Can we turn cancer into a more manageable disease, like Diabetes, in our lifetime? Hopeful New Genetic Targets from Multi-Platform High-Throughput Sequencing: Individualized Medicine, Here We Come!

This slide was taken from: Sandhu et al., Microarray-Based Gene Expression Profiling For Molecular Classification of Breast Cancer and Identification of New Targets for Therapy. These are hematoxylin and eosin stained breast cancer sections from different patients displaying distinct types of  breast cancer. First pay attention to the histology without the brown stain on the far left. Try to notice differences between Luminal A, Luminal B, Her2, and Basal-like types. Now look at the rest of the figure. Note that the blue is marking the nuclei of individual cells and the brown is marking a specific cellular target: on the second column to the left the antibody is against the estrogen receptor, the next column the antibody is to the progesterone receptor, the next column the antibody is against the HER2 receptor tyrosine kinase. In the article, you will see that these three markers have been the main ones used to distinguish breast cancer types and determine a therapeutic approach. Also, please be careful, because this slide represents an extremely general view of these breast cancers. Imagine, that each subtype has enormous histological heterogeneity, as well as mRNA heterogeneity which you will read about in the articles. For example, Her2 might be expressed in certain luminal types, and might even be devoid in some "Her-2 types". Hmmm...Fathom that!

Instructions for week of October 29-November 2nd: 
We are going to take a skip to Cancer Genetics. So after finishing chapter 10 on Chromosome Structure, please read: Chapter 22  (focus on section 22.4, The Genetic Basis of Cancer). You should also read sections 1 & 2 in Chapter 21 (focus on the DNA Microarray technique, The Proteome, and Protein Microarrays) and revisit Chapter 20 pages 559-565 on Next Generation Sequencing.

Instructions for Discussion on November 2nd:
In the beginning of this month, a landmark paper was published in Nature for Breast Cancer Research. (Thanks Mo for passing it to me) A global consortium of cancer biologists worked together using six high throughput platforms with a common goal: to identify novel targets in breast cancer and to attempt to better define the four emerging breast cancer subtypes. I have posted this article (but not the supplements, please go to Nature directly for those if you have time) and a review article on breast cancer subtypes on Black Board (with link below).

Instructions for the blog:
Please remark on one interesting aspect of breast cancer that you have learned for the first time from reading the Nature article and/or the review. For class: please identify one finding in the paper that seems to be novel for breast cancer research. It may be a missense mutation specific to one of the breast cancer subtypes, or a technique that was used in their study in a very different/comprehensive manner, or whatever you find interesting. Be prepared to share with the class your interesting finding.

For Nature article, Click Here: Breast Cancer Molecular Portraits_Nature Article
For Breast Cancer Review Article (a softer introduction to the topic), Click Here: Review article on Breast Cancer Subtype Array Analysis_Lab Medicine Journal

Hospitals that make you sick

Fig. 1. Patient location and overlap during the outbreak. (A) Timeline of first positive cultures of the outbreak strain for the 18 affected patients.(B) Patient traces for each of the 18 patients shown in (A). Black lines, first positive culture; blue lines, medical ICU; yellow lines, cohorted areas;other colors represent specific wards at the NIH Clinical Center. (C) Graph of possible transmission links among patients. Patient IDs are within the circles. An arrow is present from one patient to another if the two patients overlapped in the same unit before the potential recipient culturing positive. Red links, the transmission event is predicted by the analysis reported here (see Fig. 3). www.ScienceTranslationalMedicine.org 22 August 2012 Vol 4 Issue 148 148ra116

This week's article was kindly forwarded to me by Melanie. We all heard about the outbreak of the carbapenem-resistant Klebsiella pnueumoniae that killed 11 out of 18 patients at the NIH Health Clinical Center in 2011. Here we have an opportunity to review the detective science behind elucidating the super-bug, tracking it down, and stomping it out of the hospital, pipes?!?!!!! My goodness, this article stirs several questions of pre-medical students: 1.How does whole-genome sequencing work as a detective art? 2. How do you feel about working in hospitals after learning about bugs like this? 3. What will be your stance on antibiotics as a physician? 4. Should more patients be sent home or prevented from entering hospitals knowing the dangers of pathogens such as these?

Please comment on one of the questions I pose above, or comment on whatever strikes you most after reading this Nature Translational Medicine article.

Click here:Article 3_Snitkin et al. Tracking Down Carbapenem-Resistant Klebsiella Pneumoniae

Article 2: Evidence For Haploinsufficiency in Marfan's Syndrome

Radiographs of engineered mice in Marfan Study.

In this week's discussion we will delve into mouse genetics to try to determine the molecular mechanism of Marfan Syndrome. In lecture this week, we learned about different types of dominant mutations. We ased the question, How can a mutated gene be dominant? We also tried to delineate differences between gain of function, dominant negative, and haploinsufficiency mutations. The article here tries to address a conundrum: whether Marfan Syndrome is caused by a dominant negative mutation, or by another mechanism. Click onto link below:

Judge et al., "Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome", Jo Clin Invest, 2004k

I would like for you to think about whether evidence provided in the paper supports the authors' conclusion that Marfan Sydrome is due to haploinsufficiency, and not by a dominant negative mutation. Please come to class organized with notes you have taken that you feel answer this question.

For the blog please answer this question with a post:
Do you feel this study was appropriate for publication in the Journal of Clinical Investigation, or not, and why? (For this, think about quality of data, novelty of work, and overall impact on the field) Try to limit your response to 1/2 a page.

If you have trouble with the above link (which directs you to the paper on BlackBoard) try this one instead:
Judge et al. article

Discusion 1: Sequencing Patient Genomes

Diagnosing treatment strategies by sequencing patient genomes

Second Chance: Lukas Wartman, a leukemia doctor and researcher, developed the disease himself. As he faced death, his colleagues sequenced his cancer genome. The result was a totally unexpected treatment.

By GINA KOLATA New York Times Health, Published: July 7, 2012

For our first case study, from New York Times Health please read this article:

http://www.nytimes.com/2012/07/08/health/in-gene-sequencing-treatment-for-leukemia-glimpses-of-the-future.html?_r=1&pagewanted=all

Assignment: Take a look at the readers' comments as well and note some of the questions/concerns raised by the general public/scientists in the field/tax payers, and cancer survivors on this topic. Some of the techniques mentioned in the article might be new to you so please do a web search and read up on some of the basic information of these techniques to be prepared for class discussion.

Please post a response to these two questions:

1. Do you feel encouraged or discouraged by this article in regards to cancer therapy?
2. What are some flaws or concerns you can identify in the diagnosis, treatment and handling of Dr. Wartman's case by his doctors, insurers, and scientific colleagues?