Role for Genetic Anticipation in Lynch Syndrome.
(2009) In Journal of Clinical Oncology 27. p.360-364- Abstract
- PURPOSE: Anticipation (ie, an earlier age at onset in successive generations) is linked to repeat expansion in neurodegenerative syndromes, whereas its role in hereditary cancer is unclear. We assessed anticipation in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), in which DNA mismatch repair (MMR) defects cause early and accelerated tumor development with a broad tumor spectrum. PATIENTS AND METHODS: In the population-based Danish HNPCC registry, 407 MMR gene mutation carriers who had developed cancer associated with Lynch syndrome, were identified. These individuals formed 290 parent-child pairs in which age at the first cancer diagnosis was assessed. A paired t-test and a specifically developed bivariate model were... (More)
- PURPOSE: Anticipation (ie, an earlier age at onset in successive generations) is linked to repeat expansion in neurodegenerative syndromes, whereas its role in hereditary cancer is unclear. We assessed anticipation in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), in which DNA mismatch repair (MMR) defects cause early and accelerated tumor development with a broad tumor spectrum. PATIENTS AND METHODS: In the population-based Danish HNPCC registry, 407 MMR gene mutation carriers who had developed cancer associated with Lynch syndrome, were identified. These individuals formed 290 parent-child pairs in which age at the first cancer diagnosis was assessed. A paired t-test and a specifically developed bivariate model were used to assess a possible role of anticipation. RESULTS: Both methods revealed anticipation with children developing cancer mean 9.8 years (P < .001) earlier than parents using the paired t-test and 5.5 years (P < .001) earlier using the bivariate model. Birth cohort effects were excluded since anticipation with 7.2 years earlier age at onset was identified also in the oldest cohort, in which the children were observed until they were older than 80 years. The effect remained when cancers diagnosed at surveillance were excluded, applied to maternal as well as paternal inheritance, and was independent of the MMR gene mutated. CONCLUSION: The effect from anticipation demonstrated in this large, population-based Lynch syndrome cohort underscores the need to initiate surveillance programs at young age. It should also stimulate research into the genetic mechanisms that determine age at onset and whether the genetic instability that characterizes Lynch syndrome can be linked to anticipation. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1276244
- author
- Nilbert, Mef LU ; Timshel, Susanne ; Bernstein, Inge and Larsen, Klaus
- organization
- publishing date
- 2009
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Clinical Oncology
- volume
- 27
- pages
- 360 - 364
- publisher
- American Society of Clinical Oncology
- external identifiers
-
- wos:000262499100008
- pmid:19075283
- scopus:58749091265
- ISSN
- 1527-7755
- DOI
- 10.1200/JCO.2008.16.1281
- project
- Precision Medicine in Hereditary Cancer and Sarcoma; targeted surveillance, immunotherapy and individualized follow-up
- language
- English
- LU publication?
- yes
- id
- cac1c146-af80-45ac-a49e-957cd63fb8b6 (old id 1276244)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/19075283?dopt=Abstract
- date added to LUP
- 2016-04-04 08:35:51
- date last changed
- 2022-04-15 20:30:00
@article{cac1c146-af80-45ac-a49e-957cd63fb8b6,
abstract = {{PURPOSE: Anticipation (ie, an earlier age at onset in successive generations) is linked to repeat expansion in neurodegenerative syndromes, whereas its role in hereditary cancer is unclear. We assessed anticipation in Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), in which DNA mismatch repair (MMR) defects cause early and accelerated tumor development with a broad tumor spectrum. PATIENTS AND METHODS: In the population-based Danish HNPCC registry, 407 MMR gene mutation carriers who had developed cancer associated with Lynch syndrome, were identified. These individuals formed 290 parent-child pairs in which age at the first cancer diagnosis was assessed. A paired t-test and a specifically developed bivariate model were used to assess a possible role of anticipation. RESULTS: Both methods revealed anticipation with children developing cancer mean 9.8 years (P < .001) earlier than parents using the paired t-test and 5.5 years (P < .001) earlier using the bivariate model. Birth cohort effects were excluded since anticipation with 7.2 years earlier age at onset was identified also in the oldest cohort, in which the children were observed until they were older than 80 years. The effect remained when cancers diagnosed at surveillance were excluded, applied to maternal as well as paternal inheritance, and was independent of the MMR gene mutated. CONCLUSION: The effect from anticipation demonstrated in this large, population-based Lynch syndrome cohort underscores the need to initiate surveillance programs at young age. It should also stimulate research into the genetic mechanisms that determine age at onset and whether the genetic instability that characterizes Lynch syndrome can be linked to anticipation.}},
author = {{Nilbert, Mef and Timshel, Susanne and Bernstein, Inge and Larsen, Klaus}},
issn = {{1527-7755}},
language = {{eng}},
pages = {{360--364}},
publisher = {{American Society of Clinical Oncology}},
series = {{Journal of Clinical Oncology}},
title = {{Role for Genetic Anticipation in Lynch Syndrome.}},
url = {{http://dx.doi.org/10.1200/JCO.2008.16.1281}},
doi = {{10.1200/JCO.2008.16.1281}},
volume = {{27}},
year = {{2009}},
}