On October 14, a commenter who identifies himself as "Mouth of the Yellow River" (MOTYR) left one of his usual perceptive remarks in the "For the Saturday Surfer" entry. It concerned a publication by Nobelist Kary Mullis of a "scientific correspondence" in Nature when he was still in graduate school. I was motivated by it to leave a message for MOTYR inviting him to become a contributor to YBYL - in a simple and *extremely* florid Mandarin. (Both can be read here.) I ended the comment by expressing the hope that he would say 是 (yes). As the essay below shows, he did. (Otis)
The most extensive results to date concerning the repertoire of point mutations in cancer samples revealed by gene sequencing is out in the 29-author treatise published by one of the science industry’s Holy Trinity (CSN--Cell, Science, Nature) (The Consensus Coding Sequences of Human Breast and Colorectal Cancers, Science 314:268, 2006). The study costing about $5 million is an analysis that shows that the number of mutations in products of about half of the estimated genes of the human genome from eleven cell lines or xenografts from breast or colorectal cancers exceeds a mind boggling 800,000+ compared to a normal sample. Mutations are errors in the four letter alphabet that spells out in words of three the sequence of the 20 amino acid units that make a functional protein. Thousands of functional proteins working together at wide ranges of activity due to thousands of forces that modify them make up a healthy cell. Xenografts are chunks of cancer tissue removed from patients and selected for their ability to survive and grow in the artificial environment under the skin of a mouse without being attacked by the mouse’s immune system so as to provide enough material to analyze. Cell lines are mixtures of cancer cells selected one step further for their ability to survive and grow in a Petri dish like bacteria independent of their existence in tissue and even the artificial, but more close to physiological environment in the mouse.
Mutations thought to be methodological artifact, sequence differences between the two normal tissue samples, and “silent mutations” that don’t change the amino acid sequence of protein products were subtracted. [Although each amino acid of a protein is spelled out by the sequence of three letters of a four letter alphabet, the third letter of each triplet for an amino acid can be variable referred to as codon degeneracy. A mutation to one of the variants that can code for the same amino acid is termed by the authors a “silent mutation”). It was concluded that a total of 1307 mutations that could affect a protein amino acid sequence occurs in 1149 genes in the samples of the two cancers.
When the sequence of the 1149 mutated genes from the cell lines and xenografts was examined in 24 additional tissue samples of tumors taken directly from patients without xenograft or cell culture, an additional 365 mutations in 236 genes was detected showing that different tumor samples have different numbers and types of mutations. After all this, 921 and 751 mutations of potential interest (MOI’s) in the breast and colorectal tumor samples, respectively, for a total of 1672 cancer MOI’s were noted. Recall the above numbers need to be doubled since only about half of the suspected coding sequences in the genome were examined. This is an enormous number of MOI’s to begin to sort through concerning questions of whether any one or combination have anything to do with the individual cancers sampled much less other samples of the same types of tumors.
To attempt the impossible task of reducing this mind boggling number of mutations to some sort of meaning in terms of causality, the authors went on to try to rank mutations in terms of genes that might be involved in a tumor property described in the literature in single gene functional studies (CAN-genes for cancer candidate genes) in various tumor models or analyses relative to those that are along for the ride (“passenger mutations”). Mutations were found in genes that have been previously implicated in diverse cancers and cancer models and others that have not been mentioned before. Most important was the author’s conclusion that among the 24 breast and colorectal cancer samples examined, the two cancer types exhibit their own signature of mutations and each cancer sample of the same cancer type also exhibits its own signature of CAN-gene mutations and no two individual sample had more than 6 CAN-genes in common. The grapevine of unpublished results from diverse laboratories like the Sanger Institute in England examining diverse subsets of genes across diverse cancers and samples of the same cancers are reporting in with the same results, the diversity and number of mutations among different cancers is astounding.
The current Science report is being hailed as a landmark study, a “tour de force by other cancer scientists” states Science’s News section (First Pass at Cancer Genome Reveals Complex Landscape, Science 313, 1370, 2006). Rightly so, this report confirms with the most extensive analysis to date (half of the coding gene sequences in the human genome) what the data from hundreds, thousands of prior studies studying lesser numbers of single genes in diverse cancer-related samples varying from one to a few to hundreds predict despite that the authors interpreted their data as a breakthrough in cause of at least some cancers. The genome of cancers is a tangled mess awash with mutations, the number and types of mutations vary with the individual type of cancer, an individual cancer within a single type of cancer, the time in progression of an individual cancer within a single type of cancer, how an individual cancer at a specific time in progression within a single type of cancer was sampled (big chunk, little chunk) or manipulated prior to analysis (primary tissue, xenograft or cell line) and location of the individual cancer at a specific time in progression (location within the organ of origin or location outside the organ). Mutations may be happening at a rate in individual cells within a given cancer faster than the cancer can be sampled and sequenced. And the mind boggling number and diversity of mutations revealed in this first study among two types of cancers and a few samples of them focus on parts of the total genome that code for proteins. A proportional number likely occurs all up and down the genome that do not directly have to do with appearance of a protein. These may be equally important to the properties of cancers as what is seen so far.
Although the title
of the current subject paper is misleading, e.g. “The Consensus Coding
Sequences of Breast and Colorectal Cancers,” the report is a landmark
because the data in it question whether anything can be learned about cancer,
its prevention and treatment from mutational analysis. It questions the entire single or collective gene mutation theory of cancer causation, at least
for what is currently observable as a cancer sample. It should be the
basis for calls for new ideas and re-evaluation of where the basic
science, clinical science and pharmaceutical industry are headed in respect to
cancer, its understanding and management based on the collective mutation
theory of malignancy. (Continued)
The complete essay is available as a PDF file, here.
MOTYR (Mouth of the Yellow River) is a pen name of a scientist with 30 years experience in basic and applied biomedical research in academic and industrial settings. "By any measure, I have been extremely successful in my chosen profession, continuously supported by the NIH for 27 years. Yet I have never had a single, truly original idea funded when written into one of their grants.”