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Germline Variation Controls the Architecture of Somatic Alterations in Tumors
Studies have suggested that somatic events in tumors can depend on an individual's constitutional genotype. We used squamous cell carcinomas (SCC) of the skin, which arise in high multiplicity in organ transplant recipients, as a model to compare the pattern of somatic alterations within and ac...
Autores principales: | , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944791/ https://www.ncbi.nlm.nih.gov/pubmed/20885788 http://dx.doi.org/10.1371/journal.pgen.1001136 |
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author | Dworkin, Amy M. Ridd, Katie Bautista, Dianne Allain, Dawn C. Iwenofu, O. Hans Roy, Ritu Bastian, Boris C. Toland, Amanda Ewart |
author_facet | Dworkin, Amy M. Ridd, Katie Bautista, Dianne Allain, Dawn C. Iwenofu, O. Hans Roy, Ritu Bastian, Boris C. Toland, Amanda Ewart |
author_sort | Dworkin, Amy M. |
collection | PubMed |
description | Studies have suggested that somatic events in tumors can depend on an individual's constitutional genotype. We used squamous cell carcinomas (SCC) of the skin, which arise in high multiplicity in organ transplant recipients, as a model to compare the pattern of somatic alterations within and across individuals. Specifically, we performed array comparative genomic hybridization on 104 tumors from 25 unrelated individuals who each had three or more independently arisen SCCs and compared the profiles occurring within patients to profiles of tumors across a larger set of 135 patients. In general, chromosomal aberrations in SCCs were more similar within than across individuals (two-sided exact-test p-value [Image: see text]), consistent with the notion that the genetic background was affecting the pattern of somatic changes. To further test this possibility, we performed allele-specific imbalance studies using microsatellite markers mapping to 14 frequently aberrant regions of multiple independent tumors from 65 patients. We identified nine loci which show evidence of preferential allelic imbalance. One of these loci, 8q24, corresponded to a region in which multiple single nucleotide polymorphisms have been associated with increased cancer risk in genome-wide association studies (GWAS). We tested three implicated variants and identified one, rs13281615, with evidence of allele-specific imbalance (p-value = 0.012). The finding of an independently identified cancer susceptibility allele with allele-specific imbalance in a genomic region affected by recurrent DNA copy number changes suggest that it may also harbor risk alleles for SCC. Together these data provide strong evidence that the genetic background is a key driver of somatic events in cancer, opening an opportunity to expand this approach to identify cancer risk alleles. |
format | Text |
id | pubmed-2944791 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29447912010-09-30 Germline Variation Controls the Architecture of Somatic Alterations in Tumors Dworkin, Amy M. Ridd, Katie Bautista, Dianne Allain, Dawn C. Iwenofu, O. Hans Roy, Ritu Bastian, Boris C. Toland, Amanda Ewart PLoS Genet Research Article Studies have suggested that somatic events in tumors can depend on an individual's constitutional genotype. We used squamous cell carcinomas (SCC) of the skin, which arise in high multiplicity in organ transplant recipients, as a model to compare the pattern of somatic alterations within and across individuals. Specifically, we performed array comparative genomic hybridization on 104 tumors from 25 unrelated individuals who each had three or more independently arisen SCCs and compared the profiles occurring within patients to profiles of tumors across a larger set of 135 patients. In general, chromosomal aberrations in SCCs were more similar within than across individuals (two-sided exact-test p-value [Image: see text]), consistent with the notion that the genetic background was affecting the pattern of somatic changes. To further test this possibility, we performed allele-specific imbalance studies using microsatellite markers mapping to 14 frequently aberrant regions of multiple independent tumors from 65 patients. We identified nine loci which show evidence of preferential allelic imbalance. One of these loci, 8q24, corresponded to a region in which multiple single nucleotide polymorphisms have been associated with increased cancer risk in genome-wide association studies (GWAS). We tested three implicated variants and identified one, rs13281615, with evidence of allele-specific imbalance (p-value = 0.012). The finding of an independently identified cancer susceptibility allele with allele-specific imbalance in a genomic region affected by recurrent DNA copy number changes suggest that it may also harbor risk alleles for SCC. Together these data provide strong evidence that the genetic background is a key driver of somatic events in cancer, opening an opportunity to expand this approach to identify cancer risk alleles. Public Library of Science 2010-09-23 /pmc/articles/PMC2944791/ /pubmed/20885788 http://dx.doi.org/10.1371/journal.pgen.1001136 Text en Dworkin et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Dworkin, Amy M. Ridd, Katie Bautista, Dianne Allain, Dawn C. Iwenofu, O. Hans Roy, Ritu Bastian, Boris C. Toland, Amanda Ewart Germline Variation Controls the Architecture of Somatic Alterations in Tumors |
title | Germline Variation Controls the Architecture of Somatic Alterations in Tumors |
title_full | Germline Variation Controls the Architecture of Somatic Alterations in Tumors |
title_fullStr | Germline Variation Controls the Architecture of Somatic Alterations in Tumors |
title_full_unstemmed | Germline Variation Controls the Architecture of Somatic Alterations in Tumors |
title_short | Germline Variation Controls the Architecture of Somatic Alterations in Tumors |
title_sort | germline variation controls the architecture of somatic alterations in tumors |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944791/ https://www.ncbi.nlm.nih.gov/pubmed/20885788 http://dx.doi.org/10.1371/journal.pgen.1001136 |
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