MLH1-silenced and non-silenced subgroups of hypermutated colorectal carcinomas have distinct mutational landscapes.
Approximately 15% of colorectal carcinomas (CRCs) exhibit a hypermutated genotype accompanied by high levels of microsatellite instability (MSI-H) and defects in DNA mismatch repair. These tumours, unlike the majority of colorectal carcinomas, are often diploid, exhibit frequent epigenetic silencing of the MLH1 DNA mismatch repair gene, and have a better clinical prognosis. As an adjunct study to The Cancer Genome Atlas consortium that recently analysed 224 colorectal cancers by whole exome sequencing, we compared the 35 CRCs (15.6%) with a hypermutated genotype to those with a non-hypermutated genotype. We found that 22 (63%) of the hypermutated CRCs exhibited transcriptional silencing of the MLH1 gene, a high frequency of BRAF V600E gene mutations, and infrequent APC and KRAS mutations, a mutational pattern significantly different from their non-hypermutated counterparts. However, the remaining 13 (37%) hypermutated CRCs lacked MLH1 silencing, contained tumours with the highest mutation rates ('ultramutated' CRCs), and exhibited higher incidences of APC and KRAS mutations, but infrequent BRAF mutations. These patterns were confirmed in an independent validation set of 250 exome-sequenced CRCs. Analysis of mRNA and microRNA expression signatures revealed that hypermutated CRCs with MLH1 silencing had greatly reduced levels of WNT signalling and increased BRAF signalling relative to non-hypermutated CRCs. Our findings suggest that hypermutated CRCs include one subgroup with fundamentally different pathways to malignancy than the majority of CRCs. Examination of MLH1 expression status and frequencies of APC, KRAS, and BRAF mutation in CRC may provide a useful diagnostic tool that could supplement the standard microsatellite instability assays and influence therapeutic decisions.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. larryd@bcm.edu
Lawrence A
LA
Donehower
Chad J
CJ
Creighton
Nikolaus
N
Schultz
Eve
E
Shinbrot
Kyle
K
Chang
Preethi H
PH
Gunaratne
Donna
D
Muzny
Chris
C
Sander
Stanley R
SR
Hamilton
Richard A
RA
Gibbs
David
D
Wheeler
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
C555337:APC protein, human; D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; C117307:KRAS protein, human; C501486:MLH1 protein, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins