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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to uncover new gene mutations linked to hereditary cancer. Researchers collect DNA from participants through blood or saliva to explore how genetics might cause cancer in families. The study focuses on families with at least five different types of cancer over three generations. Participants should either have cancer themselves or have a close family member with cancer.

As an unphased study, this trial offers participants the chance to contribute to groundbreaking research that could lead to better understanding and prevention of hereditary cancer.

Will I have to stop taking my current medications?

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

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that whole exome sequencing (WES), like the kind used in this study, is a well-known method for exploring genetic information. It examines the parts of DNA crucial for protein production. This technique helps identify genetic changes that might cause diseases, including cancer.

The sequencing itself poses no direct safety concern for participants, as it involves analyzing DNA samples outside the body. The process includes taking a blood sample, a saliva sample, or a small skin sample. These are common medical procedures with minimal risk. For example, a blood draw might cause slight pain or bruising at the needle site, but these effects usually don't last long.

The WES method used in this study, conducted with the Illumina NextSeq 550 system, is known for its accuracy in reading DNA sequences. This ensures reliable results, which are important for understanding genetic risks related to cancer. Overall, the procedures involved in this trial are considered safe and are standard practice for genetic research. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores a new way to understand hereditary cancer through genomic analysis. Unlike traditional methods that may only look at specific genes, this trial uses Whole Exome Sequencing (WES) to examine all the protein-coding regions of a person's DNA, allowing for a more comprehensive search for genetic variants linked to cancer. By analyzing blood, saliva, and skin samples, the trial aims to identify hereditary cancer risks that might be overlooked with standard genetic testing. This approach could lead to earlier and more accurate diagnoses, better personalized treatment plans, and improved counseling for families with a history of cancer.

What evidence suggests that this trial's methods could be effective for identifying hereditary cancer gene mutations?

Research has shown that Whole Exome Sequencing (WES) is a powerful tool for identifying genetic changes linked to inherited cancers. In this trial, participants with a family history of five or more discordant cancers may undergo WES to examine monogenic variant diagnostic yield. WES focuses on the parts of DNA that produce proteins, which often contain changes leading to cancer. Studies have found that WES can discover new gene mutations related to cancer in families with a history of the disease. This method helps identify specific genetic changes that might explain why some families have a higher cancer risk. By identifying these mutations, families can better understand their cancer risk and take steps to manage it. Overall, WES provides valuable insights into the genetic causes of cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Anna Mitchell, MD, PhD

Principal Investigator

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: SOC genetic counseling (routine clinical care) Experimental Treatment 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.

Group II: 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

Who Is Running the Clinical Trial?

Case Comprehensive Cancer Center

Lead Sponsor

Trials

472

Recruited

33,400+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11137314/

Assessing the impact of sequencing platforms and ... WES is becoming a rapid, cost-effective molecular diagnostic tool for patients with genetic diseases (Gahl et al., 2012; Gilissen et al., 2012; ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2352396425002038

The role of multi-organ cancer predisposition genes in ... We aimed to estimate the frequency of known cancer predisposition gene variants in GC cases with and without a cancer family history, diverse histological ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26427841/

Identification of novel hereditary cancer genes by whole ... Several dozens of WES studies involving patients with hereditary cancer syndromes have already been reported.

4. illumina.com illumina.com/areas-of-interest/cancer/research/sequencing-methods/cancer-exome-seq.html

Cancer Exome Sequencing | Insight into coding mutations Cancer exome sequencing allows researchers to assess only coding regions, which frequently contain mutations that affect tumor progression.

5. nature.com nature.com/articles/s41598-024-79872-4

Diagnostic efficacy and clinical utility of whole-exome ... When using WES, copy number variations (CNVs) can be identified by analyzing read depth and coverage across exon regions. However, the accuracy ...

6. illumina.com illumina.com/systems/sequencing-platforms/nextseq.html

NextSeq 550 System | Sequencing for everyday genomics From gene expression profiling to small whole-genome sequencing, the NextSeq 550 System provides reliable, accessible insights with integrated sequencing and ...

7. illumina.com illumina.com/systems/sequencing-platforms/nextseq/specifications.html

NextSeq 550 Sequencing System specifications The NextSeq 550 System harnesses proven Illumina sequencing by synthesis (SBS) technology to deliver highly accurate data and robust performance for multiple ...

8. illumina.com illumina.com/techniques/sequencing/dna-sequencing/targeted-resequencing/exome-sequencing.html

Whole Exome Sequencing | Detect exonic variants Whole-exome sequencing is used to investigate protein-coding regions of the genome to uncover genetic influences on disease and population health.

9. illumina.com illumina.com/areas-of-interest/cancer/clinical-cancer-research/germline-mutations.html

Identifying germline mutations associated with cancer risk ... Whole-genome sequencing provides a comprehensive picture of germline mutations across the entire cancer genome. Targeted sequencing studies use hereditary ...

10. sg.idtdna.com sg.idtdna.com/pages/products/next-generation-sequencing/methods/whole-exome-sequencing

Whole Exome Sequencing | IDT Explore how we can support your whole exome sequencing workflows with offerings from library preparation, hybridization capture, and analysis.