title: Detection of occult high graded microsatellite instabilities in MMR gene mutation negative HNPCC tumors by addition of complementary marker analysis.
abstract: BACKGROUND
  Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant tumor syndrome predisposing to predominantly colorectal and endometrial cancer. In 90% of the cases, molecular analyses reveal microsatellite instabilities due to germline mutations in DNA mismatch repair (MMR) genes, mainly MLH1, MSH2, among these tumors.
  
  
  METHODS
  Tumors from 40 HNPCC index patients (31 Amsterdam positive, 9 Bethesda positive; 21 females, 19 males; mean age 48.0 +/- 13.2 years) were examined. In contrast to the classical constellation, their tumors revealed only a microsatellite stable (MSS, n=31)--or low instable (MSI-L, n=9)--tumor phenotype following the international reference panel of 5 microsatellites. No MLH1 and MSH2 mutations were detectable. Complementary microsatellites (BAT40, D10S197, D13S153, D18S58, MYCL1) were investigated by PCR and fragment analysis to find other instabilities which might hint to the MIN-pathway of the tumors.
  
  
  RESULTS
  Due to ten microsatellites in total tumors were now reclassified in 4 MSI-H (10%), 24 MSI-L (60%) and 12 in MSS (30%) phenotypes. The mean age of onset for CRCs was the lowest in the MSI-H group with 45.7 +/- 9.6 years (vs. 48.7 +/- 14.3 and 49.0 +/- 12.9 years in MSI-L and MSS group). MSI-H-and MSI-L tumors were often localized in the proximal colon (50 and 52%), whereas MSS tumors were preferentially localized in the distal colon (77%). -
  
  
  CONCLUSIONS
  Complementary microsatellites help to subdive "non-classical" HNPCC in subgroups with different clinical appearance. It allows to detect occult MSI-H tumors with up to 10% and to confirm MSS tumors who seem to have a similar biological behaviour like sporadic CRC. Maybe that this genetic reclassification influence the decision of whether to offer patients chemotherapy or not, since it is known that patients with instable tumors do not benefit from chemotherapy as well as patients with microsatellite stable tumors.
authors.affiliation: Medizinsche Klinik und Poliklinik, Ludwig-Maximilians-Universität, München, Germany. Uwe.Schiemann@insel.ch
authors.forename: U
authors.initials: U
authors.lastname: Schiemann
authors.forename: Y
authors.initials: Y
authors.lastname: Müller-Koch
authors.forename: M
authors.initials: M
authors.lastname: Gross
authors.forename: J
authors.initials: J
authors.lastname: Glas
authors.forename: G
authors.initials: G
authors.lastname: Baretton
authors.forename: M
authors.initials: M
authors.lastname: Muders
authors.forename: T
authors.initials: T
authors.lastname: Mussack
authors.forename: E
authors.initials: E
authors.lastname: Holinski-Feder
mesh_terms: D020137:Base Pair Mismatch / Q000235:genetics*; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D051718:MutS Homolog 2 Protein; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D005819:Genetic Markers; C100852:MLF1 protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein