Patient case: 39-year-old female with melanoma; genetic feature: KIT (N822Y)

Clinical trial: Familial Investigations of Childhood Cancer Predisposition

Summary: While it is well recognized that hereditary factors contribute to the development of a subset of human cancers, the cause for many cancers remains unknown. The application of next generation sequencing (NGS) technologies has expanded knowledge in the field of hereditary cancer predisposition. Currently, more than 100 cancer predisposing genes have been identified, and it is now estimated that approximately 10% of all cancer patients have an underlying genetic predisposition.
  The purpose of this protocol is to identify novel cancer predisposing genes and/or genetic variants. For this study, the investigators will establish a Data Registry linked to a Repository of biological samples. Health information, blood samples and occasionally leftover tumor samples will be collected from individuals with familial cancer. The investigators will use NGS approaches to find changes in genes that may be important in the development of familial cancer. The information gained from this study may provide new and better ways to diagnose and care for people with hereditary cancer.
  PRIMARY OBJECTIVE:
  -  Establish a registry of families with clustering of cancer in which clinical data are linked to a repository of cryopreserved blood cells, germline DNA, and tumor tissues from the proband and other family members.
  SECONDARY OBJECTIVE:
  -  Identify novel cancer predisposing genes and/or genetic variants in families with clustering of cancer for which the underlying genetic basis is unknown.

Detailed description: During the study, blood samples will be obtained from participants, as well as medical and family histories. When possible, leftover tumor samples will also be collected. If participants agree to be re-contacted in the future, they will be asked about once each year to update their health information and family history.
  A blood sample will be drawn at St. Jude or at a convenient place of the participant's choice. Blood will be stored in the St. Jude Biorepository. The DNA of the samples will be studied to determine if there are changes in specific genes that might explain the cancers in the participant or their family members. When available, and if consent is given by the participant, previously collected and stored leftover tumor samples, bone marrow samples or stored DNA may be analyzed.
  Genetic variants of interest include: 1) mutations in known genes that may have escaped detection through prior clinical genetic testing; 2) coding mutations predicted to disrupt protein function, particularly in genes and pathways known to be associated with cancer; 3) potential mutations in regulatory regions of the genome, as predicted by epigenetic studies. In some cases, individuals with known predisposing mutations exhibit milder, more severe or atypical phenotypes. Family members who harbor a predisposing mutation but are discordant for a cancer phenotype will be selected for cellular and genetic studies. These will include DNA sequencing and possibly also creation and analysis of induce pluripotent stem cells (iPSC), transcriptome or epigenetic analysis.
  All samples will be identified by a code after removal of all personal identifiable information. Samples will remain in the repository for current and future study.

Eligibility: DEFINITION OF FAMILIAR CANCER FOR THIS PROTOCOL:
  In this protocol, the definition of "Familial Cancer" is met if any of the following is present:
  -  A proband (the individual serving as the starting point for the genetic study of a family in question) and at least one first, second or third degree relative, each with a history of neoplasmº diagnosed under 50 years of age; OR
  -  A proband under 50 years of age with multiple primary neoplasmsº (i.e., cancers occurring in paired organs such as bilateral renal cancers, or acute lymphocytic leukemia (ALL) followed by early onset breast cancer); OR
  -  A proband with a clinical or molecular diagnosis of a known cancer predisposition syndrome.
  º Excluding human papilloma virus-associated cervical cancer and nonmelanoma skin cancer occurring in adults.
  INCLUSION CRITERIA:
  -  An individual (proband) who meets the definition of "Familial Cancer", as above.
  -  Relatives of the identified proband, either affected or unaffected by cancer.
  EXCLUSION CRITERIA:
  -  An inability or unwillingness of the research participant or his/her legally authorized representative (LAR) to provide written informed consent.
  -  The participant has received allogeneic bone marrow transplantation and has NO pre-transplant germline (cancer-unaffected) DNA stored in a biorepository.

Relevance to patient case: not relevant