A method to reduce ancestry related germline false positives in tumor only somatic variant calling
Abstract Background Significant clinical and research applications are driving large scale adoption of individualized tumor sequencing in cancer in order to identify tumors-specific mutations. When a matched germline sample is available, somatic mutations may be identified using comparative callers....
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-10-01
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| Series: | BMC Medical Genomics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12920-017-0296-8 |
| _version_ | 1819161497240076288 |
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| author | Rebecca F. Halperin John D. Carpten Zarko Manojlovic Jessica Aldrich Jonathan Keats Sara Byron Winnie S. Liang Megan Russell Daniel Enriquez Ana Claasen Irene Cherni Baffour Awuah Joseph Oppong Max S. Wicha Lisa A. Newman Evelyn Jaigge Seungchan Kim David W. Craig |
| author_facet | Rebecca F. Halperin John D. Carpten Zarko Manojlovic Jessica Aldrich Jonathan Keats Sara Byron Winnie S. Liang Megan Russell Daniel Enriquez Ana Claasen Irene Cherni Baffour Awuah Joseph Oppong Max S. Wicha Lisa A. Newman Evelyn Jaigge Seungchan Kim David W. Craig |
| author_sort | Rebecca F. Halperin |
| collection | DOAJ |
| description | Abstract Background Significant clinical and research applications are driving large scale adoption of individualized tumor sequencing in cancer in order to identify tumors-specific mutations. When a matched germline sample is available, somatic mutations may be identified using comparative callers. However, matched germline samples are frequently not available such as with archival tissues, which makes it difficult to distinguish somatic from germline variants. While population databases may be used to filter out known germline variants, recent studies have shown private germline variants result in an inflated false positive rate in unmatched tumor samples, and the number germline false positives in an individual may be related to ancestry. Methods First, we examined the relationship between the germline false positives and ancestry. Then we developed and implemented a tumor only caller (LumosVar) that leverages differences in allelic frequency between somatic and germline variants in impure tumors. We used simulated data to systematically examine how copy number alterations, tumor purity, and sequencing depth should affect the sensitivity of our caller. Finally, we evaluated the caller on real data. Results We find the germline false-positive rate is significantly higher for individuals of non-European Ancestry largely due to the limited diversity in public polymorphism databases and due to population-specific characteristics such as admixture or recent expansions. Our Bayesian tumor only caller (LumosVar) is able to greatly reduce false positives from private germline variants, and our sensitivity is similar to predictions based on simulated data. Conclusions Taken together, our results suggest that studies of individuals of non-European ancestry would most benefit from our approach. However, high sensitivity requires sufficiently impure tumors and adequate sequencing depth. Even in impure tumors, there are copy number alterations that result in germline and somatic variants having similar allele frequencies, limiting the sensitivity of the approach. We believe our approach could greatly improve the analysis of archival samples in a research setting where the normal is not available. |
| first_indexed | 2024-12-22T17:13:17Z |
| format | Article |
| id | doaj.art-fde1123b7aa84a3eadeb4956afa4c35d |
| institution | Directory Open Access Journal |
| issn | 1755-8794 |
| language | English |
| last_indexed | 2024-12-22T17:13:17Z |
| publishDate | 2017-10-01 |
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| series | BMC Medical Genomics |
| spelling | doaj.art-fde1123b7aa84a3eadeb4956afa4c35d2022-12-21T18:19:01ZengBMCBMC Medical Genomics1755-87942017-10-0110111710.1186/s12920-017-0296-8A method to reduce ancestry related germline false positives in tumor only somatic variant callingRebecca F. Halperin0John D. Carpten1Zarko Manojlovic2Jessica Aldrich3Jonathan Keats4Sara Byron5Winnie S. Liang6Megan Russell7Daniel Enriquez8Ana Claasen9Irene Cherni10Baffour Awuah11Joseph Oppong12Max S. Wicha13Lisa A. Newman14Evelyn Jaigge15Seungchan Kim16David W. Craig17Center for Translational Innovation, Translational Genomics Research InstituteDepartment of Translational Genomics, University of Southern CaliforniaDepartment of Translational Genomics, University of Southern CaliforniaIntegrated Cancer Division, Translational Genomics Research InstituteIntegrated Cancer Division, Translational Genomics Research InstituteCenter for Translational Innovation, Translational Genomics Research InstituteNeurogenomics Division, Translational Genomics Research InstituteIntegrated Cancer Division, Translational Genomics Research InstituteNeurogenomics Division, Translational Genomics Research InstituteNeurogenomics Division, Translational Genomics Research InstituteIntegrated Cancer Division, Translational Genomics Research InstituteKomfo Anokye Teaching HospitalKomfo Anokye Teaching HospitalUniversity of MichiganHenry Ford Health SystemsUniversity of MichiganIntegrated Cancer Division, Translational Genomics Research InstituteDepartment of Translational Genomics, University of Southern CaliforniaAbstract Background Significant clinical and research applications are driving large scale adoption of individualized tumor sequencing in cancer in order to identify tumors-specific mutations. When a matched germline sample is available, somatic mutations may be identified using comparative callers. However, matched germline samples are frequently not available such as with archival tissues, which makes it difficult to distinguish somatic from germline variants. While population databases may be used to filter out known germline variants, recent studies have shown private germline variants result in an inflated false positive rate in unmatched tumor samples, and the number germline false positives in an individual may be related to ancestry. Methods First, we examined the relationship between the germline false positives and ancestry. Then we developed and implemented a tumor only caller (LumosVar) that leverages differences in allelic frequency between somatic and germline variants in impure tumors. We used simulated data to systematically examine how copy number alterations, tumor purity, and sequencing depth should affect the sensitivity of our caller. Finally, we evaluated the caller on real data. Results We find the germline false-positive rate is significantly higher for individuals of non-European Ancestry largely due to the limited diversity in public polymorphism databases and due to population-specific characteristics such as admixture or recent expansions. Our Bayesian tumor only caller (LumosVar) is able to greatly reduce false positives from private germline variants, and our sensitivity is similar to predictions based on simulated data. Conclusions Taken together, our results suggest that studies of individuals of non-European ancestry would most benefit from our approach. However, high sensitivity requires sufficiently impure tumors and adequate sequencing depth. Even in impure tumors, there are copy number alterations that result in germline and somatic variants having similar allele frequencies, limiting the sensitivity of the approach. We believe our approach could greatly improve the analysis of archival samples in a research setting where the normal is not available.http://link.springer.com/article/10.1186/s12920-017-0296-8Somatic mutationGermline variantNext generation sequencingCancerPrecision medicineTumor purity |
| spellingShingle | Rebecca F. Halperin John D. Carpten Zarko Manojlovic Jessica Aldrich Jonathan Keats Sara Byron Winnie S. Liang Megan Russell Daniel Enriquez Ana Claasen Irene Cherni Baffour Awuah Joseph Oppong Max S. Wicha Lisa A. Newman Evelyn Jaigge Seungchan Kim David W. Craig A method to reduce ancestry related germline false positives in tumor only somatic variant calling BMC Medical Genomics Somatic mutation Germline variant Next generation sequencing Cancer Precision medicine Tumor purity |
| title | A method to reduce ancestry related germline false positives in tumor only somatic variant calling |
| title_full | A method to reduce ancestry related germline false positives in tumor only somatic variant calling |
| title_fullStr | A method to reduce ancestry related germline false positives in tumor only somatic variant calling |
| title_full_unstemmed | A method to reduce ancestry related germline false positives in tumor only somatic variant calling |
| title_short | A method to reduce ancestry related germline false positives in tumor only somatic variant calling |
| title_sort | method to reduce ancestry related germline false positives in tumor only somatic variant calling |
| topic | Somatic mutation Germline variant Next generation sequencing Cancer Precision medicine Tumor purity |
| url | http://link.springer.com/article/10.1186/s12920-017-0296-8 |
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