What can 546 dogs tell us about cancer, and STDs (sexually transmitted diseases)? An enormous amount ! [ Science vol 365 pp. 440 – 441, 464 3aau9923 1 –> 7 ’19 ]. You may have heard about the transmissible tumor that has reduced the Tasmanian Devil population from its appearance in ’96 by 80%. The animals bite each other transmitting the tumor. Only 10 – 100 cells are transferred, but death occurs within a year. The cells survive because Tasmanian devels have low genetic diversity.
The work concerns a much older transmissible tumor (Canine Transmissible Venereal Tumor — aka CTVT) which appeared in Asia an estimated 6,000 year ago, and began dispersing worldwide 2,000 years ago. Unlike the Tasmanian devil tumor, the tumor is usually cleared by the immune system.
The Science paper has 80+ authors from all over the world, who sequenced the protein coding part of the dog genome (the exome) to a > 100fold depth. The exome contains 43.6 megabases. The tumor is transmitted by sex, and the authors note that this mode of transmission nearly requires a rather indolent clinical course, as the animal must survive long enough to transmit the organism again. This fits with syphilis, AIDs, gonorrhea. Contrast this with anthrax, cholera, plague which spread differently and kill much faster.
So what does CTVT tell us about cancer? Quite a bit. First some background. The Cancer Genome Atlas (CGA) was criticized as being a boondoggle, but it at least gave us an idea of how many mutations are present in various cancers– around 100 in colon and breast cancers.
Viewed across all dogs, the CTVT genome is riddled with somatic mutations (as compared to the genome of the dog carrying the tumor) –148,030 single nucleotide variants (3.4/1000 !) 12,177 insertion/deletions. Of the 20,000 dog genes only 2,000 didn’t contain a mutation. This implies that most genes in the mammalian genome aren’t needed by the cancer cells. The CTVTs also show no signs of the high rates of chromosomal instability seen in human tumors.
The work provides evidence that cancer isn’t inherently progressive. This gives hope that some relatively indolent human cancers (say cancer of the prostate) can be controlled. This calls for ‘adaptive therapy’ — something that limits tumor growth rather than trying to kill every cancer cell with curative therapy which, if it fails, essentially selects for more aggressive cancer cells.
Some 14,412 genes have 1 mutation changing the amino acid sequence (nonSynonymous) and 5,704 have protein truncating mutations. The ratio of synonymous to non synonymous mutations is about 3 implying that the mutations which have arisen haven’t been selected for (after all the triplet code for 20 amino acids and 1 stop codon has 64 possibilities), so the average amino acid has 3 codons for it. This is called neutral genetic drift.
They also found 5 mutated genes present in all 541 tumors — these are the driver mutations, 3 are well known, MYC, PTEN, and retinoblastoma1.
Tons to think about here. I’ll be away for a few weeks traveling and playing music, but this work should keep you busy thinking about its implications.
Chemiotics II 