Genomic Analysis of Families With a History of Discordant Cancers
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 150
- 试验地点
- 1
- 主要终点
- Number of participants with a family history of 5 or more discordant cancers that have monogenic germline variants identifiable with WES sequencing
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Observational
- 观察模型
- Other
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
结局指标
主要结局
Number of participants with a family history of 5 or more discordant cancers that have monogenic germline variants identifiable with WES sequencing
时间窗: 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
时间窗: 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
时间窗: 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"
次要结局
未报告次要终点