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Lynch Syndrome: structural biology in the service of diagnostic support

Researchers at the CEA, CNRS and Université Paris-Sud have presented the first model of the architecture of the MLH1 protein associated with Lynch syndrome, a genetic predisposition to colorectal cancer. This atomic level “image” of MLH1 will lead to better understanding of the genetic processes that cause the disease. This result is the starting point of a clinical diagnostic support project with La Timone University Hospital (Marseille public hospital system) and Institut Curie (Paris) to target treatments based on numerous variants of this anomaly.
Published on 25 February 2013

Lynch syndrome is a genetic, hereditary ailment that predisposes a person to colorectal cancer. It is thought that three genes, MLH1, MSH2 and MSH6, are primarily responsible and that these genes regulate errors that occur during DNA replication, especially during cellular division.Researchers targeted the protein corresponding to MLH1, one of the central proteins involved in the DNA repair pathway (termed the “mismatch repair pathway” because it repairs errors related to DNA replication). They used X-ray crystallography to understand how it functions and detected exactly where the mutations occur. The technique consists of crystallizing a protein and studying how the crystal refracts an X-ray beam, in much the same way as a prism refracts sunlight. Since the angle of deviation is related to the distance between atoms, crystallography provides the atomic structure of the protein. Rather obvious in this summary, in this case the method required twelve years of work from creation of the first crystals to the final “image”. Illustration of the atomic structure of MLH1 structure (light and dark green) used to locate the mutations identified on a panel of patients. This image shows a classification of mutations: very severe (red), moderately severe (cyan) or whose severity if difficult to predict according to the image (gray). Illustration credit: CEA/CNRS/Université Paris-Sud.In addition to its contribution to basic research, this article is the starting point of a clinical diagnostic support project. Numerous mutations identified on MLH1 do not directly explain the syndrome. Their involvement can only be established by integrating various clinical, tumoral and familial factors.

Researchers and clinicians are working on a list of 70 MLH1 mutations observed in a patient panel. With results from Saclay, researchers have already pinpointed the potential impact of each mutation on the DNA mismatch repair pathway. Conducted by the Marseille public hospital system and Institut Curie, the objective of this project is to use functional data to personalize treatment for patients who carry these mutations, in combination with other factors. The impact of these mutations can be divided into three categories: 1. Very severe (harmful mutation, protein deployed) ; 2. Moderately severe (protein cannot interact with its environment); 3. Not pronounced. After sequencing the genome of persons at risk (since the syndrome is hereditary), doctors may then have a classification system at their disposal to help them determine preventive treatment for colorectal cancer .

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