title: Somatic mutations of amino acid metabolism-related genes in gastric and colorectal cancers and their regional heterogeneity--a short report.
abstract: BACKGROUND
  Metabolic reprogramming is an emerging topic in cancer research. However, genetic alterations in genes encoding enzymes involved in amino acid metabolism are largely unknown. The aim of this study was to explore whether genes known to be involved in amino acid metabolism are mutated in gastric cancer (GC) and/or colorectal cancer (CRC).
  
  
  METHODS
  Through a public database search, we found that a number of genes known to be involved in amino acid metabolism, i.e., AGXT, ALDH2, APIP, MTR, DNMT1, ASH1L, ASPA, CAD, DDC, GCDH, DLD, LAP3, MCEE and MUT, harbor mononucleotide repeats that may serve as mutation targets in cancers exhibiting microsatellite instability (MSI). We assessed these genes for the presence of the mutations in 79 GCs and 124 CRCs using single-strand conformation polymorphism (SSCP) and direct sequencing analyses.
  
  
  RESULTS
  Using SSCP in conjunction with DNA sequencing we detected frameshift mutations in AGXT (17 cases), ALDH2 (3 cases), APIP (4 cases), MTR (5 cases), DNMT1 (1 case), ASH1L (1 case), ASPA (2 cases), CAD (2 cases), DDC (1 case), GCDH (3 cases), DLD (1 case), LAP3 (1 case), MCEE (5 cases) and MUT (1 case). These mutations were exclusively detected in MSI-high (MSI-H), and not in MSI-low or MSI-stable (MSI-L/MSS) cases. In addition, we analyzed 16 CRCs for the presence of intra-tumor heterogeneity (ITH) and found that two CRCs harbored regional ITH for GCDH frameshift mutations.
  
  
  CONCLUSIONS
  Our data indicate that genes known to be involved in amino acid metabolism recurrently acquire somatic mutations in MSH-H GCs and MSH-H CRCs and that, in addition, mutation ITH does occur in at least some of these tumors. Together, these data suggest that metabolic reprogramming may play a role in the etiology of MSI-H GCs and CRCs. Our data also suggest that ultra-regional mutation analysis is required for a more comprehensive evaluation of the mutation status in these tumors.
authors.affiliation: Departments of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul, 137-701, South Korea.
authors.forename: Hye Rim
authors.initials: HR
authors.lastname: Oh
authors.forename: Chang Hyeok
authors.initials: CH
authors.lastname: An
authors.forename: Nam Jin
authors.initials: NJ
authors.lastname: Yoo
authors.forename: Sug Hyung
authors.initials: SH
authors.lastname: Lee
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D000444:Aldehyde Dehydrogenase / Q000235:genetics; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D016368:Frameshift Mutation / Q000235:genetics; D006801:Humans; D053842:Microsatellite Instability; D018807:Polymorphism, Single-Stranded Conformational / Q000235:genetics; D019998:Racemases and Epimerases / Q000235:genetics; D000637:Transaminases / Q000235:genetics
chemical_list: C573917:APIP protein, human; D000596:Amino Acids; D051017:Apoptosis Regulatory Proteins; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; C585801:MTR protein, human; D000637:Transaminases; C019635:Alanine-glyoxylate transaminase; D019998:Racemases and Epimerases; C021581:methylmalonyl-coenzyme A racemase