The apparent genetic anticipation in PMS2-associated Lynch syndrome families is explained by birth cohort effect

Sanne W Ten Broeke, Mar Rodríguez-Girondo, Manon Suerink, Stefan Aretz, Inge Bernstein, Gabriel Capella, Christoph Engel, Encarna B Gomez-Garcia, Liselotte P van Hest, Magnus von Knebel Doeberitz, Kristina Lagerstedt-Robinson, Tom G W Letteboer, Pål Møller, Theo A M van Os, Marta Pineda, Nils Rahner, Maran J W Olderode-Berends, Jenny von Salomé, Hans K Schackert, Liesbeth SpruijtVerena Steinke-Lange, Anja Wagner, Carli M J Tops, Maartje Nielsen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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) andHR= 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.

OriginalsprogEngelsk
TidsskriftCancer Epidemiology, Biomarkers & Prevention
Vol/bind28
Udgave nummer6
Sider (fra-til)1010-1014
Antal sider5
ISSN1055-9965
DOI
StatusUdgivet - jun. 2019

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Genetic Anticipation
Hereditary Nonpolyposis Colorectal Neoplasms
Cohort Effect
Parturition
Colorectal Neoplasms
Confidence Intervals
Penetrance
Age of Onset
Weights and Measures
Mutation

Citer dette

Ten Broeke, Sanne W ; Rodríguez-Girondo, Mar ; Suerink, Manon ; Aretz, Stefan ; Bernstein, Inge ; Capella, Gabriel ; Engel, Christoph ; Gomez-Garcia, Encarna B ; van Hest, Liselotte P ; von Knebel Doeberitz, Magnus ; Lagerstedt-Robinson, Kristina ; Letteboer, Tom G W ; Møller, Pål ; van Os, Theo A M ; Pineda, Marta ; Rahner, Nils ; Olderode-Berends, Maran J W ; von Salomé, Jenny ; Schackert, Hans K ; Spruijt, Liesbeth ; Steinke-Lange, Verena ; Wagner, Anja ; Tops, Carli M J ; Nielsen, Maartje. / The apparent genetic anticipation in PMS2-associated Lynch syndrome families is explained by birth cohort effect. I: Cancer Epidemiology, Biomarkers & Prevention. 2019 ; Bind 28, Nr. 6. s. 1010-1014.
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title = "The apparent genetic anticipation in PMS2-associated Lynch syndrome families is explained by birth cohort effect",
abstract = "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) andHR= 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.",
author = "{Ten Broeke}, {Sanne W} and Mar Rodr{\'i}guez-Girondo and Manon Suerink and Stefan Aretz and Inge Bernstein and Gabriel Capella and Christoph Engel and Gomez-Garcia, {Encarna B} and {van Hest}, {Liselotte P} and {von Knebel Doeberitz}, Magnus and Kristina Lagerstedt-Robinson and Letteboer, {Tom G W} and P{\aa}l M{\o}ller and {van Os}, {Theo A M} and Marta Pineda and Nils Rahner and Olderode-Berends, {Maran J W} and {von Salom{\'e}}, Jenny and Schackert, {Hans K} and Liesbeth Spruijt and Verena Steinke-Lange and Anja Wagner and Tops, {Carli M J} and Maartje Nielsen",
note = "{\circledC}2019 American Association for Cancer Research.",
year = "2019",
month = "6",
doi = "10.1158/1055-9965.EPI-18-0576",
language = "English",
volume = "28",
pages = "1010--1014",
journal = "Cancer Epidemiology, Biomarkers & Prevention",
issn = "1055-9965",
publisher = "American Association for Cancer Research (A A C R)",
number = "6",

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Ten Broeke, SW, Rodríguez-Girondo, M, Suerink, M, Aretz, S, Bernstein, I, Capella, G, Engel, C, Gomez-Garcia, EB, van Hest, LP, von Knebel Doeberitz, M, Lagerstedt-Robinson, K, Letteboer, TGW, Møller, P, van Os, TAM, Pineda, M, Rahner, N, Olderode-Berends, MJW, von Salomé, J, Schackert, HK, Spruijt, L, Steinke-Lange, V, Wagner, A, Tops, CMJ & Nielsen, M 2019, 'The apparent genetic anticipation in PMS2-associated Lynch syndrome families is explained by birth cohort effect', Cancer Epidemiology, Biomarkers & Prevention, bind 28, nr. 6, s. 1010-1014. https://doi.org/10.1158/1055-9965.EPI-18-0576

The apparent genetic anticipation in PMS2-associated Lynch syndrome families is explained by birth cohort effect. / Ten Broeke, Sanne W; Rodríguez-Girondo, Mar; Suerink, Manon; Aretz, Stefan; Bernstein, Inge; Capella, Gabriel; Engel, Christoph; Gomez-Garcia, Encarna B; van Hest, Liselotte P; von Knebel Doeberitz, Magnus; Lagerstedt-Robinson, Kristina; Letteboer, Tom G W; Møller, Pål; van Os, Theo A M; Pineda, Marta; Rahner, Nils; Olderode-Berends, Maran J W; von Salomé, Jenny; Schackert, Hans K; Spruijt, Liesbeth; Steinke-Lange, Verena; Wagner, Anja; Tops, Carli M J; Nielsen, Maartje.

I: Cancer Epidemiology, Biomarkers & Prevention, Bind 28, Nr. 6, 06.2019, s. 1010-1014.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - The apparent genetic anticipation in PMS2-associated Lynch syndrome families is explained by birth cohort effect

AU - Ten Broeke, Sanne W

AU - Rodríguez-Girondo, Mar

AU - Suerink, Manon

AU - Aretz, Stefan

AU - Bernstein, Inge

AU - Capella, Gabriel

AU - Engel, Christoph

AU - Gomez-Garcia, Encarna B

AU - van Hest, Liselotte P

AU - von Knebel Doeberitz, Magnus

AU - Lagerstedt-Robinson, Kristina

AU - Letteboer, Tom G W

AU - Møller, Pål

AU - van Os, Theo A M

AU - Pineda, Marta

AU - Rahner, Nils

AU - Olderode-Berends, Maran J W

AU - von Salomé, Jenny

AU - Schackert, Hans K

AU - Spruijt, Liesbeth

AU - Steinke-Lange, Verena

AU - Wagner, Anja

AU - Tops, Carli M J

AU - Nielsen, Maartje

N1 - ©2019 American Association for Cancer Research.

PY - 2019/6

Y1 - 2019/6

N2 - 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) andHR= 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.

AB - 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) andHR= 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.

UR - http://www.scopus.com/inward/record.url?scp=85067217962&partnerID=8YFLogxK

U2 - 10.1158/1055-9965.EPI-18-0576

DO - 10.1158/1055-9965.EPI-18-0576

M3 - Journal article

C2 - 30824524

VL - 28

SP - 1010

EP - 1014

JO - Cancer Epidemiology, Biomarkers & Prevention

JF - Cancer Epidemiology, Biomarkers & Prevention

SN - 1055-9965

IS - 6

ER -