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A comprehensive framework for detecting copy number signatures of high-grade serous carcinoma using shallow whole-genome sequencing

Tang, Guyuan (2024) BINP52 20232
Degree Projects in Bioinformatics
Abstract
High-grade serous carcinoma (HGSC) accounts for most ovarian cancer deaths, due to it often being diagnosed at late stages (III and IV). However, there is currently no early screening method sufficient for improving survival rates. HGSC primarily harbors structural variants, typically copy number (CN) aberrations caused by homologous recombination deficiency (HRD). CN can be calculated based on reads after shallow whole genome sequencing (sWGS), an inexpensive and efficient low-coverage technique. There are three published CN signatures (HGSC-derived CN, pan-cancer chromosomal instability (CIN) and panConusig signatures) describing the chromosomal instability of cancer. We aimed to develop a Snakemake pipeline to analyze sWGS reads and to... (More)
High-grade serous carcinoma (HGSC) accounts for most ovarian cancer deaths, due to it often being diagnosed at late stages (III and IV). However, there is currently no early screening method sufficient for improving survival rates. HGSC primarily harbors structural variants, typically copy number (CN) aberrations caused by homologous recombination deficiency (HRD). CN can be calculated based on reads after shallow whole genome sequencing (sWGS), an inexpensive and efficient low-coverage technique. There are three published CN signatures (HGSC-derived CN, pan-cancer chromosomal instability (CIN) and panConusig signatures) describing the chromosomal instability of cancer. We aimed to develop a Snakemake pipeline to analyze sWGS reads and to detect published CN signatures in various types of samples, especially liquid-based cervical samples from women with HGSC and which also contained ovarian cancer cells. The Snakemake pipeline was applied to 319 samples collected from 129 women in the study cohort. All participants were further divided into three categories: women with benign conditions, BRCA mutation carriers receiving risk-reducing salpingo-oophorectomy (RRSO), and patients with HGSC. After running the pipeline, patterns presented in our samples were close to signatures correlated with HRD (s3 of HGSC-derived CN signatures, CX3 of pan-cancer CIN signatures and CN9 of panConusig). The signature similarity exposure profiles of cervical samples from HGSC patients were more similar to tumor samples than samples from the benign and RRSO categories. Additionally, the percentage of tumor-like exposure profiles of HGSC patients increased when the collection time approached the time of diagnosis. The results support the potential of applying CN signatures discovered in cervical samples or early detection of HGSC. To the best of our knowledge, our study is the first to compare three published CN signatures in cervical samples through sWGS. We suggest that it is meaningful to construct a set of HGSC-specific CN signatures that are sensitive for cervical samples in future studies. Optimizing the liquid-based sampling method for ovarian cancer cells is also warranted. (Less)
Popular Abstract
A pipeline to detect copy number signatures of ovarian cancer

High-grade serous carcinoma (HGSC) is a subtype that accounts for 70-80% of ovarian cancer deaths, because it is often diagnosed at late stages. There is no early screening method that can sufficiently reduce the mortality. Of note, HGSC is a typical example of cancers harboring primarily structural variants, especially copy number (CN) aberrations. To date, three different CN signatures aimed at describing the complex features of CN changes in heterogenous cancer genomes have been published. Therefore, we would like to construct a pipeline to explore the potential of applying CN signatures as a biomarker for early detection of HGSC.

Materials and methods
The study cohort... (More)
A pipeline to detect copy number signatures of ovarian cancer

High-grade serous carcinoma (HGSC) is a subtype that accounts for 70-80% of ovarian cancer deaths, because it is often diagnosed at late stages. There is no early screening method that can sufficiently reduce the mortality. Of note, HGSC is a typical example of cancers harboring primarily structural variants, especially copy number (CN) aberrations. To date, three different CN signatures aimed at describing the complex features of CN changes in heterogenous cancer genomes have been published. Therefore, we would like to construct a pipeline to explore the potential of applying CN signatures as a biomarker for early detection of HGSC.

Materials and methods
The study cohort included individuals from three categories: women with benign conditions, BRCA mutation carriers receiving risk-reducing salpingo-oophorectomy (RRSO) and patients with HGSC. They provided samples of various types, such as tissue and liquid-based cervical samples collected as vaginal smears (VS) which have been proven to contain ovarian cancer cells. Pre-diagnostic and diagnostic VS samples were included.

Our pipeline consisted of three parts. Part I started with the shallow whole-genome sequencing reads to estimate the ploidy and tumor cellularity that were required to calculate the absolute total CN states. Part II applied two published CN signatures based on the absolute total CN states to calculate the similarity between signature components and patterns in our samples. Similarly, Part III calculated the allele-specific CN profiles to detect the third set of published CN signatures. After running the pipeline, we further ranked the most similar signatures and calculated the signature similarity exposure profile for each sample.

Results and Conclusions
All of the three published CN signatures were detected in our samples. We discovered that signatures correlated with homologous recombination deficiency were the most prevalent signatures. In addition, signature exposure profiles of VS samples can distinguish between the three individual categories, with samples from HGSC patients being more tumor-like than samples from the benign and RRSO categories. Further, the percentage of tumor-like exposure profiles increased when the collection time approached the time of diagnosis. Our study supports the potential of using CN signatures as a biomarker for early detection of HGSC. We suggest that a set of HGSC-specific CN signatures that are sensitive to VS samples with low cellularity is warranted.

Master’s Degree Project in Bioinformatics 60 credits 2024
Department of Biology, Lund University

Advisors: Ingrid Hedenfalk, Srinivas Veerla
Division of Oncology, Department of Clinical Sciences, Lund University (Less)
Please use this url to cite or link to this publication:
author
Tang, Guyuan
supervisor
organization
course
BINP52 20232
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
9175568
date added to LUP
2024-09-27 12:23:09
date last changed
2024-09-27 12:23:09
@misc{9175568,
  abstract     = {{High-grade serous carcinoma (HGSC) accounts for most ovarian cancer deaths, due to it often being diagnosed at late stages (III and IV). However, there is currently no early screening method sufficient for improving survival rates. HGSC primarily harbors structural variants, typically copy number (CN) aberrations caused by homologous recombination deficiency (HRD). CN can be calculated based on reads after shallow whole genome sequencing (sWGS), an inexpensive and efficient low-coverage technique. There are three published CN signatures (HGSC-derived CN, pan-cancer chromosomal instability (CIN) and panConusig signatures) describing the chromosomal instability of cancer. We aimed to develop a Snakemake pipeline to analyze sWGS reads and to detect published CN signatures in various types of samples, especially liquid-based cervical samples from women with HGSC and which also contained ovarian cancer cells. The Snakemake pipeline was applied to 319 samples collected from 129 women in the study cohort. All participants were further divided into three categories: women with benign conditions, BRCA mutation carriers receiving risk-reducing salpingo-oophorectomy (RRSO), and patients with HGSC. After running the pipeline, patterns presented in our samples were close to signatures correlated with HRD (s3 of HGSC-derived CN signatures, CX3 of pan-cancer CIN signatures and CN9 of panConusig). The signature similarity exposure profiles of cervical samples from HGSC patients were more similar to tumor samples than samples from the benign and RRSO categories. Additionally, the percentage of tumor-like exposure profiles of HGSC patients increased when the collection time approached the time of diagnosis. The results support the potential of applying CN signatures discovered in cervical samples or early detection of HGSC. To the best of our knowledge, our study is the first to compare three published CN signatures in cervical samples through sWGS. We suggest that it is meaningful to construct a set of HGSC-specific CN signatures that are sensitive for cervical samples in future studies. Optimizing the liquid-based sampling method for ovarian cancer cells is also warranted.}},
  author       = {{Tang, Guyuan}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{A comprehensive framework for detecting copy number signatures of high-grade serous carcinoma using shallow whole-genome sequencing}},
  year         = {{2024}},
}