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DICER1-related Pleuropulmonary Blastoma Cancer Predisposition Syndrome: A Natural History Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01247597
Recruitment Status : Recruiting
First Posted : November 24, 2010
Last Update Posted : July 2, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date November 23, 2010
First Posted Date November 24, 2010
Last Update Posted Date July 2, 2020
Actual Study Start Date February 13, 2011
Primary Completion Date Not Provided
Current Primary Outcome Measures
 (submitted: December 1, 2018)
  • Clinical Phenotype [ Time Frame: Ongoing ]
    To characterize the clinical phenotype of, and study the incident and prevalent cancer rates in, these patients and their family members, for all cancers combined, and for each type of cancer, and to identify and confirm the specific types of cancer and benign neoplasms associated with this disorder.
  • DICER1-Related Pleuropulmonary Blastoma Cancer Predisposition Syndrome [ Time Frame: Ongoing ]
    To establish a cohort of patients with PPB and/or specific neoplasms of the PPB spectrum (cystic nephroma, nasal chondromesenchymal hamartoma, ovarian Sertoli-Leydig cell and other sex cord-stromal tumors, ocular medulloepithelioma, Wilms tumor, embryonal rhabdomyosarcoma, pineoblastoma, others to be defined), in order to determine the frequency of DICER1 germline mutations in these patients and their family members. This will also allow us to identify DICER1 mutation-negative patients who will be crucial for future gene discovery efforts.
  • Genetic & Environmental Interactions [ Time Frame: Ongoing ]
    To identify differences between patients with a germline mutation in DICER1 (or another gene(s) from this pathway) who do develop cancer and those who do not develop cancer. These differences may include genotype/phenotype/cancer susceptibility differences, modifier genes (gene-gene interactions) and environmental risk factors (gene-environment interactions). The latter two may be informative for modification of cancer risk in the general population.
  • Management Guidelines & Riskreduction Strategies [ Time Frame: Ongoing ]
    To develop evidence-based management guidelines for cancer prevention and risk-reduction strategies for PPB patients and their family members prior to and after obtaining answers to the questions/objectives above.
  • Psychosocial and Behavioral Issues [ Time Frame: Ongoing ]
    To evaluate various parameters related to psychosocial and behavioral issues resulting from being a member of a family at increased risk of PPB.
  • Biospecimen Repository [ Time Frame: Ongoing ]
    To create a biospecimen repository of carefully-annotated tissue samples for use in subsequent etiologically-oriented translational research projects. These samples comprise an invaluable resource for current and future studies related to the etiology of, and outcomes following, the various neoplasms that are now known, or later found to be, part of the PPB syndrome.
Original Primary Outcome Measures Not Provided
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title DICER1-related Pleuropulmonary Blastoma Cancer Predisposition Syndrome: A Natural History Study
Official Title DICER1-Related Pleuropulmonary Blastoma Cancer Predisposition Syndrome: A Natural History Study
Brief Summary

Background:

- Pleuropulmonary blastoma (PPB) is a rare fast-growing lung tumor that is associated with other, rare tumor types. Most cases of PPB appear in children younger than 6 years of age. Recently, it has been shown that this condition can be inherited (e.g., mutation of the DICER1 gene). Researchers are studying both clinical and genetic aspects of this newly described condition. They are interested in collecting further medical history and genetic information on individuals and close relatives of individuals who have PPB or other rare associated tumors.

Objectives:

- To study individuals with a personal or a family history of pleuropulmonary blastoma (PPB) or other rare tumors that can be associated with PPB (e.g., cystic nephroma, nasal chondromesenchymal hamartoma, ovarian Sertoli-Leydig cell tumors, ocular medulloepithelioma).

Eligibility:

  • Individuals who have been diagnosed with PPB and/or PPB-related tumors.
  • Close blood relatives (e.g., parents, siblings, grandparents) of individuals who have been diagnosed with PPB and/or PPB-related tumors.

Design:

  • Interested participants can enroll or inquire about this study by calling 1-800-518-8474.
  • Participants will be asked to complete family history and medical history questionnaires. They will complete the questionnaire if they are at least 18 years of age, or another person will complete the questionnaire if the key family member is too young to do so on his or her own.
  • Participants will be asked to sign a medical record release form to allow researchers to examine detailed medical history information.
  • Participants may be asked to have a physical examination and imaging studies, provide blood and saliva samples, or provide tumor tissue from prior biopsies or cancer surgeries.
  • Annually, participants will update the family history and individual information questionnaires to document important changes in medical history, and will also update the medical record release form. Participants may be asked to provide additional cheek lining cells and/or blood samples, as well as tumor tissue from any new or planned biopsies or tumor surgeries.
  • Treatment will not be provided as part of this protocol.
Detailed Description

BACKGROUND:

In 2009, Hill and colleagues identified heterozygous germline mutations in DICER1, a gene which encodes a crucial component of the microRNA processing machinery, in patients with familial pleuropulmonary blastoma (PPB). This disorder represents the first reported cancer predisposition syndrome that is due to altered microRNA biogenesis, and its discovery presents a unique and extraordinary opportunity for CGB and DCEG to play a substantial role in the development of this new area, one which is virtually certain to have etiologic ramifications far beyond those related to PPB itself.

OBJECTIVES:

  1. To establish a cohort of patients with PPB and/or specific neoplasms of the PPB spectrum (cystic nephroma, nasal chondromesenchymal hamartoma, ovarian Sertoli-Leydig cell and other sex cord-stromal tumors, ocular medulloepithelioma, Wilms tumor, embryonal rhabdomyosarcoma, pineoblastoma, others to be defined), in order to determine the frequency of DICER1 germline mutations in these patients and their family members. This will also allow us to identify DICER1 mutation-negative patients who will be crucial for future gene discovery efforts.
  2. To characterize the clinical phenotype of, and study the incident and prevalent cancer rates in, these patients and their family members, for all cancers combined, and for each type of cancer, and to identify and confirm the specific types of cancer and benign neoplasms associated with this disorder.
  3. To identify differences between patients with a germline mutation in DICER1 (or another gene(s) from this pathway) who do develop cancer and those who do not develop cancer. These differences may include genotype/phenotype/cancer susceptibility differences, modifier genes (gene-gene interactions) and environmental risk factors (gene-environment interactions). The latter two may be informative for modification of cancer risk in the general population.
  4. To develop evidence-based management guidelines for cancer prevention and risk-reduction strategies for PPB patients and their family members prior to and after obtaining answers to the questions/objectives above.
  5. To evaluate various parameters related to psychosocial and behavioral issues resulting from being a member of a family at increased risk of PPB.
  6. To create a biospecimen repository of carefully-annotated tissue samples for use in subsequent etiologically-oriented translational research projects. These samples comprise an invaluable resource for current and future studies related to the etiology of, and outcomes following, the various neoplasms that are now known, or later found to be, part of the DICER1 syndrome.

ELIGIBILITY:

  • Individuals with PPB and their relatives of interest (parents, siblings, grandparents, other affecteds).
  • Individuals in the general population with one or more of the unique tumors reported in patients and families with PPB: cystic nephroma, ovarian Sertoli-Leydig cell tumors, ocular medulloepithelioma, and nasal chondromesenchymal hamartoma, and other associated conditions that will be identified under objective 2. Relatives of these patients will be eligible for study enrollment as well (parents, siblings, mutation carriers, other affecteds).

DESIGN:

  • Multidisciplinary natural history study with self-administered questionnaires, clinical/epidemiologic/genetic evaluations, clinical and research laboratory tests, review of medical records, cancer surveillance, and biospecimen acquisition:

    • Field Cohort: consented subjects who provide questionnaire data, biological samples, medical records, imaging results, etc., from their home communities.
    • NIH Cohort: consented subjects who do all the above, and who also travel to the NIH Clinical Center for a detailed in-person assessment and data collection.
  • Primary endpoints include all cancers, with specific attention to those currently thought to be part of the DICER 1 syndrome.
  • Secondary endpoints include non-malignant health issues.
  • Systematic analysis of the entire data set will occur on a yearly basis.
  • Ancillary studies will be performed using the data and biospecimens collected from study participants, as new collaborative opportunities and research hypotheses become available. We will do our best to articulate the specific uses that will be made of the information and materials collected as part of this project. We also recognize that both knowledge and technology are progressing at such a rapid rate that it is impossible to predict all the ways in which this material will be used in the future. The Consent Form will provide an outline of the kinds of research anticipated, and seek subject approval for our having some latitude in how these samples/data are used (with an opportunity to opt out of such uses), in order to minimize the likelihood that additional consent would need to be sought in the future, and to ensure that we are positioned, as the public stewards of this incredibly valuable resource, to take maximum advantage of its utility for advancing scientific and clinical knowledge.
Study Type Observational
Study Design Observational Model: Family-Based
Time Perspective: Other
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Non-Probability Sample
Study Population A cohort of patients with PPB and/or specific neoplasms of the PPB spectrum (cystic nephroma, nasal chondromesenchymal hamartoma, ovarian Sertoli-Leydig cell and other sex cord-stromal tumors, ocular medulloepithelioma, Wilms tumor, embryonal rhabdomyosarcoma, pineoblastoma, others to be defined)
Condition
  • Pleuropulmonary Blastoma
  • Cystic Nephroma
  • Ovarian Sertoli-Leydig Cell Tumors
  • Ocular Medulloepithelioma
  • Nasal Chondromesenchymal Hamartoma
Intervention Not Provided
Study Groups/Cohorts
  • Controls
    People without pathogenic DICERl germline variation
  • DICERl (cases)
    People with pathogenic DICERl germline variation or history of DICERl-associated tumors
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: April 1, 2014)
1500
Original Estimated Enrollment
 (submitted: November 23, 2010)
300
Study Completion Date Not Provided
Primary Completion Date Not Provided
Eligibility Criteria
  • INCLUSION CRITERIA:
  • Patients with histologically-confirmed PPB and other (DICER1-associated tumors) and their relatives of interest (parents, siblings, extended family). Individuals with a known or suspected DICER1 mutation and family controls (those without a known or suspected DICER1 mutation) are eligible. Given the rarity of this disorder, we are open to patients from all over the world, at the discretion of the PI (e.g. availability of medical records in English, ability of patient/family to communicate in English) but will follow NIH travel regulations.
  • Patients from the general population with one or more of the unique tumors of the types seen in patients/families with PPB, cystic nephroma, ovarian Sertoli-Leydig cell and other sex cord-stromal tumors, ocular medulloepithelioma, nasal chondromesenchymal hamartoma, Wilms tumor, embryonal rhabdomyosarcoma, pineoblastoma, pituitary blastoma, thyroid cancer - regardless of family history. Relatives of these patients will be eligible for the study as well (parents, siblings, extended family). As above, individuals with a known or suspected DICER1 mutation and family controls (those without a known or suspected DICER1 mutation) are eligible. Additional syndrome-associated neoplasms may be identified in the future, and they will be added to the protocol as needed.
  • There is no age restriction.
  • There is no restriction related to organ and marrow function.
  • Ability of the proband or their guardians to understand, and their willingness to sign, a written informed consent document
  • All types and amounts of prior therapies are allowed.

Pregnant Women: Pregnant women will be included in this study as several endpoints are assessed during pregnancy; counseling, education, and other minimal risk procedures (i.e. blood draw) may be done. We will postpone full clinical evaluations at the Clinical Center for pregnant women until the subject has recovered post-partum. No imaging studies will be performed on pregnant women at the Clinical Center.

Research Eligibility Evaluation: This is entirely a function of meeting the inclusion criteria and not being excluded by the exclusion criteria. In most instances, patients with histologically-confirmed PPB and/or another neoplasm within the DICER1 syndrome and their families will be referred to the Clinical Genetics Branch (CGB) by the IPPBR, provided that the family has previously or currently indicated a desire to be notified of such research opportunities. In non IPPBR-cases, the diagnosis will be confirmed by reviewing relevant medical records and relevant surgical pathology material.

Adult patients and family members who are unable to provide consent: This category includes adults who lack the capacity to consent, for whom the legal representative or appropriate surrogate may give consent. This group is included because below normal intellectual function may be observed in a small proportion of families although it has not been described in association with the DICER1 syndrome. The permission of the appropriate surrogate will be obtained per the latest NIH Policy M87-4 (rev). It would be discriminatory as well as scientifically biased to exclude this group. This protocol is designated as "more than a minimal risk with generalizable knowledge with no prospect of direct benefit," and patients who are unable to provide consent may receive the same benefit. Where appropriate we will ask the subject to sign an assent form; we will honor a verbal dissent by the subject with regard to specific studies/procedures.

EXCLUSION CRITERIA:

Individuals and families referred for evaluation in whom reported diagnoses are not verifiable.

Sex/Gender
Sexes Eligible for Study: All
Ages up to 100 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers Yes
Contacts
Contact: Douglas R Stewart, M.D. (240) 276-7238 drstewart@mail.nih.gov
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT01247597
Other Study ID Numbers 110034
11-C-0034
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor National Cancer Institute (NCI)
Collaborators Not Provided
Investigators
Principal Investigator: Douglas R Stewart, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date December 3, 2019