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.
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 Type
OBSERVATIONAL
Enrollment
150
Sequencing will be performed on an Illumina sequencing system
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 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
Participant will provide a saliva sample which be shipped to University Hospitals Laborator site at room temperature
University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
Cleveland, Ohio, United States
RECRUITINGNumber 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"
Time frame: 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
Time frame: 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"
Time frame: At baseline for an average of 1.5 hours
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