Genomic Analysis of Families With a History of Discordant Cancers

NCT04860453 | Recruiting

• 1 other identifier: CASE13Z20
• Study Type: observational
• Target: 150
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Discordant Cancers

Outcome Measures

Primary Outcomes (3)

• Number of participants with a family history of 5 or more discordant cancers that have monogenic germline variants identifiable with WES sequencing

  Number of participants with a family history of 5 or more discordant cancers that have monogenic germline variants identifiable with WES sequencing The diagnostic yield of monogenic germline variants will be calculated as the discovery rate for a monogenic pathogenic variant within each category (ie 10 pathogenic variants / 30 families = 33% yield rate). A 2-way ANOVA will be performed, with the null hypothesis being that "family history supportive of a known syndrome versus discordant cancers does not significantly affect diagnostic yield"

  At baseline for an average of 1.5 hours

• Number of gHFI variants

  Number of gHFI variants in participants with a family history of 5 or more discordant and no identified monogenic pathogenic germline variants on WES compared to population averages Number of gHFI variants in family members within such kindreds and no cancer diagnoses will compared to those with cancer diagnoses

  At baseline for an average of 1.5 hours

• Diagnostic yield for monogenic germline variants in two arms

  Diagnostic yield for monogenic germline variants in arm I (routine real-world clinical practice) vs arm II (5 or more relatives with discordant cancer diagnoses) using multicancer panels The diagnostic yield of monogenic germline variants will be calculated as the discovery rate for a monogenic pathogenic variant within each category (ie 10 pathogenic variants / 30 families = 33% yield rate). A 2-way ANOVA will be performed, with the null hypothesis being that "family history supportive of a known syndrome versus discordant cancers does not significantly affect diagnostic yield"

  At baseline for an average of 1.5 hours

Study Arms (2)

Affected participants with 5 or more discordant cancers - WES

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

Genetic: WES via Illumina NextSeq 550 sequencing system; Diagnostic Test: Blood Draw; Diagnostic Test: Skin biopsy; Diagnostic Test: Saliva Sample

SOC genetic counseling (routine clinical care)

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.

Diagnostic Test: Blood Draw; Diagnostic Test: Skin biopsy; Diagnostic Test: Saliva Sample

Interventions

WES via Illumina NextSeq 550 sequencing system GENETIC

Sequencing will be performed on an Illumina sequencing system

Affected participants with 5 or more discordant cancers - WES

Blood Draw DIAGNOSTIC_TEST

Blood draw will be via any University Hospitals Laboratory site and sent at room temperature via courier to the Center for Human Genetics (CHG) Laboratory

Affected participants with 5 or more discordant cancers - WES; SOC genetic counseling (routine clinical care)

Skin biopsy DIAGNOSTIC_TEST

Skin samples obtained via 3mm punch biopsy will be suspended in cell culture media prepared per CHG routine and sent via courier to the Center for Human Genetics Laboratory

Affected participants with 5 or more discordant cancers - WES; SOC genetic counseling (routine clinical care)

Saliva Sample DIAGNOSTIC_TEST

Participant will provide a saliva sample which be shipped to University Hospitals Laborator site at room temperature

Affected participants with 5 or more discordant cancers - WES; SOC genetic counseling (routine clinical care)

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

1. Family history suggestive of a known hereditary cancer syndrome 2. 5 or more relatives with discordant cancer diagnoses

You may qualify if:

• Affected patient with a family history suggestive of a known hereditary syndrome or meeting NCCN criteria for germline testing and consent to a multicancer panel
• This cohort is meant as a real world control group receiving routine standard of care and is not eligible for WES.
• Affected patient with a family history of 5 or more discordant cancers in unilateral descent within a 3-generation pedigree.
• Unaffected family members within such kindreds will be eligible for WES as long as a minimum of 2 affected and 1 unaffected family members consent to WES as trial participants.

You may not qualify if:

• Unable to safely provide a blood sample for genetic testing
• Unable to receive or decline to receive genetic counselling through the telephone, video conference, or in person
• Families known to segregate a previously identified high penetrance cancer susceptibility gene identified through routine medical genetics evaluation are not eligible WES
• Family is not amenable to routine medical genetics SOC genetics evaluation.

Sponsors & Collaborators

• Case Comprehensive Cancer Center: lead

Study Sites (1)

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Cleveland, Ohio, 44106, United States

RECRUITING

MeSH Terms

Interventions

Blood Specimen Collection

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Anna Mitchell, MD PhD

  University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anna Mitchell, MD PhD

CONTACT

1-800-641-2422; CTUReferral@UHhospitals.org

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 22, 2021
• First Posted: April 27, 2021
• Study Start: November 17, 2020
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2028
• Last Updated: September 3, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)