RGD Reference Report - Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair-deficiency and Lynch syndrome. - Rat Genome Database

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Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair-deficiency and Lynch syndrome.

Authors: Maletzki, Claudia  Huehns, Maja  Bauer, Ingrid  Ripperger, Tim  Mork, Maureen M  Vilar, Eduardo  Klöcking, Sabine  Zettl, Heike  Prall, Friedrich  Linnebacher, Michael 
Citation: Maletzki C, etal., Mol Carcinog. 2017 Jul;56(7):1753-1764. doi: 10.1002/mc.22632. Epub 2017 Mar 30.
RGD ID: 153297765
Pubmed: PMID:28218421   (View Abstract at PubMed)
DOI: DOI:10.1002/mc.22632   (Journal Full-text)

Mismatch-repair deficient (MMR-D) malignancies include Lynch Syndrome (LS), which is secondary to germline mutations in one of the MMR genes, and the rare childhood-form of constitutional mismatch repair-deficiency (CMMR-D); caused by bi-allelic MMR gene mutations. A hallmark of LS-associated cancers is microsatellite instability (MSI), characterized by coding frameshift mutations (cFSM) in target genes. By contrast, tumors arising in CMMR-D patients are thought to display a somatic mutation pattern differing from LS. This study has the main goal to identify cFSM in MSI target genes relevant in CMMR-D and to compare the spectrum of common somatic mutations, including alterations in DNA polymerases POLE and D1 between LS and CMMR-D. CMMR-D-associated tumors harbored more somatic mutations compared to LS cases, especially in the TP53 gene and in POLE and POLD1, where novel mutations were additionally identified. Strikingly, MSI in classical mononucleotide markers BAT40 and CAT25 was frequent in CMMR-D cases. MSI-target gene analysis revealed mutations in CMMR-D-associated tumors, some of them known to be frequently hit in LS, such as RNaseT2, HT001, and TGFβR2. Our results imply a general role for these cFSM as potential new drivers of MMR-D tumorigenesis.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Lynch syndrome  IAGP 153297765; 153297765; 153297765; 153297765; 153297765; 153297765; 153297765; 153297765; 153297765; 153297765; 153297765; 153297765; 153297765; 153297765; 153297765DNA:mutations:cds: (human)RGD 
Lynch syndrome  ISOACVR2A (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
Lynch syndrome  ISOE2F4 (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
Lynch syndrome  ISOKRAS (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
Lynch syndrome  ISOMARCKS (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
Lynch syndrome  ISOMLH1 (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
Lynch syndrome  ISOMRE11 (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
Lynch syndrome  ISOMSH2 (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
Lynch syndrome  ISOMSH6 (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
Lynch syndrome  ISOPMS2 (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
Lynch syndrome  ISORNASET2 (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
Lynch syndrome  ISOTAF1B (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
Lynch syndrome  ISOTCF4 (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
Lynch syndrome  ISOTGFBR2 (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
mismatch repair cancer syndrome  IAGP 153297765; 153297765; 153297765; 153297765; 153297765; 153297765; 153297765DNA:mutations:cds: (human)RGD 
mismatch repair cancer syndrome  IAGP 153297765DNA:SNP:CDS:rs4077170 (human)RGD 
mismatch repair cancer syndrome  ISOPOLE (Homo sapiens)153297765; 153297765DNA:SNP:CDS:rs4077170 (human)RGD 
mismatch repair cancer syndrome  ISORNASET2 (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
mismatch repair cancer syndrome  ISOTAF1B (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
mismatch repair cancer syndrome  ISOTFDP1 (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
mismatch repair cancer syndrome  ISOTGFBR2 (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 
mismatch repair cancer syndrome  ISOTP53 (Homo sapiens)153297765; 153297765DNA:mutations:cds: (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Acvr2a  (activin A receptor type 2A)
E2f4  (E2F transcription factor 4)
Kras  (KRAS proto-oncogene, GTPase)
Marcks  (myristoylated alanine rich protein kinase C substrate)
Mlh1  (mutL homolog 1)
Mre11  (MRE11 homolog, double strand break repair nuclease)
Msh2  (mutS homolog 2)
Msh6  (mutS homolog 6)
Pms2  (PMS1 homolog 2, mismatch repair system component)
Pole  (DNA polymerase epsilon, catalytic subunit)
Rnaset2  (ribonuclease T2)
Taf1b  (TATA-box binding protein associated factor, RNA polymerase I subunit B)
Tcf4  (transcription factor 4)
Tfdp1  (transcription factor Dp-1)
Tgfbr2  (transforming growth factor, beta receptor 2)
Tp53  (tumor protein p53)

Genes (Mus musculus)
Acvr2a  (activin receptor IIA)
E2f4  (E2F transcription factor 4)
Kras  (Kirsten rat sarcoma viral oncogene homolog)
Marcks  (myristoylated alanine rich protein kinase C substrate)
Mlh1  (mutL homolog 1)
Mre11a  (MRE11A homolog A, double strand break repair nuclease)
Msh2  (mutS homolog 2)
Msh6  (mutS homolog 6)
Pms2  (PMS1 homolog2, mismatch repair system component)
Pole  (polymerase (DNA directed), epsilon)
Rnaset2a  (ribonuclease T2A)
Taf1b  (TATA-box binding protein associated factor, RNA polymerase I, B)
Tcf4  (transcription factor 4)
Tfdp1  (transcription factor Dp 1)
Tgfbr2  (transforming growth factor, beta receptor II)
Trp53  (transformation related protein 53)

Genes (Homo sapiens)
ACVR2A  (activin A receptor type 2A)
ASTE1  (asteroid homolog 1)
E2F4  (E2F transcription factor 4)
KRAS  (KRAS proto-oncogene, GTPase)
MARCKS  (myristoylated alanine rich protein kinase C substrate)
MLH1  (mutL homolog 1)
MRE11  (MRE11 homolog, double strand break repair nuclease)
MSH2  (mutS homolog 2)
MSH6  (mutS homolog 6)
PMS2  (PMS1 homolog 2, mismatch repair system component)
POLE  (DNA polymerase epsilon, catalytic subunit)
RNASET2  (ribonuclease T2)
SLC22A9  (solute carrier family 22 member 9)
TAF1B  (TATA-box binding protein associated factor, RNA polymerase I subunit B)
TCF4  (transcription factor 4)
TFDP1  (transcription factor Dp-1)
TGFBR2  (transforming growth factor beta receptor 2)
TP53  (tumor protein p53)


Additional Information