Genomic Analysis for Hereditary Cancer

Overseen By Anna Mitchell, MD PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Case Comprehensive Cancer Center

Disqualifiers: Blood sample, Genetic counselling, High penetrance gene, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

150 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

What data supports the effectiveness of this treatment for hereditary cancer?

The use of next-generation sequencing (NGS) in clinical diagnostics has shown high accuracy and cost-effectiveness for identifying genetic mutations, such as BRCA1 and BRCA2, which are linked to hereditary cancers. Studies have demonstrated that NGS can detect genetic variants with 100% sensitivity and specificity, making it a reliable method for genomic analysis in hereditary cancer. ^{1 2 3 4 5}

Is genomic analysis for hereditary cancer safe for humans?

The procedures involved in genomic analysis, such as blood draws, saliva samples, and skin biopsies, are generally considered safe for humans. Studies have shown that DNA from saliva and buccal cells (cells from the inside of the cheek) can be effectively used for genetic testing, offering a safe alternative to blood samples. ^{3 4 6 7 8}

How does the genomic analysis treatment for hereditary cancer differ from other treatments?

This genomic analysis treatment is unique because it uses next-generation sequencing (NGS) to identify genetic mutations that increase cancer risk, allowing for personalized prevention strategies. Unlike traditional methods, it provides a comprehensive analysis of multiple genes simultaneously, improving diagnostic accuracy and revealing complex genetic variations. ^{4 5 9 10 11}

What is the purpose of this trial?

The purpose of this study is to identify novel gene mutations which have contributed to significant personal and family history of cancer. Adults with and without cancer will be accrued to the study. Participants qualify to take part in this research study because someone in their family has been diagnosed with or because they themselves have a cancer diagnosis. Participants' DNA and other clinical information will be obtained from a blood sample in order to study the genetic basis of cancer and related complications. All portions in the DNA that code for proteins (i.e., the exome) will be studied. Participant DNA sample and information about family structure and family medical history and ethnic origin may also be collected to better understand this information. Clinical information will be stored and biological samples, including DNA, will be kept for up to three (3) years after collection for future. Ultimately, once identified, the role of the specific genetics changes in the development of inherited cancer(s) will be characterized.

Research Team

Anna Mitchell, MD, PhD

Principal Investigator

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with a family history of many different types of cancer, known as discordant cancers. Eligible participants include those who meet criteria for hereditary syndrome testing or have at least five different cancers in their family across three generations. Both affected and unaffected members can join if they agree to genetic testing.

Inclusion Criteria

I am part of a control group receiving standard treatment without genetic testing.

I am an unaffected family member willing to undergo WES, with at least 2 affected and 1 other unaffected family member also participating.

My family has a history of 5 or more different cancers over three generations.

Exclusion Criteria

My family does not have a known high-risk cancer gene.

My family cannot undergo standard genetic testing.

I cannot or choose not to get genetic counseling.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Visit and DNA Collection

Participants provide blood samples for DNA extraction and initial genetic counseling is provided

1 day

1 visit (in-person)

Whole Exome Sequencing and Analysis

Whole exome sequencing is performed and monogenic variants are identified and validated

6 months

Follow-up

Participants are monitored for genetic counseling and results discussion, including any incidental findings

6 months

1 visit (in-person)

Treatment Details

Interventions

• Blood Draw
• Saliva Sample
• Skin biopsy
• WES via Illumina NextSeq 550 sequencing system

Trial Overview The study involves Whole Exome Sequencing (WES) using the Illumina NextSeq 550 system, blood draws, skin biopsies, and saliva samples to find new gene mutations linked to cancer. It will analyze DNA from participants with diverse familial cancer backgrounds.

Participant Groups

Group I: Affected participants with 5 or more discordant cancers - WES Experimental Treatment 4 Interventions

Affected individuals with a family history of 5 or more discordant cancers in unilateral descent with a 3-generation pedigree will receive SOC CLIA/CAP multicancer panel (DNA collected via blood draw or punch biopsy) to examine monogenic variant diagnostic yield. Eligible participants (families with no mutations and at least 2 affected and 1 non-affected family members) may move forward with WES. Any identified monogenic variants of interest will be sent to an industry partner with CLIA/CAP certification for validation. A 6-month follow-up visit will take place during which variants will be discussed and participants who underwent gHFI variant counting (those who were not considered a gene candidate) will have results explained. Appropriate genetic counselling, recurrence risk, and additional clinical referrals will be made as necessary

Group II: SOC genetic counseling (routine clinical care) Active Control 3 Interventions

Affected individuals (cancer) with a family history suggestive of a known hereditary syndrome or meeting NCCN criteria for germline testing will receive SOC CLIA/CAP multicancer panel in order to examine monogenic variant diagnostic yield (retrospective data) This arm would also include prospective participants from the "5 or more discordant cancers" group who DID have a variant identified and therefore did not move on to WES.

Who Is Running the Clinical Trial?

Case Comprehensive Cancer Center

Lead Sponsor

Trials

472

Recruited

33,400+

Findings from Research

In a study of 153 patients undergoing percutaneous core biopsies for a 46-gene NGS panel, the adequacy rate for genomic testing was found to be 69.9%, indicating a significant potential for using these biopsies in targeted cancer therapies.

Factors such as a higher imaging-based likelihood of adequacy score, the type of primary malignancy (with melanoma showing better results than breast cancer), and the absence of prior systemic therapy were associated with increased likelihood of obtaining adequate samples for NGS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics of percutaneous core biopsies adequate for next generation genomic sequencing. Sabir, SH., Krishnamurthy, S., Gupta, S., et al.[2021]

Touch preparations (TPs) from core needle biopsies (CNBs) can be effectively used for whole genome structural variant analysis and mutation calling, showing high consistency with results from associated CNBs and bulk resected tissues.

The novel methodology of using TPs enhances the detection of genetic variants and loss of heterozygosity, making it a valuable tool for both clinical and research genomic testing, despite challenges from sample input limitations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing clinical cytology touch preparations for next generation sequencing. Murphy, SJ., Harris, FR., Smadbeck, JB., et al.[2022]

The implementation of a broad-based next generation sequencing (NGS) assay at the University of Minnesota resulted in a steady diagnostic yield of 25% across 2509 tests conducted from 2012 to 2017, with notable variations in yield by specialty, such as 60% in dermatology.

Over time, the percentage of patient reports containing variants of uncertain significance (VUS) decreased significantly from 50% in 2012 to 22% in 2017, indicating improved clarity in genetic testing results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next generation sequencing for clinical diagnostics: Five year experience of an academic laboratory. Hartman, P., Beckman, K., Silverstein, K., et al.[2020]

Alternative tissue sources (ATS) like Guthrie/FTA card blood spots, buccal scrapes, and fingernail clippings can provide high-quality DNA, making them valuable for genetic testing, especially in populations where venipuncture is challenging.

A systematic comparison of DNA extraction methods from these ATS shows that they can yield DNA of comparable quality and utility to traditional venous blood, supporting their use in various genomic analysis applications such as population screening and diagnostics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative analytical utility of DNA derived from alternative human specimens for molecular autopsy and diagnostics. Klassen, TL., von Rüden, EL., Drabek, J., et al.[2021]

A next-generation sequencing (NGS) pipeline was clinically validated for detecting BRCA1 and BRCA2 mutations, showing 100% sensitivity and specificity in analyzing 402 retrospective and 240 prospective patients.

The NGS method effectively identified 183 unique genetic variants, demonstrating its capability to replace traditional sequencing methods while providing high-depth coverage and reproducibility for larger gene panels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Next-Generation Sequencing Pipeline Outperforms a Combined Approach Using Sanger Sequencing and Multiplex Ligation-Dependent Probe Amplification in Targeted Gene Panel Analysis. Schenkel, LC., Kerkhof, J., Stuart, A., et al.[2018]

Buccal cell DNA samples show high genotyping efficiency (99.32%) and concordance (99.29%) with blood DNA samples, making them a reliable alternative for genetic studies.

Genotyping accuracy remains high with buccal DNA concentrations above 1.7 ng/μl, but declines significantly at lower concentrations, indicating that sufficient DNA quantity is crucial for effective genetic analysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility of High-Throughput Genome-Wide Genotyping using DNA from Stored Buccal Cell Samples. Loomis, SJ., Olson, LM., Pasquale, LR., et al.[2021]

The Hi-Plex sequencing method successfully analyzed DNA from 93 Guthrie Card-derived specimens, with a remarkable 99% success rate in processing and sequencing, demonstrating its effectiveness for genetic screening.

All known variants of the PALB2 gene were detected without any false positives, indicating that this method is both reliable and accurate for identifying genetic predispositions to breast cancer from archived dried blood spots.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hi-Plex targeted sequencing is effective using DNA derived from archival dried blood spots. Nguyen-Dumont, T., Mahmoodi, M., Hammet, F., et al.[2018]

Saliva-extracted DNA can be effectively used for genotyping, showing high quality and concordance with blood-derived DNA, making it a viable alternative for clinical trials.

Using saliva for DNA collection could enhance participant recruitment and simplify logistics in multicenter studies, despite lower DNA yields compared to blood samples.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Saliva samples are a viable alternative to blood samples as a source of DNA for high throughput genotyping. Abraham, JE., Maranian, MJ., Spiteri, I., et al.[2021]

In a study of 305 individuals, 75 were found to have pathogenic or likely pathogenic variants in cancer-related genes, primarily in MUTYH, BRCA2, and CHEK2, highlighting the importance of genetic testing in identifying hereditary cancer risks.

The research identified nine novel variants in genes associated with hereditary cancer, confirming that next-generation sequencing (NGS) is a crucial tool for assessing cancer risk in families and guiding treatment and prevention strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic Characterization of Hereditary Cancer Syndromes Based on Targeted Next-Generation Sequencing. Ercoskun, P., Yuce Kahraman, C., Ozkan, G., et al.[2022]

The automated workflow for preparing NGS libraries for hereditary cancer testing achieved comparable results to the manual method, processing over 1,000 DNA samples with improved consistency and reduced variability in sequencing data.

This automation minimizes human error and streamlines the laboratory process, making it a reliable and efficient option for genetic testing in cancer risk assessment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Automated capture-based NGS workflow: one thousand patients experience in a clinical routine framework. Tenedini, E., Celestini, F., Iapicca, P., et al.[2022]

The I2HCP panel, a custom next-generation sequencing (NGS) tool covering 122 hereditary cancer genes, achieved over 99% accuracy, sensitivity, and specificity in diagnosing hereditary cancers, based on a training set of patients with colorectal, breast, ovarian cancers, and neurofibromatosis.

This new NGS strategy not only improved diagnostic sensitivity and resolved uncertain clinical diagnoses but also identified mutations in previously unrecognized genes, highlighting the complexity of genetic variations associated with hereditary cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape. Castellanos, E., Gel, B., Rosas, I., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Characteristics of percutaneous core biopsies adequate for next generation genomic sequencing. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Optimizing clinical cytology touch preparations for next generation sequencing. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Next generation sequencing for clinical diagnostics: Five year experience of an academic laboratory. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Comparative analytical utility of DNA derived from alternative human specimens for molecular autopsy and diagnostics. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Clinical Next-Generation Sequencing Pipeline Outperforms a Combined Approach Using Sanger Sequencing and Multiplex Ligation-Dependent Probe Amplification in Targeted Gene Panel Analysis. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Feasibility of High-Throughput Genome-Wide Genotyping using DNA from Stored Buccal Cell Samples. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Hi-Plex targeted sequencing is effective using DNA derived from archival dried blood spots. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Saliva samples are a viable alternative to blood samples as a source of DNA for high throughput genotyping. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Genetic Characterization of Hereditary Cancer Syndromes Based on Targeted Next-Generation Sequencing. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Automated capture-based NGS workflow: one thousand patients experience in a clinical routine framework. [2022]

11. England pubmed.ncbi.nlm.nih.gov

A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape. [2019]