Thursday, May 8, 2014

Examination of Paralogue Genes

    In preparation for my project with Sonya, I discovered a study on a paralogue to the L3MBTL1 gene.  This gene is critical to the randomized clinical trial entitled, "Physical Activity and
Breast Cancer Survival: an epigenetic link through reduced methylation of a tumor suppressor gene L3MBTL1".  If this study we are evaluating has significance, then it requires this gene encode a tumor suppressor.  A study of a paralogue gene entitled, "Loss, mutation, and deregulation of L3MBTL4 in breast cancer" provides evidence that L3MBTL4 is a tumor suppressor gene and implies our gene of interest the L3MBT1 is one as well.

    First, a paralogue is a duplicate of a gene which has evolved a new function.  The paralogue to L3MBTL1 is the L3MTL4 gene.  L3MBTL1 is located on chromosome 20 and L3MBTL4 is located on chromosome 18.  The L3MBTL family has MBT domains which modify chromatin and repress transcription. All four of the human L3MBTL genes have been connected to cancer.  Specifically, LL3MBTL1 appears to repress p53 and Rb while L3MBTl4 appears to repress transcription. Secondly, the L3MBTL family is part of the polycomb group of genes which can alter chromatin and epigenetically silence genes.
   Now, I cannot assert L3MBTL1 is a tumor suppressor because L3MBTL4 is a tumor suppressor.  This avoids the pitfall of committing the logical fallacy of argument by analogy.  However, I intend to indicate a relationship between breast cancer survival and the role of L3MBTL1 and L3MBTL4 expression.
   The epigenetic study illustrated the increase of L3MBTL1 expression correlates with a 60% reduction of risk from breast cancer death compared to low expressions.  Moreover, the higher expression of L3MBTL1 is correlated to a less aggressive cancer phenotypes and survival outcomes.  The researchers clustered L3MBTL1 expression as high, medium, and low based on a comparison to the average level of expression. The Kaplan-Meier Table below suggests that survival is greatest with higher expression of L3MBTL1.

     The loss of L3MBTL4 study demonstrates a loss of this gene occurs in the more aggressive breast cancer phenotypes.  There appears to be a 9% decrease in 5 years metastasis free survival and a 5% decrease in 5 year overall specific survival when L3MBTL4 is eliminated.  Additionally, L3MBTL4 loss is related to lymph node metastasis.  Notably, a relapse is higher by 6% for patients who lose L3MBTL4.  In addition, this area appears to be a target. This area is frequently deleted in breast cancers targeted by mutations, breakages and is down regulated in tumors.  This study used tumor tissues from 307 primary adenocarcinoma patients.
    These studies propose the presence and absence of the L3MBTL family is related to breast cancer survival outcomes. The importance of the presence of the L3MBTL family is emphasized by what seems to be the targeting of L3MBTL4.  Furthermore, the importance of L3MBTL1 is realized by the impact it has on increasing survival.  This evidence supports the validity of the L3MBTL family being pertinent to breast cancer survival.

Addou-Klouche, Lynda, Jose Adelaid, Pascal Finetti, Nathalie Cerveral, Anthony Ferrari, Ismahane Bekhouche, Fabrice Sircoulomb, Christos Sotiriou, Patrice Viens, Soraya Moulessehoul, Francois Bertucci, Daniel Birnbaum, Max Chaffanet. "Loss, mutation and deregulation of L3MBTL4 in breast cancers". Molecular Cancer (2010) 9:213. Web Apr. 20, 2014

Zeng, Hongmei, Melinda L. Irwin, Lingeng Lu, Harvey Risch, Susan Matne, Liama Mu, Qian Deng, Luca Scarampi, Marco Mitidieri, Dionyssios Katsaros, Herbert Yu. "Physical activity and breast cancer survival: an epigenetic link through reduced methylation of a tumor suppressor gene L3MBTL1".Breast Cancer Research Treatment (2012) 133:127-135 Web April 9, 2014.