro, C. A., Nakken, S., Hovig, E., Green, K., Lalloo, F., Hill, J., Vasen, H. F. A., Perne, C., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., Doeberitz, M. V. K., Loeffler, M., Rahner, N., Weitz, J., Steinke-Lange, V., Schmiegel, W., Vangala, D., Crosbie, E. J., Pineda, M., Navarro, M., Brunet, J., Moreira, L., Sanchez, A., Serra-Burriel, M., Mints, M., Kariv, R., Rosner, G., Pinero, T. A., Pavicic, W. H., Kalfayan, P., Ten Broeke, S. W., Mecklin, J. -P., Pylvanainen, K., Renkonen-Sinisalo, L., Lepisto, A., Peltomaki, P., Hopper, J. L., Win, A. K., Buchanan, D. D., Lindor, N. M., Gallinger, S., Marchand, L. L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Therkildsen, C., Hansen, T. V. O., Lindberg, L., Rodland, E. A., Neffa, F., Esperon, P., Tjandra, D., Moslein, G., Seppala, T. T., and Moller, P.

Subjects
cancer incidence, 0302 clinical medicine, Malalties hereditàries, Missense mutation, 8Q23.3, Càncer, Cancer, Genetics, 0303 health sciences, medicine.diagnostic_test, Factors de risc en les malalties, MISMATCH REPAIR GENES, MLH1, General Medicine, Penetrance, Lynch syndrome, 3. Good health, syöpägeenit, 030220 oncology & carcinogenesis, Medicine, syöpätaudit, ilmaantuvuus, Genetic diseases, congenital, hereditary, and neonatal diseases and abnormalities, missense, 11Q23.1, Risk factors in diseases, CANCER-RISK, Article, aberrant splicing, 03 medical and health sciences, AGE, medicine, Genetic predisposition, ddc:610, MSH2, Lynchin oireyhtymä, penetrance, 030304 developmental biology, Genetic testing, truncating, perinnölliset taudit, business.industry, MUTATIONS, HMSH2, nutritional and metabolic diseases, medicine.disease, digestive system diseases, 3121 General medicine, internal medicine and other clinical medicine, business
Abstract

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.

Published
2021

20. Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants:a Prospective Lynch Syndrome Database report

Author

Einar Andreas Rødland, Joan B. Vida, Heike Görgens, Eivind Hovig, Kirsi Pylvänäinen, Monika Morak, Wouter H. de Vos tot Nederveen Cappel, Lone Sunde, Mark A. Jenkins, Lucio Bertario, Patricia Esperon, Reinhard Büttner, Finlay A. Macrae, Inge Bernstein, Marc S. Greenblatt, Wolff Schmiegel, Giulia Martina Cavestro, Maria Grazia Tibiletti, Silke Redler, Zohreh Ketabi, Karl Heinimann, Fiona Lalloo, Huw Thomas, Christina Therkildsen, Deepak Vangala, Magnus von Knebel Doeberitz, Matilde Navarro, Erik Rokkones, Douglas Tjandra, D. G. Evans, Marta Pineda, Marian J.E. Mourits, Lior H. Katz, Bernardo Bonanni, Pablo Kalfayan, Stephen N. Thibodeau, Loic Le Marchand, Revital Kariv, Maartje Nielsen, Emma J Crosbie, Oliver G. Denton, Stefanie Holzapfel, Guy Rosner, Mev Dominguez-Valentin, John Burn, Verena Steinke-Lange, Carlos A. Vaccaro, Gabriela Möslein, Elke Holinski-Feder, Gabriel Capellá, Johanna Tecklenburg, Karin Wadt, Kate Green, Christoph Engel, Miriam Mints, Anna Lepistö, Tamara Alejandra Piñero, Jukka-Pekka Mecklin, John L. Hopper, Robert Hüneburg, Markus Loeffler, Florencia Neffa, Toni T. Seppälä, Claudia Perne, Polly A. Newcomb, Karin Alvarez, Adriana Della Valle, Julian R. Sampson, Sanne W. ten Broeke, Francisco Lopez-Koestner, John-Paul Plazzer, James Hill, Hans Georg Strauß, Ingrid Winship, Nathan Gluck, Aung Ko Win, Jane C. Figueiredo, Jürgen Weitz, Hans F. A. Vasen, Rolf H. Sijmons, Walter Hernán Pavicic, Stefan Aretz, Steven Gallinger, Noralane M. Lindor, Pål Møller, Laura Renkonen-Sinisalo, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Seppala, T. T., Dominguez-Valentin, M., Crosbie, E. J., Engel, C., Aretz, S., Macrae, F., Winship, I., Capella, G., Thomas, H., Hovig, E., Nielsen, M., Sijmons, R. H., Bertario, L., Bonanni, B., Tibiletti, M. G., Cavestro, G. M., Mints, M., Gluck, N., Katz, L., Heinimann, K., Vaccaro, C. A., Green, K., Lalloo, F., Hill, J., Schmiegel, W., Vangala, D., Perne, C., Strauss, H. -G., Tecklenburg, J., Holinski-Feder, E., Steinke-Lange, V., Mecklin, J. -P., Plazzer, J. -P., Pineda, M., Navarro, M., Vida, J. B., Kariv, R., Rosner, G., Pinero, T. A., Pavicic, W., Kalfayan, P., ten Broeke, S. W., Jenkins, M. A., Sunde, L., Bernstein, I., Burn, J., Greenblatt, M., de Vos tot Nederveen Cappel, W. H., Della Valle, A., Lopez-Koestner, F., Alvarez, K., Buttner, R., Gorgens, H., Morak, M., Holzapfel, S., Huneburg, R., von Knebel Doeberitz, M., Loeffler, M., Redler, S., Weitz, J., Pylvanainen, K., Renkonen-Sinisalo, L., Lepisto, A., Hopper, J. L., Win, A. K., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Therkildsen, C., Wadt, K. A. W., Mourits, M. J. E., Ketabi, Z., Denton, O. G., Rodland, E. A., Vasen, H., Neffa, F., Esperon, P., Tjandra, D., Moslein, G., Rokkones, E., Sampson, J. R., Evans, D. G., Moller, P., Genome-Scale Biology (GSB) Research Program, HUS Abdominal Center, Clinicum, II kirurgian klinikka, Department of Surgery, and Doctoral Programme in Clinical Research

Subjects
0301 basic medicine, Cancer Research, Oophorectomy, Databases, Factual, Colorectal cancer, SURGERY, medicine.medical_treatment, Càncer d'ovari, computer.software_genre, DNA Mismatch Repair, 0302 clinical medicine, Endometrial cancer, munasarjasyöpä, Medicine, Prospective Studies, Colectomy, Salpingo-oophorectomy/methods, Database, Manchester Cancer Research Centre, COLON-CANCER, MLH1, WOMEN, Middle Aged, Prognosis, Lynch syndrome, 3. Good health, kohdunrungon syöpä, Oncology, COLECTOMY, 030220 oncology & carcinogenesis, Female, Biomarkers, Tumor/genetics, Adult, Heterozygote, Genital Neoplasms, Female, Salpingo-oophorectomy, Hysterectomy, 03 medical and health sciences, Genital Neoplasms, Female/prevention & control, Ovarian cancer, Colorectal Neoplasms, Hereditary Nonpolyposis/genetics, Biomarkers, Tumor, Mortalitat, Humans, Hysterectomy/methods, Mortality, Lynchin oireyhtymä, Risk-reducing surgery, Aged, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, Cancer, MSH6, 3126 Surgery, anesthesiology, intensive care, radiology, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, MSH2, 030104 developmental biology, Cross-Sectional Studies, PMS2, Càncer d'endometri, Mutation, kohdunpoisto, business, computer, Follow-Up Studies
Abstract

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd.

Published
2021

21. Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report

Author

Eivind Hovig, Bernardo Bonanni, Monika Morak, Mark A. Jenkins, Patricia Esperon, Toni T. Seppälä, Lone Sunde, Pablo Kalfayan, Gabriel Capellá, Inge Bernstein, Matilde Navarro, Marc S. Greenblatt, John Burn, Zohreh Ketabi, Johanna Tecklenburg, Francisco Lopez-Koestner, Miriam Mints, Heike Görgens, Neil A J Ryan, Kate Green, Annika Auranen, Douglas Tjandra, Robert W. Haile, Marta Pineda, Tamara Alejandra Piñero, Stefan Aretz, Robert Hüneburg, Verena Steinke-Lange, Markus Loeffler, Christina Therkildsen, John L. Hopper, Deepak Vangala, Huw Thomas, Reinhard Büttner, James Hill, Einar Andreas Rødland, Revital Kariv, Maria Grazia Tibiletti, Sigve Nakken, Stefanie Holzapfel, D. Gareth Evans, Oliver G. Denton, Julian R. Sampson, Henrik Okkels, Joan Vidal, Loic Le Marchand, Hans Georg Strauß, Gabriela Möslein, Claudia Perne, Ingrid Winship, Nathan Gluck, Jane C. Figueiredo, Mev Dominguez-Valentin, Wolff Schmiegel, Karl Heinimann, Kirsi Pylvänäinen, Karin Alvarez, Maartje Nielsen, Wouter H. de Vos tot Nederveen Cappel, Fiona Lalloo, Aung Ko Win, Guy Rosner, Carlos A. Vaccaro, Polly A. Newcomb, Elke Holinski-Feder, John-Paul Plazzer, Lior H. Katz, Christoph Engel, Anna Lepistö, Jukka-Pekka Mecklin, Giulia Martina Cavestro, Adriana Della Valle, Finlay A. Macrae, Sanne W. ten Broeke, Florencia Neffa, Rolf H. Sijmons, María Laura Gonzalez, Nils Rahner, Jürgen Weitz, Hans F. A. Vasen, Stephen N. Thibodeau, Emma J Crosbie, Lucio Bertario, Steven Gallinger, Noralane M. Lindor, Pål Møller, Laura Renkonen-Sinisalo, Magnus von Knebel Doeberitz, Dominguez-Valentin, M., Crosbie, E. J., Engel, C., Aretz, S., Macrae, F., Winship, I., Capella, G., Thomas, H., Nakken, S., Hovig, E., Nielsen, M., Sijmons, R. H., Bertario, L., Bonanni, B., Tibiletti, M. G., Cavestro, G. M., Mints, M., Gluck, N., Katz, L., Heinimann, K., Vaccaro, C. A., Green, K., Lalloo, F., Hill, J., Schmiegel, W., Vangala, D., Perne, C., Strauss, H. -G., Tecklenburg, J., Holinski-Feder, E., Steinke-Lange, V., Mecklin, J. -P., Plazzer, J. -P., Pineda, M., Navarro, M., Vidal, J. B., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Ryan, N., ten Broeke, S. W., Jenkins, M. A., Sunde, L., Bernstein, I., Burn, J., Greenblatt, M., de Vos tot Nederveen Cappel, W. H., Della Valle, A., Lopez-Koestner, F., Alvarez, K., Buttner, R., Gorgens, H., Morak, M., Holzapfel, S., Huneburg, R., von Knebel Doeberitz, M., Loeffler, M., Rahner, N., Weitz, J., Pylvanainen, K., Renkonen-Sinisalo, L., Lepisto, A., Auranen, A., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Therkildsen, C., Okkels, H., Ketabi, Z., Denton, O. G., Rodland, E. A., Vasen, H., Neffa, F., Esperon, P., Tjandra, D., Moslein, G., Sampson, J. R., Evans, D. G., Seppala, T. T., Moller, P., ATG - Applied Tumor Genomics, HUS Abdominal Center, II kirurgian klinikka, Department of Surgery, Clinicum, Helsinki University Hospital Area, and University of Helsinki

Subjects
0301 basic medicine, medicine.medical_treatment, DNA Mismatch Repair, Gynecologic surgery, 0302 clinical medicine, Malalties hereditàries, Prospective Studies, Prospective cohort study, Genetics (clinical), Mismatch Repair Endonuclease PMS2, Incidence (epidemiology), Middle Aged, 16. Peace & justice, Lynch syndrome, 3. Good health, 030220 oncology & carcinogenesis, Female, syöpätaudit, MutL Protein Homolog 1, Genetic diseases, Heterozygote, medicine.medical_specialty, Salpingo-oophorectomy, Cirurgia ginecològica, Hysterectomy, Article, 03 medical and health sciences, Càncer colorectal, CAPP2, medicine, Humans, Lynchin oireyhtymä, Gynecology, perinnölliset taudit, HEREDITARY COLORECTAL-CANCER, business.industry, Endometrial cancer, Cancer, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Colorectal cancer, ASPIRIN, 030104 developmental biology, Clinical research, 3121 General medicine, internal medicine and other clinical medicine, kohdunpoisto, 3111 Biomedicine, Ovarian cancer, business
Abstract

Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR ( path_MMR ) variants. Methods The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. Results Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1 , path_MSH2 , path_MSH6 , and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. Conclusion Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

Published
2021

22. Correction:Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

Author

Gabriel Capellá, Patricia Esperon, Christoph Engel, Rolf H. Sijmons, María Laura Gonzalez, Matilde Navarro, Francisco López-Köstner, Julian R. Sampson, Miquel Serra-Burriel, Karin Alvarez, Ingrid Winship, Nathan Gluck, Lone Sunde, Reinhard Büttner, Giulia Martina Cavestro, Wouter H. de Vos tot Nederveen Cappel, Jukka-Pekka Mecklin, Marc S. Greenblatt, Kate Green, Robert Hüneburg, Markus Loeffler, Maria Grazia Tibiletti, Tamara Alejandra Piñero, Florencia Neffa, Lucio Bertario, Ariadna Sánchez, Verena Steinke-Lange, Christina Therkildsen, Jane C. Figueiredo, Douglas Tjandra, Magnus von Knebel Doeberitz, Lior H. Katz, Steven Gallinger, Noralane M. Lindor, Gabriela Möslein, Adriana Della Valle, John L. Hopper, Einar Andreas Rødland, Miriam Mints, Annika Lindblom, Ian M. Frayling, Polly A. Newcomb, Pål Møller, Sanne W. ten Broeke, Laura Renkonen-Sinisalo, Sigve Nakken, Stefanie Holzapfel, Finlay A. Macrae, Stefan Aretz, Nils Rahner, Karin Wadt, Robert W. Haile, Francesc Balaguer, Revital Kariv, Stephen N. Thibodeau, Huw D. Thomas, Emma J Crosbie, Deepak Vangala, Monika Morak, Ignacio Blanco, Hans K. Schackert, Henrik Okkels, Mev Dominguez-Valentin, Oliver G. Denton, John-Paul Plazzer, Zohreh Ketabi, James Hill, Loic Le Marchand, Mark A. Jenkins, Inge Bernstein, D. Gareth Evans, Heike Görgens, Marta Pineda, John Burn, Kirsi Pylvänäinen, Eivind Hovig, Hans F. A. Vasen, Pablo Kalfayan, Toni T. Seppälä, Aung Ko Win, Maartje Nielsen, Wolff Schmiegel, Guy Rosner, Karl Heinimann, Fiona Lalloo, Carlos A. Vaccaro, Elke Holinski-Feder, Leticia Moreira, HUS Abdominal Center, Clinicum, II kirurgian klinikka, University of Helsinki, Department of Surgery, ATG - Applied Tumor Genomics, Research Programs Unit, Dominguez-Valentin, M., Sampson, J. R., Seppala, T. T., ten Broeke, S. W., Plazzer, J. -P., Nakken, S., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., Hovig, E., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Bertario, L., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Della Valle, A., Lopez-Kostner, F., Gluck, N., Katz, L. H., Heinimann, K., Vaccaro, C. A., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., Knebel Doeberitz, M., Loeffler, M., Rahner, N., Schackert, H. K., Steinke-Lange, V., Schmiegel, W., Vangala, D., Pylvanainen, K., Renkonen-Sinisalo, L., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Wadt, K., Therkildsen, C., Okkels, H., Ketabi, Z., Moreira, L., Sanchez, A., Serra-Burriel, M., Pineda, M., Navarro, M., Blanco, I., Green, K., Lalloo, F., Crosbie, E. J., Hill, J., Denton, O. G., Frayling, I. M., Rodland, E. A., Vasen, H., Mints, M., Neffa, F., Esperon, P., Alvarez, K., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Tjandra, D., Winship, I. M., Macrae, F., Moslein, G., Mecklin, J. -P., Nielsen, M., Moller, P., and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Oncology, Male, Colorectal cancer, Lynch syndrome, Penetrance, DNA Mismatch Repair, 0302 clinical medicine, Databases, Genetic, Malalties hereditàries, Prospective Studies, Càncer, PMS2, Genetics (clinical), Mismatch Repair Endonuclease PMS2, Cancer, 0303 health sciences, Sex Characteristics, Factors de risc en les malalties, 1184 Genetics, developmental biology, physiology, MLH1, Middle Aged, 16. Peace & justice, 3. Good health, DNA-Binding Proteins, MutS Homolog 2 Protein, syöpägeenit, MSH2, 030220 oncology & carcinogenesis, MSH6, 030211 gastroenterology & hepatology, DNA mismatch repair, Female, geneettiset tekijät, MutL Protein Homolog 1, Genetic diseases, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Risk factors in diseases, suolistosyövät, MUTATION CARRIERS, Risk Assessment, Article, sukupuoli, Age and gender, 03 medical and health sciences, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Lynchin oireyhtymä, Gene, 030304 developmental biology, Aged, business.industry, Endometrial cancer, Correction, nutritional and metabolic diseases, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Survival Analysis, digestive system diseases, Mutation, 3111 Biomedicine, ikä, business, Ovarian cancer
Abstract

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in independent cohorts,3-5 and inconsistent classification of genetic variants. Unexpected findings from previous studies have included path_MLH1 and path_MSH2 carriers appearing to have a lifetime risk of colorectal cancer (CRC) of approximately 50%, despite surveillance colonoscopy,6-8 and that shorter intervals between colonoscopies do not seem to reduce the incidence of CRC in LS.9,10 These findings challenge the assumptions that CRC in LS usually develops from a noninfiltrative adenoma precursor and that CRC can be prevented by colonoscopic detection and removal of adenomas in the colon and rectum. Additionally, previous studies in the Prospective Lynch Syndrome Database (PLSD) have shown no increase in cancer risk in path_PMS2 carriers before 40 years of age and, although observation years were limited in older path_PMS2 carriers, LS-associated cancers other than endometrial and prostate were not observed.6-8 In this study we collected prospective data from a new large cohort of path_MMR carriers to validate previous findings from PLSD. We also updated information on the original cohort to ensure consistent classification of pathogenicity of MMR gene variants. We then combined both data sets, providing larger numbers that allowed us to derive more precise risk estimates for cancers in LS categorized by gene and gender.

Published
2020

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