Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor

Jaclyn Schienda; Alanna J. Church; Laura B. Corson; Brennan Decker; Catherine M. Clinton; Danielle K. Manning; Alma Imamovic-Tuco; Deirdre Reidy; Gianna R. Strand; Mark A. Applebaum; Rochelle Bagatell; Steven G. DuBois; Julia L. Glade-Bender; Wenjun Kang; Ae Rang Kim; Theodore W. Laetsch; Margaret E. Macy; Luke Maese; Navin Pinto; Amit J. Sabnis; Joshua D. Schiffman; Susan I. Colace; Samuel L. Volchenboum; Daniel A. Weiser; Jonathan A. Nowak; Neal I. Lindeman; Katherine A. Janeway; Brian D. Crompton; Junne Kamihara

doi:10.1200/PO.21.00281

Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor

Jaclyn Schienda, Alanna J. Church, Laura B. Corson, Brennan Decker, Catherine M. Clinton, Danielle K. Manning, Alma Imamovic-Tuco, Deirdre Reidy, Gianna R. Strand, Mark A. Applebaum, Rochelle Bagatell, Steven G. DuBois, Julia L. Glade-Bender, Wenjun Kang, Ae Rang Kim, Theodore W. Laetsch, Margaret E. Macy, Luke Maese, Navin Pinto, Amit J. SabnisJoshua D. Schiffman, Susan I. Colace, Samuel L. Volchenboum, Daniel A. Weiser, Jonathan A. Nowak, Neal I. Lindeman, Katherine A. Janeway, Brian D. Crompton, Junne Kamihara

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

PURPOSE Molecular tumor profiling is becoming a routine part of clinical cancer care, typically involving tumor-only panel testing without matched germline. We hypothesized that integrated germline sequencing could improve clinical interpretation and enhance the identification of germline variants with significant hereditary risks. MATERIALS AND METHODS Tumors from pediatric patients with high-risk, extracranial solid malignancies were sequenced with a targeted panel of cancer-associated genes. Later, germline DNA was analyzed for a subset of these genes. We performed a post hoc analysis to identify how an integrated analysis of tumor and germline data would improve clinical interpretation. RESULTS One hundred sixty participants with both tumor-only and germline sequencing reports were eligible for this analysis. Germline sequencing identified 38 pathogenic or likely pathogenic variants among 35 (22%) patients. Twenty-five (66%) of these were included in the tumor sequencing report. The remaining germline pathogenic or likely pathogenic variants were single-nucleotide variants filtered out of tumor-only analysis because of population frequency or copy-number variation masked by additional copy-number changes in the tumor. In tumor-only sequencing, 308 of 434 (71%) single-nucleotide variants reported were present in the germline, including 31% with suggested clinical utility. Finally, we provide further evidence that the variant allele fraction from tumor-only sequencing is insufficient to differentiate somatic from germline events. CONCLUSION A paired approach to analyzing tumor and germline sequencing data would be expected to improve the efficiency and accuracy of distinguishing somatic mutations and germline variants, thereby facilitating the process of variant curation and therapeutic interpretation for somatic reports, as well as the identification of variants associated with germline cancer predisposition.

Original language	English (US)
Pages (from-to)	1840-1852
Number of pages	13
Journal	JCO Precision Oncology
Volume	5
DOIs	https://doi.org/10.1200/PO.21.00281
State	Published - 2021
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1200/PO.21.00281

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Schienda, J., Church, A. J., Corson, L. B., Decker, B., Clinton, C. M., Manning, D. K., Imamovic-Tuco, A., Reidy, D., Strand, G. R., Applebaum, M. A., Bagatell, R., DuBois, S. G., Glade-Bender, J. L., Kang, W., Kim, A. R., Laetsch, T. W., Macy, M. E., Maese, L., Pinto, N., ... Kamihara, J. (2021). Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor. JCO Precision Oncology, 5, 1840-1852. https://doi.org/10.1200/PO.21.00281

Schienda, J, Church, AJ, Corson, LB, Decker, B, Clinton, CM, Manning, DK, Imamovic-Tuco, A, Reidy, D, Strand, GR, Applebaum, MA, Bagatell, R, DuBois, SG, Glade-Bender, JL, Kang, W, Kim, AR, Laetsch, TW, Macy, ME, Maese, L, Pinto, N, Sabnis, AJ, Schiffman, JD, Colace, SI, Volchenboum, SL, Weiser, DA, Nowak, JA, Lindeman, NI, Janeway, KA, Crompton, BD & Kamihara, J 2021, 'Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor', JCO Precision Oncology, vol. 5, pp. 1840-1852. https://doi.org/10.1200/PO.21.00281

@article{1595da2dcba9472a92fac255b608ef87,

title = "Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor",

abstract = "PURPOSE Molecular tumor profiling is becoming a routine part of clinical cancer care, typically involving tumor-only panel testing without matched germline. We hypothesized that integrated germline sequencing could improve clinical interpretation and enhance the identification of germline variants with significant hereditary risks. MATERIALS AND METHODS Tumors from pediatric patients with high-risk, extracranial solid malignancies were sequenced with a targeted panel of cancer-associated genes. Later, germline DNA was analyzed for a subset of these genes. We performed a post hoc analysis to identify how an integrated analysis of tumor and germline data would improve clinical interpretation. RESULTS One hundred sixty participants with both tumor-only and germline sequencing reports were eligible for this analysis. Germline sequencing identified 38 pathogenic or likely pathogenic variants among 35 (22%) patients. Twenty-five (66%) of these were included in the tumor sequencing report. The remaining germline pathogenic or likely pathogenic variants were single-nucleotide variants filtered out of tumor-only analysis because of population frequency or copy-number variation masked by additional copy-number changes in the tumor. In tumor-only sequencing, 308 of 434 (71%) single-nucleotide variants reported were present in the germline, including 31% with suggested clinical utility. Finally, we provide further evidence that the variant allele fraction from tumor-only sequencing is insufficient to differentiate somatic from germline events. CONCLUSION A paired approach to analyzing tumor and germline sequencing data would be expected to improve the efficiency and accuracy of distinguishing somatic mutations and germline variants, thereby facilitating the process of variant curation and therapeutic interpretation for somatic reports, as well as the identification of variants associated with germline cancer predisposition.",

author = "Jaclyn Schienda and Church, {Alanna J.} and Corson, {Laura B.} and Brennan Decker and Clinton, {Catherine M.} and Manning, {Danielle K.} and Alma Imamovic-Tuco and Deirdre Reidy and Strand, {Gianna R.} and Applebaum, {Mark A.} and Rochelle Bagatell and DuBois, {Steven G.} and Glade-Bender, {Julia L.} and Wenjun Kang and Kim, {Ae Rang} and Laetsch, {Theodore W.} and Macy, {Margaret E.} and Luke Maese and Navin Pinto and Sabnis, {Amit J.} and Schiffman, {Joshua D.} and Colace, {Susan I.} and Volchenboum, {Samuel L.} and Weiser, {Daniel A.} and Nowak, {Jonathan A.} and Lindeman, {Neal I.} and Janeway, {Katherine A.} and Crompton, {Brian D.} and Junne Kamihara",

year = "2021",

doi = "10.1200/PO.21.00281",

language = "English (US)",

volume = "5",

pages = "1840--1852",

journal = "JCO Precision Oncology",

issn = "2473-4284",

publisher = "American Society of Clinical Oncology",

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TY - JOUR

T1 - Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor

AU - Schienda, Jaclyn

AU - Church, Alanna J.

AU - Corson, Laura B.

AU - Decker, Brennan

AU - Clinton, Catherine M.

AU - Manning, Danielle K.

AU - Imamovic-Tuco, Alma

AU - Reidy, Deirdre

AU - Strand, Gianna R.

AU - Applebaum, Mark A.

AU - Bagatell, Rochelle

AU - DuBois, Steven G.

AU - Glade-Bender, Julia L.

AU - Kang, Wenjun

AU - Kim, Ae Rang

AU - Laetsch, Theodore W.

AU - Macy, Margaret E.

AU - Maese, Luke

AU - Pinto, Navin

AU - Sabnis, Amit J.

AU - Schiffman, Joshua D.

AU - Colace, Susan I.

AU - Volchenboum, Samuel L.

AU - Weiser, Daniel A.

AU - Nowak, Jonathan A.

AU - Lindeman, Neal I.

AU - Janeway, Katherine A.

AU - Crompton, Brian D.

AU - Kamihara, Junne

PY - 2021

Y1 - 2021

N2 - PURPOSE Molecular tumor profiling is becoming a routine part of clinical cancer care, typically involving tumor-only panel testing without matched germline. We hypothesized that integrated germline sequencing could improve clinical interpretation and enhance the identification of germline variants with significant hereditary risks. MATERIALS AND METHODS Tumors from pediatric patients with high-risk, extracranial solid malignancies were sequenced with a targeted panel of cancer-associated genes. Later, germline DNA was analyzed for a subset of these genes. We performed a post hoc analysis to identify how an integrated analysis of tumor and germline data would improve clinical interpretation. RESULTS One hundred sixty participants with both tumor-only and germline sequencing reports were eligible for this analysis. Germline sequencing identified 38 pathogenic or likely pathogenic variants among 35 (22%) patients. Twenty-five (66%) of these were included in the tumor sequencing report. The remaining germline pathogenic or likely pathogenic variants were single-nucleotide variants filtered out of tumor-only analysis because of population frequency or copy-number variation masked by additional copy-number changes in the tumor. In tumor-only sequencing, 308 of 434 (71%) single-nucleotide variants reported were present in the germline, including 31% with suggested clinical utility. Finally, we provide further evidence that the variant allele fraction from tumor-only sequencing is insufficient to differentiate somatic from germline events. CONCLUSION A paired approach to analyzing tumor and germline sequencing data would be expected to improve the efficiency and accuracy of distinguishing somatic mutations and germline variants, thereby facilitating the process of variant curation and therapeutic interpretation for somatic reports, as well as the identification of variants associated with germline cancer predisposition.

AB - PURPOSE Molecular tumor profiling is becoming a routine part of clinical cancer care, typically involving tumor-only panel testing without matched germline. We hypothesized that integrated germline sequencing could improve clinical interpretation and enhance the identification of germline variants with significant hereditary risks. MATERIALS AND METHODS Tumors from pediatric patients with high-risk, extracranial solid malignancies were sequenced with a targeted panel of cancer-associated genes. Later, germline DNA was analyzed for a subset of these genes. We performed a post hoc analysis to identify how an integrated analysis of tumor and germline data would improve clinical interpretation. RESULTS One hundred sixty participants with both tumor-only and germline sequencing reports were eligible for this analysis. Germline sequencing identified 38 pathogenic or likely pathogenic variants among 35 (22%) patients. Twenty-five (66%) of these were included in the tumor sequencing report. The remaining germline pathogenic or likely pathogenic variants were single-nucleotide variants filtered out of tumor-only analysis because of population frequency or copy-number variation masked by additional copy-number changes in the tumor. In tumor-only sequencing, 308 of 434 (71%) single-nucleotide variants reported were present in the germline, including 31% with suggested clinical utility. Finally, we provide further evidence that the variant allele fraction from tumor-only sequencing is insufficient to differentiate somatic from germline events. CONCLUSION A paired approach to analyzing tumor and germline sequencing data would be expected to improve the efficiency and accuracy of distinguishing somatic mutations and germline variants, thereby facilitating the process of variant curation and therapeutic interpretation for somatic reports, as well as the identification of variants associated with germline cancer predisposition.

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DO - 10.1200/PO.21.00281

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AN - SCOPUS:85131303152

SN - 2473-4284

VL - 5

SP - 1840

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JO - JCO Precision Oncology

JF - JCO Precision Oncology

ER -

Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor

Abstract

ASJC Scopus subject areas

UN SDGs

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