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Previously unknown gene mutation in hereditary colon cancer identified.

It is known that the formation of large numbers of polyps in the colon has a high probability of developing into colon cancer, if left untreated. The large-scale appearance of polyps is often due to a hereditary cause, where the disease can occur in multiple family members. Now, a study from researchers led by University Hospital Bonn identifies genetic changes in the MSH3 gene in patients with colorectal polyposis, and a new rare form of hereditary colon cancer. The team state that their findings will extend the knowledge of disease mechanisms, biological pathways, and potential therapeutic targets for colon cancer.  The opensource study is published in the American Journal of Human Genetics.

Previous studies show that colon polyps form mushroom-shaped growths from the mucosa and are several millimeters to several centimeters in size. They are benign and generally do not cause any symptoms, but they can turn into colon cancer. Researchers refer to the development of a large number of polyps in the colon as polyposis, and have already identified several genes associated with a polyposis.  However, about one-third of families affected by the disease do not have any abnormalities in these genes. Therefore, the lab hypothesized there would have to be even more genes involved in the formation of polyps in the colon.  The current study sequenced the germline exomes of 102 unrelated individuals, with unexplained adenomatous polyposis, to identify the additional genes.

The current study analyzed the genetic material of 102 polyposis patients using blood samples, with all of the known 20,000 protein-coding genes simultaneously examined in each patient.  Results in two patients show genetic mutations in the MSH3 gene on chromosome 5.

The group investigated the consequences for patients resulting from the loss of function of the MSH3 gene.  Data findings show that since the protein is missing in the cell nucleus of the patient´s tissues, there is an accumulation of genetic defects. Results show that the mutations which are not repaired leads to more frequent occurrence of polyps in the colon.

The researchers state that the newly discovered type of polyposis, in contrast to many other forms of hereditary colon cancer, is not inherited dominantly, but instead recessively.  They go on to explain that this means siblings have a 25% chance of developing the disease; however, the parents and children of affected persons only have a very low risk of developing the disease.

The team surmise that their findings suggest by investigating the MSH3 gene, a clear diagnosis can be made prospectively in previously unexplained polyposis cases.  For the future, the researchers state medicine could gain new insights into the development and biological foundations of tumours through the identification of mutations in the MSH3 gene.  They go on to conclude that the knowledge about molecular mechanisms which lead to cancer is also a precondition for the development of new targeted drugs.

Source: University Hospital Bonn

 

PMS 2 germline mutations.  (C) Immunohistochemical staining of both tumor and normal tissue shows complete loss of PMS 2 protein, whereas (D) MLH 1 expression is normal (E) H-E staining.  Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis.  Aretz et al 2016.
PMS 2 germline mutations. (C) Immunohistochemical staining of both tumor and normal tissue shows complete loss of PMS 2 protein, whereas (D) MLH 1 expression is normal (E) H-E staining. Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. Aretz et al 2016.

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