Tumor Marker Questions
Title:  Intratumor Heterogeneity and Branched Evolution Revealed by Multi-region Sequencing
Journal:  The New England Journal of Medicine
Date:  March 8, 2012

1.     This is a multi-part question.  To answer it, you will need to go to www.ncbi.nlm.nih.gov and follow these instructions.

From the drop-down search menu, choose “Nucleotide.” Type mTOR in the box to the right and hit “Search”.

Click on the Rattus norvegicus mechanistic target of rapamycin (serine/threonine kinase) (Mtor), mRNA (sixth entry). On the right side of the page, click “Run BLAST.” On the next page, click the BLAST button at the bottom (and wait…).

1. Scroll down your results page.  Name ten other taxa (scientific and common names) that share some sequence identity with this Rattus gene?
2. What is Rattus? In an evolutionary sense, why study the mTOR gene in this animal?
3. What does wild type mTOR gene do in these animals?  Why is it conserved across so many disparate species?

1a.)        
                                 Scientific Name                                         Common Name

                                  Mus musculus                                              House mouse
                          Peromyseus maniculatus                                      Deer mouse
                            Mesocricetus auratus                                      Golden hamster
                              Cricetulus griseus                                         Chinese hamster
                      Ceratotherium simum simum                               White rhinoceros
                                 Homo Sapiens                                                   Human
                                 Equus caballus                                                   Horse
                              Saimiri boliviensis                              Black-capped squirrel monkey
                                  Pan paniscus                                                    Bonobo
                              Macaca fasicularis                                     Long-tailed macaque


1b.) Rattus is commonly known as the brown rat and is the organism often studied in laboratories around the world or kept as pets. The reasons why the mTOR gene is studied in these organisms are that they grow to sexual maturity rapidly and multiple generations can be studied in a relatively short period of time, allowing us to test for mutations and changes in the gene due to heredity.

1c.) The wild type mTOR gene codes for protein mammalian target of rapamycin, it is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. It is conserved in so many species because it is a crucial protein in the developmental process of mammals even though it can contribute to a group of health problems. For example, hyperactivity of the protein can cause Alzheimer's in mammals.

2.    Apply Darwin’s postulates to tumor adaptation in drug-resistant clones.

2.) Postulate 1 states that within a population, genetic variation will exist among tumors formed in individual organisms. Postulate 2 goes on to state that at least some of the genes will be heritable. Mutations within a tumor site will be passed on to other cells within the same tumor or other tumor metastases. Postulate 3 states that not all of these populations of tumor cells will survive. This is shown when certain drugs and therapies do not have an effect on certain areas of a tumor in an organism. Postulate 4 allows natural selection to take place within the tumor cells, slowly allowing the resistant portions to develop and form a more resistant tumor over time.

3. The authors assert that intratumor heterogeneity will influence medical decisions and personalized treatments.  Why, then, might it be important for an Oncologist to understand evolution?

3.) Understanding the evolutionary processes of tumor development would be important to an Oncologist because it is the only way to truly understand and provide proper treatment. By understanding this evolutionary process, Oncologists can provide individualized treatment plans and help prevent resistant tumors.

4.  Considering Figures 2C and 4B, explain how phylogenetics can contribute to the understanding of tumor heterogeneity and to the generation of better tumor markers.

4.) "Reconstructing tumor clonal architectures and the identification of common mutations located in the trunk of the phylogenetic tree may contribute to more robust biomarkers and therapeutic approaches."