Frequent mutations of hepatocyte nuclear factor 1 in colorectal cancer with microsatellite instability.
OBJECTIVE
The TCF1 gene encoding hepatocyte nuclear factor 1 alpha (HNF1), a transcription factor germline mutated in patients with maturity-onset diabetes of the young type 3, was recently found to be frequently inactivated by biallelic alterations in liver adenoma and in rare hepatocellular carcinomas. The impact of HNF1 in colorectal carcinogenesis has not been studied until now. Colorectal cancer is characterized by the existence of different molecular mechanisms known as microsatellite stable or unstable tumors.


METHODS
At first, a series of 10 adenomas and 29 colon cancers regardless of microsatellite instability status were screened for TCF1 mutations on the entire coding sequence.


RESULTS
Three mutations in microsatellite instability high (MSI-H) tumors were found in the exon 4 polymorphic poly-cytosin (C)(8) or (C)(9) tract and consisted of a cytosin deletion at position 291. To further characterize the prevalence of TCF1 mutations in the subgroup of MSI-H tumors, 52 additional MSI-H samples were screened for exon 4 alterations; 23% of MSI-H tumors (95% confidence interval, 14%-36%) were found to harbor frameshift at the poly-cytosin tract. The (C)(9) allele was significantly more frequently mutated than the (C)(8) allele (22% vs. 8%; P = 0.03), showing a higher instability of the longer repetition.


CONCLUSIONS
These results show a role for HNF1 in MSI-H colorectal carcinogenesis.
INSERM Unité 434, CEPH Fondation Jean Dausset, Paris. pierre.laurent-puig@biomedicale.univ-paris5.fr
Pierre
P
Laurent-Puig
Olivier
O
Plomteux
Olivier
O
Bluteau
Franck
F
Zinzindohoué
Emmanuelle
E
Jeannot
Karin
K
Dahan
Alex
A
Kartheuser
Caroline
C
Chapusot
Paul-Henri
PH
Cugnenc
Jessica
J
Zucman-Rossi
D000236:Adenoma / Q000453:epidemiology / Q000235:genetics*; D000368:Aged; D000483:Alleles; D002277:Carcinoma / Q000453:epidemiology / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005820:Genetic Testing; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009687:Nuclear Proteins; D015995:Prevalence; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta