title: Progression and tumor heterogeneity analysis in early rectal cancer.
abstract: OBJECTIVE
  Adequate preoperative staging of large sessile rectal tumors requires identifying adenomas that already contain an invasive focus, specifically those that are growing in or beyond the submucosa. We systematically compared chromosomal instability patterns in adenoma and carcinoma fractions of the same lesion to assess specific steps in rectal tumor progression.
  
  
  METHODS
  We analyzed 36 formalin-fixed, paraffin-embedded tumors. Both the adenoma and carcinoma fractions were typed with single nucleotide polymorphism arrays and compared with 21 previously described pure adenomas. Eighteen cases were included in an intratumor heterogeneity analysis.
  
  
  RESULTS
  Five specific "malignant" events (gain of 8q, 13q, and 20q and loss of 17p and 18q) and aberrant staining for p53 and SMAD4 were all increased in the adenoma fractions of carcinoma cases compared with pure adenomas. Paired analysis revealed that 31% of the samples had an equal amount of malignant aberrations in their adenoma and carcinoma fractions, whereas 25% had one and 33% had two or more extra malignant events in the carcinoma fraction. Analysis of three core biopsies per patient showed a large degree of intratumor heterogeneity. However, the number of malignant aberrations in the biopsy with the most aberrations per tumor correlated with the corresponding adenoma or carcinoma fraction (r = 0.807; P < 0.001).
  
  
  CONCLUSIONS
  Five specific chromosomal aberrations, combined with immunohistochemistry for p53 and SMAD4, can predict possible progression of sessile rectal adenomas to early rectal cancer and can, after validation studies, be added to preoperative staging. Preferably, three biopsies should be taken from each tumor to address intratumor heterogeneity.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Esther H
authors.initials: EH
authors.lastname: Lips
authors.forename: Ronald
authors.initials: R
authors.lastname: van Eijk
authors.forename: Eelco J R
authors.initials: EJ
authors.lastname: de Graaf
authors.forename: Pascal G
authors.initials: PG
authors.lastname: Doornebosch
authors.forename: Noel F C C
authors.initials: NF
authors.lastname: de Miranda
authors.forename: Jan
authors.initials: J
authors.lastname: Oosting
authors.forename: Tom
authors.initials: T
authors.lastname: Karsten
authors.forename: Paul H C
authors.initials: PH
authors.lastname: Eilers
authors.forename: Rob A E M
authors.initials: RA
authors.lastname: Tollenaar
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000473:pathology / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics / Q000473:pathology / Q000601:surgery; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000235:genetics; D012004:Rectal Neoplasms / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger