Chemotherapy resistant ovarian cancer in carriers of an hMSH2 mutation?
Hereditary Non-Polyposis Colorectal Cancer (HNPCC, Lynch syndrome) is an autosomal dominant condition of cancer susceptibility with high penetrance, characterised by early onset of colon tumours as well as a variety of extracolonic tumours including ovarian cancer and, in particular, cancer of the endometrium. Germline mutations in one of five DNA-mismatch repair (MMR) genes (hMLH1, hMSH2, hMSH6, PMS1, PMS2) are known to cause HNPCC. To date, mutations in two of these genes (hMSH2 and hMLH1) are found in the majority of mutation positive families. Recent literature suggests that especially hMSH2 mutations are associated with extracolonic tumours. We describe two women from an HNPCC family carrying an hMSH2 mutation (deletion of exon 6 of this gene) who developed ovarian cancer. In these patients (full cousins) the ovarian cancers were noted for their aggressive development and rapid recurrence after surgical debulking and during regular multichemotherapy including Cisplatin. This report strengthens recent in vitro studies suggesting an involvement of MMR-gene mutations in ovarian cancer cell biology with decreased susceptibility to Cisplatin therapy. The possible implications for the therapy of ovarian cancer, the screening and genetic counselling of family members are discussed.
Marcelis
C L
CL
Department of Clinical Genetics, University Hospital Maastricht, P.O. Box 1475, 6201 BL Maastricht, The Netherlands. Carlo.Marcelis@Gen.Unimaas.nl
van der Putten
H W
HW
Tops
C
C
Lutgens
L C
LC
Moog
U
U
D000251:Adenosine Triphosphatases; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D020137:Base Pair Mismatch; D002945:Cisplatin / Q000494:pharmacology*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004260:DNA Repair; D004268:DNA-Binding Proteins; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D051718:MutS Homolog 2 Protein; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017384:Sequence Deletion
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D000251:Adenosine Triphosphatases; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; D002945:Cisplatin