Nonrandom variations in human cancer ESTs indicate that mRNA heterogeneity increases during carcinogenesis.
Virtually all cancer biological attributes are heterogeneous. Because of this, it is currently difficult to reconcile results of cancer transcriptome and proteome experiments. It is also established that cancer somatic mutations arise at rates higher than suspected, but yet are insufficient to explain all cancer cell heterogeneity. We have analyzed sequence variations of 17 abundantly expressed genes in a large set of human ESTs originating from either normal or cancer samples. We show that cancer ESTs have greater variations than normal ESTs for >70% of the tested genes. These variations cannot be explained by known and putative SNPs. Furthermore, cancer EST variations were not random, but were determined by the composition of the substituted base (b0) as well as that of the bases located upstream (up to b - 4) and downstream (up to b + 3) of the substitution event. The replacement base was also not randomly selected but corresponded in most cases (73%) to a repetition of b - 1 or of b + 1. Base substitutions follow a specific pattern of affected bases: A and T substitutions were preferentially observed in cancer ESTs. In contrast, cancer somatic mutations [Sjoblom T, et al. (2006) Science 314:268-274] and SNPs identified in the genes of the current study occurred preferentially with C and G. On the basis of these observations, we developed a working hypothesis that cancer EST heterogeneity results primarily from increased transcription infidelity.
Brulliard
Marie
M
Institut National Polytechnique de Lorraine, Vandoeuvre-lès-Nancy, France.
Lorphelin
Dalia
D
Collignon
Olivier
O
Lorphelin
Walter
W
Thouvenot
Benoit
B
Gothié
Emmanuel
E
Jacquenet
Sandrine
S
Ogier
Virginie
V
Roitel
Olivier
O
Monnez
Jean-Marie
JM
Vallois
Pierre
P
Yen
Frances T
FT
Poch
Olivier
O
Guenneugues
Marc
M
Karcher
Gilles
G
Oudet
Pierre
P
Bihain
Bernard E
BE
D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D020224:Expressed Sequence Tags; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D014746:Vimentin / Q000235:genetics
D012333:RNA, Messenger; D014746:Vimentin