Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome

Authors: Chen, Jinyun1; Etzel, Carol2; Amos, Christopher2; Zhang, Qing2; Viscofsky, Nancy2; Lindor, Noralane3; Lynch, Patrick4; Frazier, Marsha5

Source: Cancer Causes and Control, Volume 20, Number 9, November 2009 , pp. 1769-1777(9)

Publisher: Springer

Buy & download fulltext article:

OR

Price: $47.00 plus tax (Refund Policy)

Abstract:

Lynch syndrome is an autosomal dominant syndrome of familial malignancies resulting from germ line mutations in DNA mismatch repair (MMR) genes. Our goal was to take a pathway-based approach to investigate the influence of polymorphisms in cell cycle-related genes on age of onset for Lynch syndrome using a tree model.

We evaluated polymorphisms in a panel of cell cycle-related genes (AURKA, CDKN2A, TP53, E2F2, CCND1, TP73, MDM2, IGF1, and CDKN2B) in 220 MMR gene mutation carriers from 129 families. We applied a novel statistical approach, tree modeling (Classification and Regression Tree), to the analysis of data on patients with Lynch syndrome to identify individuals with a higher probability of developing colorectal cancer at an early age and explore the gene–gene interactions between polymorphisms in cell cycle genes.

We found that the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats ≥19, E2F2 variant genotype, AURKA wild-type genotype, and CCND1 variant genotype had the youngest age of onset, with a 45-year median onset age, while the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats ≥19, E2F2 wild-type genotype, and AURKA variant genotype had the latest median age of onset, which was 70¬†years. Furthermore, we found evidence of a possible gene–gene interaction between E2F2 and AURKA genes related to CRC age of onset.

Polymorphisms in these cell cycle-related genes work together to modify the age at the onset of CRC in patients with Lynch syndrome. These studies provide an important part of the foundation for development of a model for stratifying age of onset risk among those with Lynch syndrome.

Keywords: Age of onset; Cell cycle pathway; Lynch syndrome; Polymorphisms; Tree model

Document Type: Research Article

DOI: http://dx.doi.org/10.1007/s10552-009-9416-x

Affiliations: 1: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Unit 1365, 1155 Pressler Boulevard, Houston, TX, 77030, USA, Email: janechen@mdanderson.org 2: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Unit 1365, 1155 Pressler Boulevard, Houston, TX, 77030, USA 3: Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA 4: Department of Gastrointestinal Medicine and Nutrition, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA 5: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Unit 1365, 1155 Pressler Boulevard, Houston, TX, 77030, USA, Email: mlfrazier@mail.mdanderson.org

Publication date: November 1, 2009

Related content

Key

Free Content
Free content
New Content
New content
Open Access Content
Open access content
Subscribed Content
Subscribed content
Free Trial Content
Free trial content

Text size:

A | A | A | A
Share this item with others: These icons link to social bookmarking sites where readers can share and discover new web pages. print icon Print this page