The Pⁿ Blog is a forum for opinions, questions, controversies, and instructive discussions across the field of pathology and its relevant subspecialties.
Wednesday, November 27, 2013
High-powered genetic sequencing techniques are increasingly being applied to a wide spectrum of human cancers in an attempt to bring some order and understanding to the seemingly chaotic world of neoplasia.
A recent open source article in Nature (Nature 2013;502:333-8
) looked at over 3000 examples of twelve common human tumors (glioblastoma, ENT squamous carcinoma, breast carcinoma, renal carcinoma, endometrial carcinoma, rectal carcinoma, pulmonary adenocarcinoma, pulmonary squamous carcinoma, bladder carcinoma, ovarian carcinoma, colonic carcinoma, and leukemia).
This study looked at not just DNA mutational data but also copy number variations, DNA methylation, micro RNA activity, cellular protein activity and clinical data. The purpose of the study was to find "core" cancer genes and carcinogenic pathways as distinct from "collateral genetic damage unrelated to pathogenesis; in essence to look for order in apparent chaos. 127 significantly mutated genes were identified across the 12 tumor types. Some were well known oncogenes and others are emerging as factors in oncogenesis. The average number of mutations in the significantly mutated genes varied across tumour types; most tumours had two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators showed tissue specificity, whereas histone modifiers were often mutated across several cancer types.
The article is heavy reading and you may not wish to indulge, but there is an excellent accompanying editorial by Alan Ashworth (Nature 2013;502;306-7
) which outlines the power as well as the limitations of this high volume approach to cancer genetics. Numerous publications of this type have gone into the development of the "Cancer Genome Atlas." One of the most obvious goals of these studies is the identification of common and necessary genetic events in carcinogenesis that may lead to the identication of further therapeutic targets for drug development. Such drugs may well be active over multiple tumor types.
Is the day coming when no one will care about the "morphology" or even the anatomic origin of a tumor and will be only interested in its genetic abberations? If you had asked me that 10 years ago I would have laughed and said, "(expletive deleted) NO!" Now.... I'm not quite so sure. Probably not in my or your lifetime but NEVER is a very long time. Clearly pathologists need to embrace this new world and own a spot within it as we move into the molecular unknown of neoplasia.
Thursday, November 14, 2013
My next two blogs (this one and the one that will follow) will deal with a couple of very different uses for molecular testing. The first represents a breakthrough in pre-natal screening and was recently reviewed on MedScape
by Dr. Eric Topol.
Like Dr. Topol, I'm a current and future grandfather and it's easy to see how this paradigm shift (sorry for using that cliche) will impact parents and grandparents. In the past, fetal testing required amniocentesis and chorionic villi sampling, invasive procedures that were not without some, albeit low, fetal risk.
Now it is possible to detect cell-free fetal DNA at 8-10 weeks of fetal age in a single vial of maternal blood, subtract out any maternal DNA and assay the fetal DNA for a variety of abnormalities including trisomy 13, 18, and 21, as well as determining fetal sex. As Dr. Topol discusses, there are already four tests on the market and their accuracy has been shown to be as good or better than amniocentesis. It seems quite likely, in fact, that these tests will quickly lead to the end of amniocentesis. I doubt that its death will be mourned given the nature of its replacement.
Although initial tests are focused on common trisomies and gender determination, this is just the beginning, as this methodology could allow far more detailed genetic study up to the level of whole genome sequencing. The tools to do this are available right now. I think this is extremely exciting technology but, needless to say, there will be HUGE ethical considerations associated with these new techniques, the information they will provide, and how this will affect decisions regarding termination of early pregnancies. Stay tuned.
Thursday, October 24, 2013
One of my colleagues recently directed my attention to an article in the special section of the October 4th issue of Science (p.60) entitled, "Who's Afraid of Peer Review?" The subtitle to the article basically says it all, "A spoof paper concocted by Science reveals little or no scrutiny at many open-access journals." The article is written by John Bohannon.
This is one of the more fascinating "sting operations" I've ever read about and the 6-page article makes for quick and enjoyable if somewhat frightening reading. The details of how the author prepared his multiple manuscript versions, replete with fictious names and institutions, and non-native English prose are described in some detail. Basically, Dr. Bohannon sent out over 300 minor variations of an article describing a "wonder drug" in cancer therapy to various on-line, open access journals. The study is so riddled with methodologic errors that anyone with a high-school science background should easily spot them.
For example it's clear that the tumoricidal effect on cancer cells, which in spite of a claim to the contrary is clearly NOT dose dependent, is due to the ethanol included with the buffer in the "wonder drug" and not applied to the control cells. Nonetheless, over half of the journals accepted the study, often requesting hefty fees for publication. Here we go "down the rabit hole," as Dr. Bohannon exclaims.
In the end, 157 on-line journals accepted the blatantly flawed manuscript and 98 rejected it. 49 journals never quite followed up with the author and some appeared to have "folded."
In essence, open access on-line journals have exploded onto the scene because they are lucrative, extracting fees from authors rather than subscribers or advertisers. Many of these journals have "American" in their title and list virtually non-existent offices in the United States but are, in reality, based in remote locations around the world, notably Mumbai, India, the site of a company known as Medknow which publishes 270 (at last count) on-line journals! Some of these third-world paper mills have even been recently acquired by reputable publishing houses (who will hopefully put an end to this mess).
It's not that there's anything wrong with open access. Most agree it's a good thing. The problem is controlling it and guaranteeing quality. Open access is not "free access." Someone has to support the operation if quality is to be maintained. In the traditional model, subscribers and advertisers supported journal costs, which can be substantial even in an on-line only publication. In the open access model, the authors pay a fee to allow any reader to access the article free of charge. Many funding agencies now mandate open access publication of any results produced from their funded studies, and fees for open access publication can be included in grant requests.
It will be interesting to see how this all shakes out. Clearly some unscrupulous folks have seen an opportunity to cash in on this new paradigm, fueled by increasing "publish or perish" pressures. As Dr. Bohannon noted we're currently in the "Wild West" phase of open access. Here's hoping for eventual law and order. Several watchdog sites, such as the Directory of Open Access Journals (DOAJ) have already sprung up to rate these on-line journals, some of which are legitmate and publish first rate science. The end user would be well-advised to see out such sites before submitting any works.
Thursday, October 03, 2013
Once again I must apologize for delays in updating my Pathology Network blog. Travel to meetings, vacation, service work, and beginning to edit the next (6th) edition of Diagnostic Surgical Pathology are all taking their toll on my time. I have several more trips this month but things will, I hope, calm down after that. If you are an attendee at the Scientific Symposiums course on the big island of Hawaii next week, I'll see you there! On top of all this, we're 5 months into our move to a new home, and we're still not completely settled. The adage that it take a year to settle in from a move seems all too real.
For your reading enjoyment, I'd like to (again) refer you to a couple of posts, linked above, in "The Pathology Blawg" by Dr. Lee Dilworth. These deal with a proposal in the works at at least one pathology assistant program to grant the degree of "doctor of anatomic pathology" to graduates of a "beefed up" pathology assistant program. Although this hasn't yet come to pass, it is clearly part of a trend to grant doctorates in a variety of specialized medical ancillary services.
I'm not in principle opposed to this general approach at all. My older daughter has a doctorate in physical therapy and practices in southern California. She went through three years of complex training and certification, but she would never want to be called anything other than a physical therapist. "Doctor of Anatomic Pathology," however sounds rather much like an "anatomic pathologist" who is a doctor and the title is almost certain to cause confusion. See what you think. At any rate, the blog postings are short and make for easy reading.
Even more thought provoking, and more than a bit disconcerting are the comments following the blog that give a snapshot of some of the biases and misconceptions that exist, even among our supposedly enlightened clinician colleagues, about what we do. Several of the commenters seem convinced that pathology is dead. Happily, that is far from the case.
Friday, September 06, 2013
The next time one of your non-pathology friends asks you what cancer is and how it starts, here's an article from the March 2013 issue of Cell
that will answer all their questions, and then some!
Well... maybe if they have a PhD level intellect and a good background in biologic science. Otherwise, it's way too much for the average person to digest. Nonetheless, it makes for interesting reading for those of us in the pathology world.
In 2000 Douglas Hanahan and Robert Weinberg proposed six related, organizing principles for understanding malignant transformation. These were:
Sustaining proliferative signaling
Evading growth suppressors
Resisting cell death
Enabling replicative immortality
Activating invasion and metastasis
The current article in the March 2013 issue of Cell (Cell 2013;144:646) is an update by the same authors on what we have learned in the last 13 years about these principles, along with selected illustrations of the multiple pathways by which neoplastic cells may achieve each of these requirements. The authors then add two new hallmarks of malignancy:
Reprogramming energy metabolism
Evading immune destruction
This review article by experts in the field is an excellent summary of the complex topic of malignant transformation. It is a tribute to how far we've come in understanding the complexities of cancer and a roadmap for where we need to go. You don't need to be a basic researcher (and I'm certainly not!) to completely understand this well-written article. I found this to be enjoyable and thought-provoking reading. I hope that you'll agree.