title: Regional Bias of Intratumoral Genetic Heterogeneity of Apoptosis-Related Genes BAX, APAF1, and FLASH in Colon Cancers with High Microsatellite Instability.
abstract: BACKGROUND
  Apoptosis inactivation and intratumoral heterogeneity (ITH) are common features of cancers, including colorectal cancer (CRC). Inactivation of apoptosis prolongs cancer cell survival, and ITH may contribute to CRC progression.
  
  
  OBJECTIVE
  To examine the presence and extent of mutational ITH in the pro-apoptotic genes APAF1, BAX, and FLASH and the association of mutational ITH with pathologic parameters of CRC.
  
  
  METHODS
  The ITH of mutations in the mononucleotide repeats of APAF1, BAX and FLASH in different tumors were analyzed in 16 cases of CRC with high microsatellite instability (MSI-H) and 41 cases of CRC with stable MSI/low MSI (MSS/MSI-L) by single-strand conformation polymorphism and DNA sequencing analyses.
  
  
  RESULTS
  Frameshift mutations of APAF1, BAX, and FLASH were identified in 19, 31, and 6 % of CRC with MSI-H, respectively, but also in cases of CRC with MSS/MSI-L. All but one CRC with a mutation (8/9) harbored regional ITH of the APAF1, BAX and FLASH frameshift mutations. ITH, however, was not associated with histopathologic features of CRC with MSI-H, suggesting that ITH might not be related to development of the MSI-H phenotype itself, but rather to disease progression.
  
  
  CONCLUSIONS
  Our results indicate that the APAF1, BAX, and FLASH genes not only harbor frameshift mutations but also demonstrate mutational ITH, which together might play a role in the tumorigenesis of CRC with MSI-H by affecting the apoptosis of cancer cells. Our data also suggest that multiregional mutation analysis is needed for a better evaluation of the mutation status in CRC.
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul, 137-701, Korea.
authors.forename: Mi Ryoung
authors.initials: MR
authors.lastname: Choi
authors.forename: Min
authors.initials: M
authors.lastname: Gwak
authors.forename: Nam Jin
authors.initials: NJ
authors.lastname: Yoo
authors.forename: Sug Hyung
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics*; D001706:Biopsy; D002135:Calcium-Binding Proteins / Q000235:genetics*; D003082:Colectomy; D003110:Colonic Neoplasms / Q000235:genetics* / Q000601:surgery; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D018807:Polymorphism, Single-Stranded Conformational; D056910:Republic of Korea; D051028:bcl-2-Associated X Protein / Q000235:genetics*
chemical_list: C506592:APAF1 protein, human; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; C485604:CASP8AP2 protein, human; D002135:Calcium-Binding Proteins; D004273:DNA, Neoplasm; D051028:bcl-2-Associated X Protein