Presumably, multiple other mutations and epigenetic changes function in concert with the above-mentioned sentinel mutations to drive the malignant phenotype.
Interestingly, in our particular series, these mutations are always associated with multiple other mutations (from four to five) and located in genes coding for proteins that play a role in cytoskeleton organisation (HSP90B1, ZFYVE26, UBR4 and PTPN21).
The lack of correlation between expression and hypomethylation in some of our target genes is expected given the fact that multiple other mechanisms such as point mutations, insertions, deletions and loss of heterozygosity could be involved in gene expression regulation in NSCLC.
But there are multiple other cases of globin gene mutations that show the same kind of pattern, and it is unlikely that this hypothesis applies to all of them (indeed, Flint et al. do not attempt a general explanation, and others do not think that conversion really applies to HbS [ 234]).
Our observation of a similar phenotype in yeast with null mutations in multiple other autophagy genes, including ATG5, VPS30/ATG6, ATG7, and ATG8, provides additional support for the finding that the autophagy pathway is essential in cell cycle progression following nitrogen starvation.
We observed SSNC with multiple RhoGEF2 alleles, but with none of the other mutations (Table 2 and Table S2).
Taken together, our genotype phenotype analysis suggests that mutations involving R402 specifically disrupt the LIS1-associated neuronal migration pathway, whereas other mutations are likely to disrupt multiple pathways and functions.
However, if mutations interact such that some mutations are beneficial only in combination with other mutations, then this 'sign epistasis' may generate multiple peaks separated by valleys of maladapted intermediates [ 33, 49].
Even in these two populations, multiple coexisting subpopulations arose together possibly indicating the presence of other mutations in these populations as well.
In the case of the HRD+4 site, 41 additional cancer mutations were identified substituting this site to multiple other residues (Table S1).
Multiple deletions in the aflatoxin gene cluster along with high frequencies of other mutations indicate origins of non-aflatoxigenicity in many lineages are old, sufficiently old to have allowed time, in some genes, for divergent adaptive evolution.
