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The unexpected landscape of in vivo somatic mutation in a human epithelial cell lineage.

ABSTRACT: Few data exist on somatic mutation in the epithelial cell lineages that play a central role in human biology and disease. To delineate the "landscape" of somatic mutation in a human epithelial cell lineage, we determined the frequency and molecular nature of somatic mutations occurring in vivo in the X-linked HPRT gene of kidney tubular epithelial cells. Kidney epithelial mutants were frequent (range 0.5 to 4.2 x 10(-4)) and contained a high proportion of unreported HPRT base substitutions, -1-bp deletions and multiple mutations. This spectrum of somatic mutation differed from HPRT mutations identified in human peripheral blood T lymphocytes and from germ-line HPRT mutations identified in Lesch-Nyhan syndrome or hyperuricemia patients. Our results indicate that DNA damage and mutagenesis may have unusual or mechanistically interesting features in kidney tubular epithelium, and that somatic mutation may play a more important role in human kidney disease than has been previously appreciated.

SUBMITTER: Colgin LM

PROVIDER: S-EPMC122209 | biostudies-literature | 2002 Feb

REPOSITORIES: biostudies-literature

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The unexpected landscape of in vivo somatic mutation in a human epithelial cell lineage.

Colgin Lorel M LM Hackmann Alden F M AF Emond Mary J MJ Monnat Raymond J RJ

Proceedings of the National Academy of Sciences of the United States of America 20020129 3

Few data exist on somatic mutation in the epithelial cell lineages that play a central role in human biology and disease. To delineate the "landscape" of somatic mutation in a human epithelial cell lineage, we determined the frequency and molecular nature of somatic mutations occurring in vivo in the X-linked HPRT gene of kidney tubular epithelial cells. Kidney epithelial mutants were frequent (range 0.5 to 4.2 x 10(-4)) and contained a high proportion of unreported HPRT base substitutions, -1-b ...[more]

PMID: 11818556

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Project description:Simple Summary The human UDP-glycosyltransferase (UGT) superfamily is involved in the metabolism of numerous anticancer drugs and endobiotic signaling molecules with pro/anti-cancer activities. Previous studies have shown abundant expression of UGT genes in many human cancers, indicative of the active intratumoral metabolism of drugs and endobiotics through the UGT conjugation pathway. Mutations of UGT genes in tumors that can affect this pathway have not yet been reported. In the present study, our analysis of somatic mutations in 10,069 tumors from 33 different cancer types identified 3427 somatic mutations in UGT genes, over half of which have been predicted to code for variant UGT proteins with no or reduced activity. As a result, somatic mutations of UGT genes may reduce the capacity of cancer cells to metabolize anticancer drugs and pro/anti-cancer endobiotics, and hence, they are likely to alter therapeutic efficacy and cancer growth, highlighting their potential utility as biomarkers predicting therapeutic efficacy and clinical outcomes. Abstract The human UDP-glycosyltransferase (UGTs) superfamily has a critical role in the metabolism of anticancer drugs and numerous pro/anti-cancer molecules (e.g., steroids, lipids, fatty acids, bile acids and carcinogens). Recent studies have shown wide and abundant expression of UGT genes in human cancers. However, the extent to which UGT genes acquire somatic mutations within tumors remains to be systematically investigated. In the present study, our comprehensive analysis of the somatic mutation profiles of 10,069 tumors from 33 different TCGA cancer types identified 3427 somatic mutations in UGT genes. Overall, nearly 18% (1802/10,069) of the assessed tumors had mutations in UGT genes with huge variations in mutation frequency across different cancer types, ranging from over 25% in five cancers (COAD, LUAD, LUSC, SKCM and UCSC) to less than 5% in eight cancers (LAML, MESO, PCPG, PAAD, PRAD, TGCT, THYM and UVM). All 22 UGT genes showed somatic mutations in tumors, with UGT2B4, UGT3A1 and UGT3A2 showing the largest number of mutations (289, 307 and 255 mutations, respectively). Nearly 65% (2260/3427) of the mutations were missense, frame-shift and nonsense mutations that have been predicted to code for variant UGT proteins. Furthermore, about 10% (362/3427) of the mutations occurred in non-coding regions (5′ UTR, 3′ UTR and splice sites) that may be able to alter the efficiency of translation initiation, miRNA regulation or the splicing of UGT transcripts. In conclusion, our data show widespread somatic mutations of UGT genes in human cancers that may affect the capacity of cancer cells to metabolize anticancer drugs and endobiotics that control pro/anti-cancer signaling pathways. This highlights their potential utility as biomarkers for predicting therapeutic efficacy and clinical outcomes.

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The unexpected landscape of in vivo somatic mutation in a human epithelial cell lineage.

Publications

The unexpected landscape of in vivo somatic mutation in a human epithelial cell lineage.

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