title: Women 50 years or younger with endometrial cancer: the argument for universal mismatch repair screening and potential for targeted therapeutics.
abstract: OBJECTIVE
  To identify young patients with endometrial cancer with potential Lynch-related DNA mismatch repair (MMR) protein expression defects and stathmin (STMN1) expression (part of the phosphoinositol 3-kinase pathway) and to correlate clinical data.
  
  
  METHODS
  This retrospective study included women with endometrial cancer who were 50 years or younger at diagnosis. Clinical data were abstracted from chart review. Immunohistochemistry for MMR protein expression, STMN1, and pSTMN1 was performed and univariate analyses performed.
  
  
  RESULTS
  The mean age of 111 patients was 43 years, and the mean body mass index was 39.6 kg/m². The majority of the endometrial cancers were endometrioid histology (87.4%), International Federation of Gynecology and Obstetrics stage I (73%) and grade 1 (58.6%). Loss of at least one MMR protein on immunohistochemistry was identified in 26% to 41% of patients depending on stringency. Women with loss of MMR protein expression were compared to women with intact tumor protein expression and were less likely to be stage I (58.6% vs 78.0%; P = 0.043), more likely to have grade 3 tumors (32.1% vs 13.9%; P = 0.034), had larger tumors (6.2 vs 3.7 cm; P < 0.001), had positive lymph nodes more often (24.1% vs 3.7%; P < 0.001), and more often reported a first-degree relative with colon cancer (17.2% vs 1.2%; P < 0.001). There were no significant differences in age, weight, body mass index, medical comorbidities, recurrence, or survival. Women with high STMN1 staining had significantly more grade 3 tumors (56.3% vs 15.8%; P = 0.001), more stage III/IV disease (37.5% vs 15.8%; P = 0.04), had higher mean percentage of myometrial invasion (38.9% vs 16.7%; P = 0.003), and more lymphovascular space invasion (43.8% vs 13.7%; P = 0.004).
  
  
  CONCLUSIONS
  Clinical factors failed to differentiate between patients with intact or missing MMR protein expression, which supports universal screening for Lynch-associated protein defects in young women with endometrial cancer. Additionally, STMN1 staining may identify more aggressive tumors, which might benefit from more aggressive treatments or targeted treatment options.
authors.affiliation: Department of Gynecologic Oncology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kari L
authors.initials: KL
authors.lastname: Ring
authors.forename: Elizabeth V
authors.initials: EV
authors.lastname: Connor
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Atkins
authors.forename: William
authors.initials: W
authors.lastname: Ricketts
authors.forename: Basel
authors.initials: B
authors.lastname: Kashlan
authors.forename: Susan C
authors.initials: SC
authors.lastname: Modesitt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D018262:Adenocarcinoma, Clear Cell / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009215:Myometrium / Q000473:pathology*; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012189:Retrospective Studies; D050777:Stathmin / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C493995:STMN1 protein, human; D050777:Stathmin; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes