PMID- 25776026
OWN - NLM
STAT- MEDLINE
DCOM- 20150616
LR  - 20211203
IS  - 1532-8392 (Electronic)
IS  - 0046-8177 (Linking)
VI  - 46
IP  - 5
DP  - 2015 May
TI  - Frameshift mutations in mammalian target of rapamycin pathway genes and their 
      regional heterogeneity in sporadic colorectal cancers.
PG  - 753-60
LID - S0046-8177(15)00043-X [pii]
LID - 10.1016/j.humpath.2015.01.017 [doi]
AB  - Mammalian target of rapamycin (mTOR) pathway is known to be involved in cancer 
      pathogenesis. The aim of our study was to find whether mTOR-related genes were 
      mutated and expressionally altered in colorectal cancers (CRCs). Through public 
      database searching, we found that PIK3CB, insulin receptor substrate 1/2 (IRS1), 
      RPS6, EIF4B, RPS6KA5, and PRKAA2 that were known as mTOR-related genes possessed 
      mononucleotide repeats in DNA coding sequences that could be mutated in cancers 
      with microsatellite instability (MSI). We analyzed 124 CRCs by single-strand 
      conformation polymorphism analysis and DNA sequencing and found 7 (8.9%), 8 
      (10.1%), and 3 (3.8%) of 79 CRCs with high MSI that harbored IRS1, EIF4B, and 
      RPS6KA5 frameshift mutations, respectively. These mutations were not identified 
      in stable MSI/low MSI (0/45). In addition, we analyzed intratumoral heterogeneity 
      (ITH) of PIK3CB, IRS1, RPS6, EIF4B, RPS6KA5, and PRKAA2 frameshift mutations in 
      16 CRCs and found that IRS1, EIF4B, and RPS6KA5 mutations had regional ITH in 2, 
      2, and 1 CRCs, respectively. We also analyzed IRS1 expression in the CRCs by 
      immunohistochemistry. Loss of IRS1 expression was identified in 31% of the CRCs. 
      The loss of expression was more common in those with IRS1 mutation than those 
      with wild-type IRS1. Our data indicate mTOR-related genes harbored not only 
      somatic mutations but also mutational ITH and loss of expression, which together 
      might play a role in tumorigenesis of CRC, especially with high MSI. Our data 
      also suggest that mutation analysis in multiregional areas is needed for a 
      precise evaluation of mutation status in CRC with MSI-H.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Choi, Mi Ryoung
AU  - Choi MR
AD  - Department of Pathology, College of Medicine, The Catholic University of Korea, 
      Seoul, Korea 137-701.
FAU - Yoo, Nam Jin
AU  - Yoo NJ
AD  - Department of Pathology, College of Medicine, The Catholic University of Korea, 
      Seoul, Korea 137-701.
FAU - An, Chang Hyeok
AU  - An CH
AD  - Department of General Surgery, College of Medicine, The Catholic University of 
      Korea, Seoul, Korea 137-701. Electronic address: achcolo@catholic.ac.kr.
FAU - Lee, Sug Hyung
AU  - Lee SH
AD  - Department of Pathology, College of Medicine, The Catholic University of Korea, 
      Seoul, Korea 137-701. Electronic address: suhulee@catholic.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150212
PL  - United States
TA  - Hum Pathol
JT  - Human pathology
JID - 9421547
RN  - 0 (DNA, Neoplasm)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Colorectal Neoplasms/*genetics/pathology
MH  - DNA Mutational Analysis/methods
MH  - DNA, Neoplasm/*genetics
MH  - Female
MH  - Frameshift Mutation/*genetics
MH  - *Genetic Heterogeneity
MH  - *Genetic Predisposition to Disease
MH  - Humans
MH  - Immunohistochemistry/methods
MH  - Male
MH  - Microsatellite Instability
MH  - Microsatellite Repeats/genetics
MH  - Middle Aged
MH  - Polymerase Chain Reaction/methods
MH  - Polymorphism, Single-Stranded Conformational/*genetics
MH  - TOR Serine-Threonine Kinases/*genetics
OTO - NOTNLM
OT  - Colon cancers
OT  - Intratumoral heterogeneity
OT  - Microsatellite instability
OT  - Mutation
OT  - mTOR
EDAT- 2015/03/18 06:00
MHDA- 2015/06/17 06:00
CRDT- 2015/03/18 06:00
PHST- 2014/11/13 00:00 [received]
PHST- 2014/12/27 00:00 [revised]
PHST- 2015/01/26 00:00 [accepted]
PHST- 2015/03/18 06:00 [entrez]
PHST- 2015/03/18 06:00 [pubmed]
PHST- 2015/06/17 06:00 [medline]
AID - S0046-8177(15)00043-X [pii]
AID - 10.1016/j.humpath.2015.01.017 [doi]
PST - ppublish
SO  - Hum Pathol. 2015 May;46(5):753-60. doi: 10.1016/j.humpath.2015.01.017. Epub 2015 
      Feb 12.