Discordant CancersNCT04860453
Genomic Analysis of Families With a History of Discordant Cancers
An observational study of Discordant Cancers, run by Case Comprehensive Cancer Center at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Discordant Cancers
- What is being tested?
- WES via Illumina NextSeq 550 sequencing system, Blood Draw and Skin biopsy
- How many people
- 150 participants
- Where
- 1 siteUnited States
- Study dates
- 17 Nov 2020to 1 Jul 2028
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: 1. Family history suggestive of a known hereditary cancer syndrome 2. 5 or more relatives with discordant cancer diagnoses
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
Cleveland, Ohio, 44106
Anna Mitchell, MD, PhD, 800-641-2422, CTUReferral@UHhospitals.org
Anna Mitchell, MD, PhD
About this study
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.
Read the detailed description
Data for this study will be obtained via both retrospectively and prospectively. Affected individuals (who have cancer) with a family history suggestive of a known hereditary syndrome or meeting National Comprehensive Cancer Network (NCCN) criteria will be accrued from routine clinical care to form a "real world" baseline of diagnostic yield using a multicancer panel. These participants will not be additionally consented for WES as part the clinical study.
Other affected individuals identified as having five or more relatives with discordant cancers will receive standard of care (SOC) multicancer panel. Families without any mutations identified (with at least a minimum of 2 members with cancer, 1 without) will be considered for additional sequencing as part of this study's primary objective of describing novel inherited cancer syndromes.
If the individual being evaluated in cancer genetics clinic (i.e. index patient) consents and their family members express interest in the study, they will move on to study visit 1. During this visit, pedigree information and medical histories will be explained, consent verified, and individual genetic counselling provided. Individuals will decide whether or not to be notified that incidental findings exist in their genomes.
Lab requisition will be done to facilitate blood draws and DNA extraction/storage and WES analysis will be completed. Any identified monogenic variants of interest will be sent to an industry partner with Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) certification for validation.
Study visit 2 to be completed within the next 6 months, at which any identified monogenetic variants of interest will be discussed with the participant. Those undergoing Germline High Functional Impact (gHFI) variant counting will be notified if they have more or less than the general population. Appropriate genetic counselling, recurrence risk, and additional clinical referrals will be made as necessary. Participants will be notified with a binary yes/no of any American College of Medical Genetics incidental findings and a routine clinical genetics follow-up appointment will be made
The primary objective of the study is to identify novel gene variants associated with generalized cancer susceptibility that is manifesting as a personal history of multiple primary tumors or a family history of discordant cancers. This will be done through exploratory, research grade (ie NOT CLIA/CAP certified) whole exome sequencing (WES) studies provided to patients/families with family histories of discordant cancers as an adjunct to SOC clinical genetics evaluation in order to clinically describe novel syndromic manifestations of cancer susceptibility. Suspected germline variants supporting a generalized cancer susceptibility will be further validated in a CLIA/CAP certified laboratory prior to being reported out to the patient's medical chart
- Conditions
- Discordant Cancers
- Being tested
- WES via Illumina NextSeq 550 sequencing system, Blood Draw, Skin biopsy, Saliva Sample
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
WES via Illumina NextSeq 550 sequencing systemGenetic
Sequencing will be performed on an Illumina sequencing system
Blood DrawDiagnostic 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
Skin biopsyDiagnostic 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
Saliva SampleDiagnostic test
Participant will provide a saliva sample which be shipped to University Hospitals Laborator site at room temperature
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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. Receives: Diagnostic Test: Blood Draw; Diagnostic Test: Skin biopsy; Diagnostic Test: Saliva Sample |
What is being measured
The primary outcome is the main question the study is designed to answer.
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"
Measured: 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
Measured: 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"
Measured: At baseline for an average of 1.5 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Apr 2021
- Study start17 Nov 2020
- Primary completion1 Jul 2028 (estimated)
- Study completion1 Jul 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Discordant CancersStudies of the same condition, open and under way.
- More trials run by Case Comprehensive Cancer CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Prospective
- Enrolment
- 150 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Case Comprehensive Cancer Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Anna Mitchell, MD PhD, Principal investigator, University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04860453
- Sponsor's protocol ID
- CASE13Z20
- Status last verified
- Aug 2025
- First submitted
- 22 Apr 2021
- Last updated
- 3 Sep 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Due to privacy concerns of family history and genetic information of data collected, individual participant data (IPD) will not be shared
Study at a glance
From the registry record, last updated by the sponsor on 3 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Genomic Analysis of Families With a History of Discordant Cancers
- ClinicalTrials.gov ID
- NCT04860453
- Acronym / sponsor ID
- CASE13Z20
- Conditions
- Discordant Cancers
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 150 participants (estimated)
- Lead sponsor
- Case Comprehensive Cancer CenterUniversity, hospital or other
- Study start
- 17 Nov 2020 (actual)
- Primary completion
- 1 Jul 2028 (estimated)
- Study completion
- 1 Jul 2028 (estimated)
- First posted
- 27 Apr 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Data for this study will be obtained via both retrospectively and prospectively. Affected individuals (who have cancer) with a family history suggestive of a known hereditary syndrome or meeting National Comprehensive Cancer Network (NCCN) criteria will be accrued from routine clinical care to form a "real world" baseline of diagnostic yield using a multicancer panel. These participants will not be additionally consented for WES as part the clinical study.
Other affected individuals identified as having five or more relatives with discordant cancers will receive standard of care (SOC) multicancer panel. Families without any mutations identified (with at least a minimum of 2 members with cancer, 1 without) will be considered for additional sequencing as part of this study's primary objective of describing novel inherited cancer syndromes.
If the individual being evaluated in cancer genetics clinic (i.e. index patient) consents and their family members express interest in the study, they will move on to study visit 1. During this visit, pedigree information and medical histories will be explained, consent verified, and individual genetic counselling provided. Individuals will decide whether or not to be notified that incidental findings exist in their genomes.
Lab requisition will be done to facilitate blood draws and DNA extraction/storage and WES analysis will be completed. Any identified monogenic variants of interest will be sent to an industry partner with Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) certification for validation.
Study visit 2 to be completed within the next 6 months, at which any identified monogenetic variants of interest will be discussed with the participant. Those undergoing Germline High Functional Impact (gHFI) variant counting will be notified if they have more or less than the general population. Appropriate genetic counselling, recurrence risk, and additional clinical referrals will be made as necessary. Participants will be notified with a binary yes/no of any American College of Medical Genetics incidental findings and a routine clinical genetics follow-up appointment will be made
The primary objective of the study is to identify novel gene variants associated with generalized cancer susceptibility that is manifesting as a personal history of multiple primary tumors or a family history of discordant cancers. This will be done through exploratory, research grade (ie NOT CLIA/CAP certified) whole exome sequencing (WES) studies provided to patients/families with family histories of discordant cancers as an adjunct to SOC clinical genetics evaluation in order to clinically describe novel syndromic manifestations of cancer susceptibility. Suspected germline variants supporting a generalized cancer susceptibility will be further validated in a CLIA/CAP certified laboratory prior to being reported out to the patient's medical chart
Study design
- Observational model
- Other
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Affected participants with 5 or more discordant cancers - WES | – | Genetic: WES via Illumina NextSeq 550 sequencing system, Diagnostic Test: Blood Draw, Diagnostic Test: Skin biopsy, Diagnostic Test: Saliva SampleAffected 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 |
| SOC genetic counseling (routine clinical care) | – | Diagnostic Test: Blood Draw, Diagnostic Test: Skin biopsy, Diagnostic Test: Saliva SampleAffected 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 may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- 1. Family history suggestive of a known hereditary cancer syndrome 2. 5 or more relatives with discordant cancer diagnoses
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (4 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| WES via Illumina NextSeq 550 sequencing systemSequencing will be performed on an Illumina sequencing system | Genetic | Affected participants with 5 or more discordant cancers - WES |
| Blood DrawBlood draw will be via any University Hospitals Laboratory site and sent at room temperature via courier to the Center for Human Genetics (CHG) Laboratory | Diagnostic test | Affected participants with 5 or more discordant cancers - WES, SOC genetic counseling (routine clinical care) |
| Skin biopsySkin 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 | Diagnostic test | Affected participants with 5 or more discordant cancers - WES, SOC genetic counseling (routine clinical care) |
| Saliva SampleParticipant will provide a saliva sample which be shipped to University Hospitals Laborator site at room temperature | Diagnostic test | Affected participants with 5 or more discordant cancers - WES, SOC genetic counseling (routine clinical care) |
Primary outcome
Number of participants with a family history of 5 or more discordant cancers that have monogenic germline variants identifiable with WES sequencing
Time frame: At baseline for an average of 1.5 hours
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"
Number of gHFI variants
Time frame: At baseline for an average of 1.5 hours
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
Diagnostic yield for monogenic germline variants in two arms
Time frame: At baseline for an average of 1.5 hours
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"
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Sep 2025.
- Individual participant dataSharing planned: No. Due to privacy concerns of family history and genetic information of data collected, individual participant data (IPD) will not be shared
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Anna Mitchell, MD PhD principal investigator
University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Discordant Cancers, run by Case Comprehensive Cancer Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 3 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Anna Mitchell, MD PhD (1-800-641-2422, CTUReferral@UHhospitals.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of participants with a family history of 5 or more discordant cancers that have monogenic germline variants identifiable with WES sequencing (time frame: At baseline for an average of 1.5 hours). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Sep 2025.