Monday, April 21, 2014

Our First Notch to Understanding NOTCH

Antonio and I started our search on cancer by looking at an issue that people could relate to. Understanding that we are in college, we looked to the affects alcohol has on cancer. What we first found is that alcohol is directly related to a set of cancers called HNSCC or Head and Neck Cancer. These cancers have to do with the oral, nasal, pharynx and larynx areas.

Source: Reference 3
This graph to the right is the result of a study that was done by individuals at the Copenhagen Centre for Prospective Population Studies. The study was titled: Population based cohort study of the associationbetween alcohol intake and cancer of the upper digestive tract and was published in Copenhagen, Denmark in 1998. This graph essentially proves that the amount of alcohol consumption directly correlates to the chance of an individual getting a cancer in the upper digestive track region.

Compared to other cancers, HNSCC has the sixth largest number of incidences in the world with about 600,000 new occurrences every year worldwide. It also can be quite devastating for patients who are in the late stages of this cancer because the 5-year survival rate after treatment is only about 40-50 percent.

Based off of this, we further researched into HNSCC and found a gene mutation that caught our attention. This gene is known as NOTCH1. Mutations in NOTCH1 can be found in about 15% of HNSCC cases making it the 2nd most mutated gene in this type of cancer. NOTCH1 encodes for a receptor protein that spans through the membrane. When activated, the cytoplasmic end of this protein gets cleaved and acts a transcription factor that increases the expression of genes that help with cell differentiation. With this basic knowledge, it is easy to understand why mutations in this gene can cause cancer.

In an Exome Sequencing Study of HNSCC, published on in July 2011, a group of researchers used Affymetrix SNP6.0 microarrays (which depict genetic abnormalities) to compare 42 normal and tumor samples pairs. With this, they came up with this figure that showed a general map of NOTCH1 mutations in different types of tumors.
Source: Reference 1
In simple terms, this image shows NOTCH1 mutations for three different sets of tumors with set C displaying the mutations observed for HNSCC. This image essentially gives at least two conclusions, one being that HNSCC can act in different manners in different types of cancer, and two being that HNSCC’s have a significantly higher amount of mutations in the NOTCH1 gene compared to the other two sets of cancers that were analyzed. Further looking at these mutations and understanding previous literature about the NOTCH1 gene in different types of cancers, this study concluded that NOTCH1 does in fact act differently in different types of cancers. For example, in T-cell Leukemia, this gene acts as an oncogene. However, in HNSCC’s this gene acts as a tumor-suppressing gene. Throughout our research, Antonio and I hope to further understand why and how this happens and hopefully look at possible treatments for both threats that mutated NOTCH1 presents.  

Agrawal, N., Y. Wu, C. R. Pickering, C. Bettegowda, L. D. Wood, K. Chang, R. J. Li, C. Fakhry, T.-X. Xie, J. Zhang, J. Wang, N. Zhang, V. E. Velculescu, A. K. El-Naggar, S. A. Jasser, J. N. Weinstein, R. H. Hruban, J. N. Myers, W. H. Westra, W. M. Koch, J. A. Califano, R. A. Gibbs, D. Sidransky, N. Papadopoulos, B. Vogelstein, D. A. Wheeler, K. W. Kinzler, D. M. Muzny, J. A. Drummond, L. Trevino, and M. J. Frederick. "Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1." Science 333.6046 (2011): 1154-1157. Web. 12 Apr. 2014.

Brakenhoff, R. H.. "Another NOTCH for Cancer." Science 333.6046 (2011): 1102-1103. Web. 10 Apr. 2014.

M., Grønbaek, Becker U., Johansen D., Tønnesen H., Jensen G., and Sørensen T.. "Population based cohort study of the association between alcohol intake and cancer of the upper digestive tract.." National Center for Biotechnology Information. U.S. National Library of Medicine, 26 Sept. 1998. Web. 21 Apr. 2014. <