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…).
- Scroll down your results
page. Name ten other taxa
(scientific and common names) that share some sequence identity with this Rattus gene?
- What is Rattus? In an evolutionary sense,
why study the mTOR gene in this
animal?
- 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."
