Advanced

Somatic frameshift alterations in mononucleotide repeat-containing genes in different tumor types from an HNPCC family with germline MSH2 mutation

Planck, M LU ; Wenngren, E; Borg, Åke LU ; Olsson, Håkan LU and Nilbert, M LU (2000) In Genes, Chromosomes and Cancer 29(1). p.33-39
Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by a germline mutation in one of several DNA repair genes, which in the tumors is reflected as microsatellite instability (MSI). MSI+ tumors have been found to carry somatic frameshift mutations in mononucleotide repeats within the coding regions of several genes involved in growth control, apoptosis, and DNA repair, e.g., TGFBRII, BAX, IGFIIR, TCF4, MSH3, and MSH6. We have studied the occurrence of somatic frameshift alterations in these mononucleotide repeat-containing genes in 24 tumors (15 colorectal cancers, 1 colon adenoma, 4 endometrial cancers, 1 ovarian cancer, 1 gastric cancer, 1 urothelial cancer, and 1 duodenal cancer) from 14 individuals in an HNPCC family with... (More)

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by a germline mutation in one of several DNA repair genes, which in the tumors is reflected as microsatellite instability (MSI). MSI+ tumors have been found to carry somatic frameshift mutations in mononucleotide repeats within the coding regions of several genes involved in growth control, apoptosis, and DNA repair, e.g., TGFBRII, BAX, IGFIIR, TCF4, MSH3, and MSH6. We have studied the occurrence of somatic frameshift alterations in these mononucleotide repeat-containing genes in 24 tumors (15 colorectal cancers, 1 colon adenoma, 4 endometrial cancers, 1 ovarian cancer, 1 gastric cancer, 1 urothelial cancer, and 1 duodenal cancer) from 14 individuals in an HNPCC family with germline hMSH2 mutation. Such somatic frameshift mutations occurred at a variable frequency; the long mononucleotide repeats that characterize intronic MSI markers were mutated in the majority of tumors, 13 of the tumors displayed alterations in the (A)(10) tract of TGFBII, eight tumors (all of gastrointestinal origin) had alterations in the (A)(9) repeat of TCF4, and one to five tumors had somatic frameshift alterations in the shorter mononucleotide repeats of IGFIIR, BAX, MSH3, and MSH6. Thus, longer mononucleotide repeats were more frequently affected by somatic frameshift mutations. The pattern of alterations varied between the tumors from different family members as well as between different tumors from the same individual. To what extent this variable pattern depends on the widespread mismatch repair deficiency induced by the underlying MSH2 mutation, or represents alternative ways whereby the tumors can achieve a tumorigenic phenotype, is unknown. We suggest, however, that the accumulation of somatic frameshifts, rather than the specific loci in which these occur, drives the development of the tumorigenic phenotype in HNPCC.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Aged, Colorectal Neoplasms, Colorectal Neoplasms, Hereditary Nonpolyposis, DNA-Binding Proteins, Female, Frameshift Mutation, Germ-Line Mutation, Humans, Male, Middle Aged, MutS Homolog 2 Protein, Pedigree, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins, Sequence Analysis, DNA, Trinucleotide Repeat Expansion
in
Genes, Chromosomes and Cancer
volume
29
issue
1
pages
33 - 39
publisher
John Wiley & Sons
external identifiers
  • Scopus:0033855479
ISSN
1045-2257
language
English
LU publication?
yes
id
00174beb-5c21-4725-8f83-45b419c924a7
date added to LUP
2016-09-18 12:28:03
date last changed
2016-10-13 05:13:42
@misc{00174beb-5c21-4725-8f83-45b419c924a7,
  abstract     = {<p>Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by a germline mutation in one of several DNA repair genes, which in the tumors is reflected as microsatellite instability (MSI). MSI+ tumors have been found to carry somatic frameshift mutations in mononucleotide repeats within the coding regions of several genes involved in growth control, apoptosis, and DNA repair, e.g., TGFBRII, BAX, IGFIIR, TCF4, MSH3, and MSH6. We have studied the occurrence of somatic frameshift alterations in these mononucleotide repeat-containing genes in 24 tumors (15 colorectal cancers, 1 colon adenoma, 4 endometrial cancers, 1 ovarian cancer, 1 gastric cancer, 1 urothelial cancer, and 1 duodenal cancer) from 14 individuals in an HNPCC family with germline hMSH2 mutation. Such somatic frameshift mutations occurred at a variable frequency; the long mononucleotide repeats that characterize intronic MSI markers were mutated in the majority of tumors, 13 of the tumors displayed alterations in the (A)(10) tract of TGFBII, eight tumors (all of gastrointestinal origin) had alterations in the (A)(9) repeat of TCF4, and one to five tumors had somatic frameshift alterations in the shorter mononucleotide repeats of IGFIIR, BAX, MSH3, and MSH6. Thus, longer mononucleotide repeats were more frequently affected by somatic frameshift mutations. The pattern of alterations varied between the tumors from different family members as well as between different tumors from the same individual. To what extent this variable pattern depends on the widespread mismatch repair deficiency induced by the underlying MSH2 mutation, or represents alternative ways whereby the tumors can achieve a tumorigenic phenotype, is unknown. We suggest, however, that the accumulation of somatic frameshifts, rather than the specific loci in which these occur, drives the development of the tumorigenic phenotype in HNPCC.</p>},
  author       = {Planck, M and Wenngren, E and Borg, Åke and Olsson, Håkan and Nilbert, M},
  issn         = {1045-2257},
  keyword      = {Aged,Colorectal Neoplasms,Colorectal Neoplasms, Hereditary Nonpolyposis,DNA-Binding Proteins,Female,Frameshift Mutation,Germ-Line Mutation,Humans,Male,Middle Aged,MutS Homolog 2 Protein,Pedigree,Polymorphism, Single Nucleotide,Proto-Oncogene Proteins,Sequence Analysis, DNA,Trinucleotide Repeat Expansion},
  language     = {eng},
  number       = {1},
  pages        = {33--39},
  publisher    = {ARRAY(0x91a9280)},
  series       = {Genes, Chromosomes and Cancer},
  title        = {Somatic frameshift alterations in mononucleotide repeat-containing genes in different tumor types from an HNPCC family with germline MSH2 mutation},
  volume       = {29},
  year         = {2000},
}