Identification of risk variants related to malignant tumors in children with birth defects by whole genome sequencing

Yichuan Liu; Hui Qi Qu; Xiao Chang; Frank D. Mentch; Haijun Qiu; Kenny Nguyen; Xiang Wang; Amir Hossein Saeidian; Deborah Watson; Joseph Glessner; Hakon Hakonarson

doi:10.1186/s40364-022-00431-y

Identification of risk variants related to malignant tumors in children with birth defects by whole genome sequencing

Yichuan Liu^*, Hui Qi Qu, Xiao Chang, Frank D. Mentch, Haijun Qiu, Kenny Nguyen, Xiang Wang, Amir Hossein Saeidian, Deborah Watson, Joseph Glessner, Hakon Hakonarson^*

^*Corresponding author for this work

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

Abstract

Background: Children with birth defects (BD) are more likely to develop cancer and the increased risk of cancer persists into adulthood. Prior population-based assessments have demonstrated that even non-chromosomal BDs are associated with at least two-fold increase of cancer risk. Identification of variants that are associated with malignant tumor in BD patients without chromosomal anomalies may improve our understanding of the underlying molecular mechanisms and provide clues for early cancer detection in children with BD. Methods: In this study, whole genome sequencing (WGS) data of blood-derived DNA for 1653 individuals without chromosomal anomalies were acquired from the Kids First Data Resource Center (DRC), including 541 BD probands with at least one type of malignant tumors, 767 BD probands without malignant tumor, and 345 healthy family members who are the parents or siblings of the probands. Recurrent variants exclusively seen in cancer patients were selected and mapped to their corresponding genomic regions. The targeted genes/non-coding RNAs were further reduced using random forest and forward feature selection (ffs) models. Results: The filtered genes/non-coding RNAs, including variants in non-coding areas, showed enrichment in cancer-related pathways. To further support the validity of these variants, blood WGS data of additional 40 independent BD probands, including 25 patients with at least one type of cancers from unrelated projects, were acquired. The counts of variants of interest identified in the Kid First data showed clear deviation in the validation dataset between BD patients with cancer and without cancer. Furthermore, a deep learning model was built to assess the predictive abilities in the 40 patients using variants of interest identified in the Kids First cohort as feature vectors. The accuracies are ~ 75%, with the noteworthy observation that variants mapped to non-coding regions provided the highest accuracy (31 out of 40 patients were labeled correctly). Conclusion: We present for the first time a panorama of genetic variants that are associated with cancers in non-chromosomal BD patients, implying that our approach may potentially serve for the early detection of malignant tumors in patients with BD.

Original language	English
Article number	84
Journal	Biomarker Research
Volume	10
Issue number	1
DOIs	https://doi.org/10.1186/s40364-022-00431-y
Publication status	Published - Dec 2022
Externally published	Yes

Bibliographical note

Funding Information:
Sample collection and biobanking for this study was supported by Institutional Development Funds from the Children’s Hospital of Philadelphia (CHOP) to the Center for Applied Genomics (CAG) and CHOP´s Endowed Chair in Genomic Research (CAG). The sequencing data was provided through the Gabriella Miller Kids First Pediatric Research Program consortium (Kids First), supported by the Common Fund of the Office of the Director of the National Institutes of Health ( www.commonfund.nih.gov/KidsFirst ), awarded to CAG. The TOPMed acknowledgements can be found at: https://www.nhlbiwgs.org/acknowledgements . We thank the CAG staff and the participating patients and families who contributed biosamples to CAG/CHOP.

Funding Information:
The study was supported by Institutional Development Funds from the Children’s Hospital of Philadelphia to the Center for Applied Genomics, The Children’s Hospital of Philadelphia Endowed Chair in Genomic Research to HH.

Publisher Copyright:
© 2022, The Author(s).

Other keywords

Birth defect
Pediatric cancer
Whole genome sequencing

UN SDGs

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

Access to Document

10.1186/s40364-022-00431-y

Cite this

@article{402fd3378989499db50e5a3a2fce29b4,

title = "Identification of risk variants related to malignant tumors in children with birth defects by whole genome sequencing",

abstract = "Background: Children with birth defects (BD) are more likely to develop cancer and the increased risk of cancer persists into adulthood. Prior population-based assessments have demonstrated that even non-chromosomal BDs are associated with at least two-fold increase of cancer risk. Identification of variants that are associated with malignant tumor in BD patients without chromosomal anomalies may improve our understanding of the underlying molecular mechanisms and provide clues for early cancer detection in children with BD. Methods: In this study, whole genome sequencing (WGS) data of blood-derived DNA for 1653 individuals without chromosomal anomalies were acquired from the Kids First Data Resource Center (DRC), including 541 BD probands with at least one type of malignant tumors, 767 BD probands without malignant tumor, and 345 healthy family members who are the parents or siblings of the probands. Recurrent variants exclusively seen in cancer patients were selected and mapped to their corresponding genomic regions. The targeted genes/non-coding RNAs were further reduced using random forest and forward feature selection (ffs) models. Results: The filtered genes/non-coding RNAs, including variants in non-coding areas, showed enrichment in cancer-related pathways. To further support the validity of these variants, blood WGS data of additional 40 independent BD probands, including 25 patients with at least one type of cancers from unrelated projects, were acquired. The counts of variants of interest identified in the Kid First data showed clear deviation in the validation dataset between BD patients with cancer and without cancer. Furthermore, a deep learning model was built to assess the predictive abilities in the 40 patients using variants of interest identified in the Kids First cohort as feature vectors. The accuracies are ~ 75%, with the noteworthy observation that variants mapped to non-coding regions provided the highest accuracy (31 out of 40 patients were labeled correctly). Conclusion: We present for the first time a panorama of genetic variants that are associated with cancers in non-chromosomal BD patients, implying that our approach may potentially serve for the early detection of malignant tumors in patients with BD.",

keywords = "Birth defect, Pediatric cancer, Whole genome sequencing",

author = "Yichuan Liu and Qu, {Hui Qi} and Xiao Chang and Mentch, {Frank D.} and Haijun Qiu and Kenny Nguyen and Xiang Wang and Saeidian, {Amir Hossein} and Deborah Watson and Joseph Glessner and Hakon Hakonarson",

note = "Funding Information: Sample collection and biobanking for this study was supported by Institutional Development Funds from the Children{\textquoteright}s Hospital of Philadelphia (CHOP) to the Center for Applied Genomics (CAG) and CHOP´s Endowed Chair in Genomic Research (CAG). The sequencing data was provided through the Gabriella Miller Kids First Pediatric Research Program consortium (Kids First), supported by the Common Fund of the Office of the Director of the National Institutes of Health ( www.commonfund.nih.gov/KidsFirst ), awarded to CAG. The TOPMed acknowledgements can be found at: https://www.nhlbiwgs.org/acknowledgements . We thank the CAG staff and the participating patients and families who contributed biosamples to CAG/CHOP. Funding Information: The study was supported by Institutional Development Funds from the Children{\textquoteright}s Hospital of Philadelphia to the Center for Applied Genomics, The Children{\textquoteright}s Hospital of Philadelphia Endowed Chair in Genomic Research to HH. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s40364-022-00431-y",

language = "English",

volume = "10",

journal = "Biomarker Research",

issn = "2050-7771",

publisher = "BioMed Central Ltd.",

number = "1",

}

TY - JOUR

T1 - Identification of risk variants related to malignant tumors in children with birth defects by whole genome sequencing

AU - Liu, Yichuan

AU - Qu, Hui Qi

AU - Chang, Xiao

AU - Mentch, Frank D.

AU - Qiu, Haijun

AU - Nguyen, Kenny

AU - Wang, Xiang

AU - Saeidian, Amir Hossein

AU - Watson, Deborah

AU - Glessner, Joseph

AU - Hakonarson, Hakon

N1 - Funding Information: Sample collection and biobanking for this study was supported by Institutional Development Funds from the Children’s Hospital of Philadelphia (CHOP) to the Center for Applied Genomics (CAG) and CHOP´s Endowed Chair in Genomic Research (CAG). The sequencing data was provided through the Gabriella Miller Kids First Pediatric Research Program consortium (Kids First), supported by the Common Fund of the Office of the Director of the National Institutes of Health ( www.commonfund.nih.gov/KidsFirst ), awarded to CAG. The TOPMed acknowledgements can be found at: https://www.nhlbiwgs.org/acknowledgements . We thank the CAG staff and the participating patients and families who contributed biosamples to CAG/CHOP. Funding Information: The study was supported by Institutional Development Funds from the Children’s Hospital of Philadelphia to the Center for Applied Genomics, The Children’s Hospital of Philadelphia Endowed Chair in Genomic Research to HH. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Background: Children with birth defects (BD) are more likely to develop cancer and the increased risk of cancer persists into adulthood. Prior population-based assessments have demonstrated that even non-chromosomal BDs are associated with at least two-fold increase of cancer risk. Identification of variants that are associated with malignant tumor in BD patients without chromosomal anomalies may improve our understanding of the underlying molecular mechanisms and provide clues for early cancer detection in children with BD. Methods: In this study, whole genome sequencing (WGS) data of blood-derived DNA for 1653 individuals without chromosomal anomalies were acquired from the Kids First Data Resource Center (DRC), including 541 BD probands with at least one type of malignant tumors, 767 BD probands without malignant tumor, and 345 healthy family members who are the parents or siblings of the probands. Recurrent variants exclusively seen in cancer patients were selected and mapped to their corresponding genomic regions. The targeted genes/non-coding RNAs were further reduced using random forest and forward feature selection (ffs) models. Results: The filtered genes/non-coding RNAs, including variants in non-coding areas, showed enrichment in cancer-related pathways. To further support the validity of these variants, blood WGS data of additional 40 independent BD probands, including 25 patients with at least one type of cancers from unrelated projects, were acquired. The counts of variants of interest identified in the Kid First data showed clear deviation in the validation dataset between BD patients with cancer and without cancer. Furthermore, a deep learning model was built to assess the predictive abilities in the 40 patients using variants of interest identified in the Kids First cohort as feature vectors. The accuracies are ~ 75%, with the noteworthy observation that variants mapped to non-coding regions provided the highest accuracy (31 out of 40 patients were labeled correctly). Conclusion: We present for the first time a panorama of genetic variants that are associated with cancers in non-chromosomal BD patients, implying that our approach may potentially serve for the early detection of malignant tumors in patients with BD.

AB - Background: Children with birth defects (BD) are more likely to develop cancer and the increased risk of cancer persists into adulthood. Prior population-based assessments have demonstrated that even non-chromosomal BDs are associated with at least two-fold increase of cancer risk. Identification of variants that are associated with malignant tumor in BD patients without chromosomal anomalies may improve our understanding of the underlying molecular mechanisms and provide clues for early cancer detection in children with BD. Methods: In this study, whole genome sequencing (WGS) data of blood-derived DNA for 1653 individuals without chromosomal anomalies were acquired from the Kids First Data Resource Center (DRC), including 541 BD probands with at least one type of malignant tumors, 767 BD probands without malignant tumor, and 345 healthy family members who are the parents or siblings of the probands. Recurrent variants exclusively seen in cancer patients were selected and mapped to their corresponding genomic regions. The targeted genes/non-coding RNAs were further reduced using random forest and forward feature selection (ffs) models. Results: The filtered genes/non-coding RNAs, including variants in non-coding areas, showed enrichment in cancer-related pathways. To further support the validity of these variants, blood WGS data of additional 40 independent BD probands, including 25 patients with at least one type of cancers from unrelated projects, were acquired. The counts of variants of interest identified in the Kid First data showed clear deviation in the validation dataset between BD patients with cancer and without cancer. Furthermore, a deep learning model was built to assess the predictive abilities in the 40 patients using variants of interest identified in the Kids First cohort as feature vectors. The accuracies are ~ 75%, with the noteworthy observation that variants mapped to non-coding regions provided the highest accuracy (31 out of 40 patients were labeled correctly). Conclusion: We present for the first time a panorama of genetic variants that are associated with cancers in non-chromosomal BD patients, implying that our approach may potentially serve for the early detection of malignant tumors in patients with BD.

KW - Birth defect

KW - Pediatric cancer

KW - Whole genome sequencing

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U2 - 10.1186/s40364-022-00431-y

DO - 10.1186/s40364-022-00431-y

M3 - Article

AN - SCOPUS:85142193984

SN - 2050-7771

VL - 10

JO - Biomarker Research

JF - Biomarker Research

IS - 1

M1 - 84

ER -

Identification of risk variants related to malignant tumors in children with birth defects by whole genome sequencing

Abstract

Bibliographical note

Other keywords

UN SDGs

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