Clinical Validation of Whole Genome Sequencing for Cancer Diagnostics

Roepman, Paul; Bruijn, Ewart de; Lieshout, Stef van; Schoenmaker, Lieke; Boelens, Mirjam C.; Dubbink, Hendrikus J.; Geurts-Giele, Willemina R.R.; Groenendijk, Floris H.; Huibers, Manon M. H.; Kranendonk, Mariëtte E.G.; Roemer, Margaretha G.M.; Samsom, Kris G.; Steehouwer, Marloes; Leng, Wendy W.J. de; Hoischen, Alexander; Ylstra, Bauke; Monkhorst, Kim; Hoeven, J.J.M. van der; Cuppen, Edwin

doi:10.1016/j.jmoldx.2021.04.011

Cited by 51 publications

(45 citation statements)

References 44 publications

(49 reference statements)

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“…We used standard procedures for WGS (Hartwig Medical Foundation, Amsterdam, The Netherlands), as previously described [ 10 ]. In brief, tumor DNA was isolated from fresh frozen tumor samples and sequenced at a depth of >90–100× coverage.…”

Section: Methodsmentioning

confidence: 99%

Clinical Impact of Prospective Whole Genome Sequencing in Sarcoma Patients

Schipper

Monkhorst

Samsom

et al. 2022

Cancers

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With more than 70 different histological sarcoma subtypes, accurate classification can be challenging. Although characteristic genetic events can largely facilitate pathological assessment, large-scale molecular profiling generally is not part of regular diagnostic workflows for sarcoma patients. We hypothesized that whole genome sequencing (WGS) optimizes clinical care of sarcoma patients by detection of diagnostic and actionable genomic characteristics, and of underlying hereditary conditions. WGS of tumor and germline DNA was incorporated in the diagnostic work-up of 83 patients with a (presumed) sarcomas in a tertiary referral center. Clinical follow-up data were collected prospectively to assess impact of WGS on clinical decision making. In 12/83 patients (14%), the genomic profile led to revision of cancer diagnosis, with change of treatment plan in eight. All twelve patients had undergone multiple tissue retrieval procedures and immunohistopathological assessments by regional and expert pathologists prior to WGS analysis. Actionable biomarkers with therapeutic potential were identified for 30/83 patients. Pathogenic germline variants were present in seven patients. In conclusion, unbiased genomic characterization with WGS identifies genomic biomarkers with direct clinical implications for sarcoma patients. Given the diagnostic complexity and high unmet need for new treatment opportunities in sarcoma patients, WGS can be an important extension of the diagnostic arsenal of pathologists.

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Section: Methodsmentioning

confidence: 99%

Clinical Impact of Prospective Whole Genome Sequencing in Sarcoma Patients

Schipper

Monkhorst

Samsom

et al. 2022

Cancers

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“…For metastatic/advanced tumor samples from the HMF database, metadata on HER2 status were available only for primary tumors, the IHC/FISH status for sequenced sample from the second biopsy was not provided. Because of the high rate of conversion from HER2-negative to HER2-positive status (and vice versa) during the cancer evolution [ 4 , 11 ], in metastatic cancers, we have taken into consideration also the patients’ treatment metadata and discarded all samples for which treatment history (pre-biopsy and post-biopsy) was discordant with initial HER2 status (e.g., if trastuzumab was included in any line of treatment even though HER2 status was reported negative). For details on discarded samples, see the ESM.…”

Section: Methodsmentioning

confidence: 99%

“…The purpose of this study was to determine the feasibility of accurately distinguishing between HER2-positive and HER2-negative cases of BC based on matched tumor-normal WGS. To date, there have been only a few studies evaluating the clinical utility of NGS testing of ERBB2 gene status, including the WGS method [4,11,[13][14][15]. Some of them directly address the clinical need to verify the relevance of their findings for patient management, reporting the overall concordance between IHC/FISH and NGS at about a 90% level.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, whole genome sequencing (WGS) is capable of acquiring absolute ERBB2 CN, CEP17 CN, and mean ploidy of tumor cells simultaneously. Moreover, WGS can confirm the presence of the neoplastic cell in the sample, providing quality control of the material for analyses [ 11 ]. As WGS is mainly based on polymerase chain reaction-free methodology, it preserves the original proportions of DNA fragments, in contrast to enrichment or PCR-based NGS panels, which may distort the original proportions of DNA fragments and skew the quantification [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Validation of HER2 Status in Whole Genome Sequencing Data of Breast Cancers with the Ploidy-Corrected Copy Number Approach

Wojtaszewska¹,

Stepien

Wozna

et al. 2021

Mol Diagn Ther

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Background and Objective Human epidermal growth factor receptor 2 (HER2) protein overexpression is one of the most significant biomarkers for breast cancer diagnostics, treatment prediction, and prognostics. The high accessibility of HER2 inhibitors in routine clinical practice directly translates into the diagnostic need for precise and robust marker identification. Even though multigene next-generation sequencing methodologies have slowly taken over the field of single-biomarker molecular tests, the copy number alterations such as amplification of the HER2-coding ERBB2 gene are hard to validate on next-generation sequencing platforms as they are characterized by chromosomal structural heterogeneity, polysomy, and genomic context of ploidy. In our study, we tested the approach of using whole genome sequencing instead of next-generation sequencing panels to determine HER2 status in the clinical set-up. Methods We used a large dataset of 876 patients with breast cancer whole genomes with curated clinical data and an additional set of 551 patients' external genomic data. We used the decision-tree-based algorithm for optimization of the diagnostic tool for HER2 status assessment by whole genome sequencing. ResultsThe most efficient approach to assess HER2 status in whole genome sequencing data was the ploidy-corrected copy number, utilizing ERBB2 copy number and mean tumor ploidy. The classifier achieved sensitivity of 91.18% and specificity of 98.69% on the internal validation dataset and 89.86% and 96.06% on the external data, which is similar to other nextgeneration sequencing methods, currently tested in the clinic. Conclusions We provide evidence that the HER2 status may be reliably determined by whole genome sequencing and is applicable across different laboratory protocols and pipelines. We suggest using the ploidy-corrected copy number for diagnostic purposes.

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“…Therefore, treatment guidance strategies that group patients into specific tumor subtypes may limit their treatment opportunities, and it may be difficult for patients to benefit from new developments in precision medicine. Comprehensive genomic profiling techniques such as whole‐genome sequencing, whole‐exome sequencing and large panel sequencing, could solve the issue mentioned above [ 9 , 10 ] because they can help clinicians to identify a full set of actionable genomic changes for each metastatic cancer patient. Additionally, systematic collection of a full actionable genomic alteration data set from cancer patients can be used to better understand the genomic‐related molecular mechanisms of drug resistance and monitor the treatment response.…”

mentioning

confidence: 99%

Single whole‐genome sequencing analysis of metastatic biopsy is sufficient for investigational treatment opportunities in cancer

Dong

2021

Cancer Communications

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Clinical Validation of Whole Genome Sequencing for Cancer Diagnostics

Cited by 51 publications

References 44 publications

Clinical Impact of Prospective Whole Genome Sequencing in Sarcoma Patients

Clinical Impact of Prospective Whole Genome Sequencing in Sarcoma Patients

Validation of HER2 Status in Whole Genome Sequencing Data of Breast Cancers with the Ploidy-Corrected Copy Number Approach

Single whole‐genome sequencing analysis of metastatic biopsy is sufficient for investigational treatment opportunities in cancer

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