Germline Analysis from Tumor–Germline Sequencing Dyads to Identify Clinically Actionable Secondary Findings

Seifert, Bryce A.; O’Daniel, Julianne; Amin, Krunal; Marchuk, Daniel S.; Patel, Nirali M.; Parker, Joel S.; Hoyle, Alan P.; Mose, Lisle E.; Marron, Andrew; Hayward, Michele C.; Bizon, C.; Wilhelmsen, Kirk C.; Evans, James P.; Earp, H. Shelton; Sharpless, Norman E.; Hayes, D. Neil; Berg, Jonathan S.

doi:10.1158/1078-0432.ccr-16-0015

Cited by 85 publications

(66 citation statements)

References 43 publications

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“…This resulted in "false somatic" calls reported as tier 3 or higher in 4 of 91 (4.4%) of patient samples. This finding is in keeping with the rate of significant occult germline variants found in cancer patients undergoing paired tumor-normal sequencing at other institutions (45).…”

Section: Discussionsupporting

confidence: 87%

Institutional implementation of clinical tumor profiling on an unselected cancer population

Sholl¹,

Khanh²,

Shivdasani³

et al. 2016

JCI Insight

362

314

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BACKGROUND.Comprehensive genomic profiling of a patient's cancer can be used to diagnose, monitor, and recommend treatment. Clinical implementation of tumor profiling in an enterprisewide, unselected cancer patient population has yet to be reported. METHODS.We deployed a hybrid-capture and massively parallel sequencing assay (OncoPanel) for all adult and pediatric patients at our combined cancer centers. Results were categorized by pathologists based on actionability. We report the results for the first 3,727 patients tested.RESULTS. Our cohort consists of cancer patients unrestricted by disease site or stage. Across all consented patients, half had sufficient and available (>20% tumor) material for profiling; once specimens were received in the laboratory for pathology review, 73% were scored as adequate for genomic testing. When sufficient DNA was obtained, OncoPanel yielded a result in 96% of cases. 73% of patients harbored an actionable or informative alteration; only 19% of these represented a current standard of care for therapeutic stratification. The findings recapitulate those of previous studies of common cancers but also identify alterations, including in AXL and EGFR, associated with response to targeted therapies. In rare cancers, potentially actionable alterations suggest the utility of a "cancer-agnostic" approach in genomic profiling. Retrospective analyses uncovered contextual genomic features that may inform therapeutic response and examples where diagnoses revised by genomic profiling markedly changed clinical management. CONCLUSIONS.Broad sequencing-based testing deployed across an unselected cancer cohort is feasible. Genomic results may alter management in diverse scenarios; however, additional barriers must be overcome to enable precision cancer medicine on a large scale.

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Section: Discussionsupporting

confidence: 87%

Institutional implementation of clinical tumor profiling on an unselected cancer population

Sholl¹,

Khanh²,

Shivdasani³

et al. 2016

JCI Insight

362

314

View full text Add to dashboard Cite

show abstract

“…To address this question, multiple groups have performed retrospective studies of patients undergoing tumor-normal sequencing. In adult patients, the range of individuals with cancer who harbor an actionable pathogenic germline variant ranged from 3% to 12.6% depending on the population and genes studied [1][2][3][4]. In the pediatric population, pathogenic germline variants have been identified in the context of tumor-normal sequencing in 8.5-10% of children and adolescents with cancer [5][6][7].…”

mentioning

confidence: 99%

The emerging significance of secondary germline testing in cancer genomics

Mandelker

Zhang

2018

The Journal of Pathology

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Many clinical laboratories now sequence the tumors from advanced cancer patients to identify oncogenic drivers and guide targeted therapies and clinical trials. One limitation of tumor sequencing is that it cannot distinguish between tumor-specific somatic (acquired) mutations and patients' germline (constitutional) variants. To definitively identify somatic variants, some clinical labs sequence both a normal sample from a patient and their tumor to subtract the germline variants from the somatic variants. Having a paired normal sample also allows for the identification of secondary germline mutations in cancer patients who may not meet the current clinical guidelines for genetic testing of cancer predisposition syndromes. Such simultaneous detection of somatic alterations and germline mutations during tumor-normal sequencing can guide therapeutic decision making for cancer patients and the identification and screening of at-risk family members. Here, we review the clinical workflow, advantages and disadvantages, and clinical utility of tumor-normal sequencing in the management of cancer patients. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…A study of targeted exome analysis of 202 genes, which included 18 actionable genes listed by ACMG and PALB2 , detected likely pathogenic variants in 43 of 1000 patients enrolled in the study . Another survey tumor‐germline paired sequencing identified germline variants suspected for hereditary tumor predisposition in 19 of 439 (4.3%) cancer patients . Recently, a study reported that 182 (17.5%) of 1040 patients with advanced cancer carried clinically actionable inherited mutations detected by tumor‐normal pair sequencing, and that 97, 52, and 33 of the 182 were identified in high‐, moderate‐, and low‐penetrance genes, respectively …”

Section: Incidental/secondary Findings In Ngs Panel Tests For Somaticmentioning

confidence: 99%

Implementation of genomic medicine for gastrointestinal tumors

Furukawa

2018

Annals of Gastroent Surgery

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Genomic medicine is an approach to take advantage of genomic data in medical practice and health care. The advancement of sequencing technologies has enabled the determination of individual genomes as well as the genome in neoplasms. In the field of human cancer, understanding genomic alterations in tumors and variations associated with drug responses has paved the way towards the development of new drugs and personalized medicine. International collaborations of cancer genome analyses have accumulated a huge body of information about somatic mutations, and identified new driver mutations and pathways in a wide range of cancers. In particular, a growing body of evidence has shown that information about mutations in neoplasms helps to assess the efficacy and resistance of anti‐cancer drugs. Information about germline mutations associated with hereditary cancer has been shown to benefit patients by enabling early detection of their tumors and disease‐specific treatment, as well as reducing the risk for those at risk. To promote personalized medicine in a more cost‐effective and personalized way, further inter‐institutional, nationwide, and international collaboration is needed. This article summarizes the background and current situation of genomic medicine in the field of gastrointestinal tumors to help physicians and medical coworkers by assisting their better understanding of genomic medicine and strengthening their confidence of its clinical use.

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Germline Analysis from Tumor–Germline Sequencing Dyads to Identify Clinically Actionable Secondary Findings

Cited by 85 publications

References 43 publications

Institutional implementation of clinical tumor profiling on an unselected cancer population

Institutional implementation of clinical tumor profiling on an unselected cancer population

The emerging significance of secondary germline testing in cancer genomics

Implementation of genomic medicine for gastrointestinal tumors

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