المؤلفون: Dominguez-Valentin, M., Haupt, S., Seppälä, T.T., Sampson, J.R., Sunde, L., Bernstein, I., Jenkins, M.A., Engel, C., Aretz, S., Nielsen, M., Capella, G., Balaguer, F., Evans, D.G., Burn, J., Holinski-Feder, E., Bertario, L., Bonanni, B., Lindblom, A., Levi, Z., Macrae, F., Winship, I., Plazzer, J.P., Sijmons, R., Laghi, L., Valle, A., Heinimann, K., Debniak, T., Fruscio, R., Lopez-Koestner, F., Alvarez-Valenzuela, K., Katz, L.H., Laish, I., Vainer, E., Vaccaro, C., Carraro, D.M., Monahan, K., Half, E., Stakelum, A., Winter des, Kennelly, R., Gluck, N., Sheth, H., Abu-Freha, N., Greenblatt, M., Rossi, B.M., Bohorquez, M., Cavestro, G.M., Lino-Silva, L.S., Horisberger, K., Tibiletti, M.G., Nascimento, I., Thomas, H., Rossi, N.T., Silva, L.A. da, Zarand, A., Ruiz-Banobre, J., Heuveline, V., Mecklin, J.P., Pylvänäinen, K., Renkonen-Sinisalo, L., Lepistö, A., Peltomäki, P., Therkildsen, C., Madsen, M.G., Burgdorf, S.K., Hopper, J.L., Win, A.K., Haile, R.W., Lindor, N., Gallinge, S., Marchand, L. le, Newcomb, P.A., Figueiredo, J., Buchanan, D.D., Thibodeau, S.N., Doeberitz, M.V., 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.B., Moreira, L., Sánchez, A., Hovig, E., Nakken, S., Green, K., Lalloo, F., Hill, J., Crosbie, E., Mints, M., Goldberg, Y., Tjandra, D., Broeke, S.W. ten, Kariv, R., Rosner, G., Advani, S.H., Thomas, L., Shah, P., Shah, M., Neffa, F., Esperon, P., Pavicic, W., Torrezan, G.T., Bassaneze, T., Martin, C.A., Moslein, G., Moller, P.

المصدر: EClinicalMedicine

مصطلحات موضوعية: Mortality, Survival, Lynch syndrome, Cancer risk, MLH1, MSH2, MSH6, PMS2, Prospective study

الوصف: 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. ; Hereditary cancer genetics

وصف الملف: application/pdf

العلاقة: https://www.sciencedirect.com/science/article/pii/S258953702300086X?via%3DihubTest; lumc-id: 185246218; https://hdl.handle.net/1887/3750350Test

الإتاحة: https://doi.org/10.1016/j.eclinm.2023.101909Test
https://hdl.handle.net/1887/3750350Test
https://www.sciencedirect.com/science/article/pii/S258953702300086X?via%3DihubTest

المؤلفون: Stolz, J.R., Foote, K.M., Veenstra-Knol, H.E., Pfundt, R., Broeke, S.W. ten, Leeuw, N. de, Roht, L., Pajusalu, S., Part, R., Rebane, I., Ounap, K., Stark, Z., Kirk, E.P., Lawson, J.A., Lunke, S., Christodoulou, J., Louie, R.J., Rogers, R.C., Davis, J.M., Innes, A.M., Wei, X.C., Keren, B., Mignot, C., Lebel, R.R., Sperber, S.M., Sakonju, A., Dosa, N., Barge-Schaapveld, D.Q.C.M., Peeters-Scholte, C.M.P.C.D., Ruivenkamp, C.A.L., Bon, B.W. van, Kennedy, J., Low, K.J., Ellard, S., Pang, L.W., Junewick, J.J., Mark, P.R., Carvill, G.L., Swanson, G.T.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=dedup_wf_001::dfce94aba2dcb4d3e32ea042fd9139d1Test
https://hdl.handle.net/1887/3264402Test

المؤلفون: Ahadova, A., Seppala, T.T., Engel, C., Gallon, R., Burn, J., Holinski-Feder, E., Steinke-Lange, V., Moslein, G., Nielsen, M., Broeke, S.W. ten, Laghi, L., Dominguez-Valentin, M., Capella, G., Macrae, F., Scott, R., Huneburg, R., Nattermann, J., Hoffmeister, M., Brenner, H., Blaker, H., Doeberitz, M.V., Sampson, J.R., Vasen, H., Mecklin, J.P., Moller, P., Kloor, M.

المصدر: International Journal of Cancer

مصطلحات موضوعية: colonoscopy surveillance, colorectal cancer, incident cancer risk, Lynch syndrome, microsatellite instability, mismatch repair deficiency

الوصف: Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy with polypectomy is recommended to reduce CRC risk in LS individuals. However, recent independent studies demonstrated that a substantial proportion of LS individuals develop CRC despite regular colonoscopy. The reasons for this surprising observation confirmed by large prospective studies are a matter of debate. In this review, we collect existing evidence from clinical, epidemiological and molecular studies and interpret them with regard to the origins and progression of LS-associated CRC. Alongside with hypotheses addressing colonoscopy quality and pace of progression from adenoma to cancer, we discuss the role of alternative precursors and immune system in LS-associated CRC. We also identify gaps in current knowledge and make suggestions for future studies aiming at improved CRC prevention for LS individuals. ; Hereditary cancer genetics

وصف الملف: application/pdf

العلاقة: lumc-id: 111453790; https://hdl.handle.net/1887/3195901Test

الإتاحة: https://doi.org/10.1002/ijc.33224Test
https://hdl.handle.net/1887/3195901Test

المؤلفون: 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., Broeke, S.W. ten, Jenkins, M.A., Sunde, L., Bernstein, I., Burn, J., Greenblatt, M., Cappel, W.H.D.T.N., Valle, A. della, Lopez-Koestner, F., Alvarez, K., Buttner, R., Gorgens, H., Morak, M., Holzapfel, S., Huneburg, R., Doeberitz, M.V., Loeffler, M., Redler, S., Weitz, J., Pylvanainen, K., Renkonen-Sinisalo, L., Lepisto, A., Hopper, J.L., Win, A.K., Lindor, N.M., Gallinger, S., Marchand, L.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.

المصدر: European Journal of Cancer

مصطلحات موضوعية: Lynch syndrome, Endometrial cancer, Ovarian cancer, Risk-reducing surgery, Hysterectomy, Oophorectomy, MLH1, MSH2, MSH6, PMS2

الوصف: 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. ; Hereditary cancer genetics

وصف الملف: application/pdf

العلاقة: http://www.ejcancer.com/article/S0959804921001052/pdfTest; lumc-id: 116125929; https://hdl.handle.net/1887/3196213Test

الإتاحة: https://doi.org/10.1016/j.ejca.2021.02.022Test
https://hdl.handle.net/1887/3196213Test
http://www.ejcancer.com/article/S0959804921001052/pdfTest

المؤلفون: 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., Cappel, W.H.D.T.N., Sijmons, R.H., Nielsen, M., Bertario, L., Bonanni, B., Tibiletti, M.G., Cavestro, G.M., Lindblom, A., Valle, A. della, 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., 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., Broeke, S.W. ten, 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. le, 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., Moller, P.

المصدر: Journal of Clinical Medicine

مصطلحات موضوعية: MLH1, MSH2, penetrance, cancer incidence, truncating, missense, aberrant splicing, Lynch syndrome

الوصف: 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. ; Hereditary cancer genetics

وصف الملف: application/pdf

العلاقة: https://www.mdpi.com/2077-0383/10/13/2856/pdfTest; lumc-id: 116677215; https://hdl.handle.net/1887/3204253Test

الإتاحة: https://doi.org/10.3390/jcm10132856Test
https://hdl.handle.net/1887/3204253Test
https://www.mdpi.com/2077-0383/10/13/2856/pdfTest

المؤلفون: Stolz, J.R., Foote, K.M., Veenstra-Knol, H.E., Pfundt, R., Broeke, S.W. ten, Leeuw, N. de, Roht, L., Pajusalu, S., Part, R., Rebane, I., Ounap, K., Stark, Z., Kirk, E.P., Lawson, J.A., Lunke, S., Christodoulou, J., Louie, R.J., Rogers, R.C., Davis, J.M., Innes, A.M., Wei, X.C., Keren, B., Mignot, C., Lebel, R.R., Sperber, S.M., Sakonju, A., Dosa, N., Barge-Schaapveld, D.Q.C.M., Peeters-Scholte, C.M.P.C.D., Ruivenkamp, C.A.L., Bon, B.W. van, Kennedy, J., Low, K.J., Ellard, S., Pang, L., Junewick, J.J., Mark, P.R., Carvill, G.L., Swanson, G.T.

المصدر: American Journal of Human Genetics

الوصف: Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development. ; Genetics of disease, diagnosis and treatment

وصف الملف: application/pdf

العلاقة: http://www.cell.com/article/S0002929721002755/pdfTest; lumc-id: 120712123; https://hdl.handle.net/1887/3277435Test

الإتاحة: https://doi.org/10.1016/j.ajhg.2021.07.007Test
https://hdl.handle.net/1887/3277435Test
http://www.cell.com/article/S0002929721002755/pdfTest

المؤلفون: Dominguez-Valentin, M., Sampson, J.R., Seppala, T.T., Broeke, S.W. ten, 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., Cappel, W.H.D.T.N.C., Sijmons, R.H., Bertario, L., Tibiletti, M.G., Cavestro, G.M., Lindblom, A., Valle, A. della, 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., Doeberitz, M.V., 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., Marchand, L. le, 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.

المصدر: Genetics in Medicine

مصطلحات موضوعية: Lynch syndrome, MLH1, MSH2, MSH6, PMS2

الوصف: Purpose Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. Methods We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. Results There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. Conclusion Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers. ; Hereditary cancer genetics

وصف الملف: application/pdf

العلاقة: https://www.sciencedirect.com/science/article/pii/S1098360021010935?via%3DihubTest; lumc-id: 84219248; https://hdl.handle.net/1887/3181546Test

الإتاحة: https://doi.org/10.1038/s41436-019-0596-9Test
https://hdl.handle.net/1887/3181546Test
https://www.sciencedirect.com/science/article/pii/S1098360021010935?via%3DihubTest

المؤلفون: Terlouw, D., Suerink, M., Singh, S.S., Gille, H.J.J.P., Hes, F.J., Langers, A.M.J., Morreau, H., Vasen, H.F.A., Vos, Y.J., Wezel, T. van, Tops, C.M., Broeke, S.W. ten, Nielsen, M.

المصدر: European Journal of Human Genetics

الوصف: This study aimed to determine the prevalence of APC-associated familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) in a large cohort, taking into account factors as adenoma count and year of diagnosis. All application forms used to send patients in for APC and MUTYH variant analysis between 1992 and 2017 were collected (n = 2082). Using the data provided on the application form, the APC and biallelic MUTYH prevalence was determined and possible predictive factors were examined using multivariate multinomial logistic regression analysis in SPSS. The prevalence of disease causing variants in the APC gene significantly increases with adenoma count while MAP shows a peak prevalence in individuals with 50-99 adenomas. Logistic regression analysis shows significant odds ratios for adenoma count, age at diagnosis, and, interestingly, a decline in the chance of finding a variant in either gene over time. Moreover, in 22% (43/200) of patients with FAP-related extracolonic manifestations a variant was identified. The overall detection rates are above 10% for patients with >10 adenomas aged 20 adenomas aged <70. Patients with variants outside these criteria had FAP-related extracolonic manifestations, colorectal cancer aged <40, somatic KRAS c.34G > T variant in the tumor or a first-degree relative with >10 adenomas. Therefore, APC and MUTYH testing in patients with >10 adenomas aged 20 adenomas aged <70 is advised. Almost all FAP and MAP patients not meeting these criteria showed other characteristics that can be used as an indication to prompt genetic testing. ; Molecular tumour pathology - and tumour genetics ; MTG2 - Moleculaire genetica van gastrointestinale tumoren

وصف الملف: application/pdf

العلاقة: https://www.nature.com/articles/s41431-019-0509-zTest; lumc-id: 81343618; https://hdl.handle.net/1887/3181477Test

الإتاحة: https://doi.org/10.1038/s41431-019-0509-zTest
https://hdl.handle.net/1887/3181477Test
https://www.nature.com/articles/s41431-019-0509-zTest

المؤلفون: Broeke, S.W. ten, Rodriguez-Girondo, M., Suerink, M., Aretz, S., Bernstein, I., Capella, G., Engel, C., Gomez-Garcia, E.B., Hest, L.P. van, Doeberitz, M. von Knebel, Lagerstedt-Robinson, K., Letteboer, T.G., Moller, P., Os, T.A. van, Pineda, M., Rahner, N., Olderode-Berends, M.J., Salome, J. von, Schackert, H.K., Spruijt, L., Steinke-Lange, V., Wagner, A., Tops, C.M., Nielsen, M.

المصدر: Cancer Epidemiology, Biomarkers & Prevention, 28, 6, pp. 1010-1014

مصطلحات موضوعية: Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health Sciences

الوصف: Contains fulltext : 206727.pdf (publisher's version ) (Closed access) ; BACKGROUND: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families. METHODS: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias. RESULTS: Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162-4.328] for the second generation and 2.644 (95% CI, 1.082-6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648-2.619) and HR = 1.074 (95% CI, 0.406-2.842) for second and third generations, respectively]. CONCLUSIONS: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome. IMPACT: This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition.

العلاقة: http://hdl.handle.net/2066/206727Test; https://doi.org/10.1158/1055-9965.EPI-18-0576Test

الإتاحة: https://doi.org/10.1158/1055-9965.EPI-18-0576Test
http://hdl.handle.net/2066/206727Test

المؤلفون: Broeke, S.W. ten, Suerink, M., Nielsen, M.

المصدر: Genetics in Medicine

الوصف: Hereditary cancer genetics

العلاقة: lumc-id: 57170603; https://hdl.handle.net/1887/119457Test

الإتاحة: https://doi.org/10.1038/s41436-018-0029-1Test
https://hdl.handle.net/1887/119457Test