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

• ClinicalTrials.gov Identifier: NCT01247597
• Recruitment Status: Recruiting
• First Posted: November 24, 2010
• Last Update Posted: April 12, 2021
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

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....

Condition or disease
Pleuropulmonary Blastoma; Cystic Nephroma; Ovarian Sertoli-Leydig Cell Tumors; Ocular Medulloepithelioma; Nasal Chondromesenchymal Hamartoma

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 Design

• Study Type: Observational
• Estimated Enrollment: 1500 participants
• Observational Model: Family-Based
• Time Perspective: Other
• Official Title: DICER1-Related Pleuropulmonary Blastoma Cancer Predisposition Syndrome: A Natural History Study
• Actual Study Start Date: February 13, 2011

Groups and Cohorts

Group/Cohort
Controls; People without pathogenic DICER1 germline variation
DICER1 (cases); People with pathogenic DICERl germline variation or history of DICER1-associated tumors

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. Management Guidelines & Risk-reduction 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.
5. 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.
6. 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.

Eligibility Criteria

• Ages Eligible for Study: up to 100 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• 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)

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.

Contacts and Locations

Contacts

Contact: Douglas R Stewart, M.D.; (240) 276-7238; drstewart@mail.nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center, 9000 Rockville Pike; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office (888) NCI-1937

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Douglas R Stewart, M.D.; National Cancer Institute (NCI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Hill DA, Ivanovich J, Priest JR, Gurnett CA, Dehner LP, Desruisseau D, Jarzembowski JA, Wikenheiser-Brokamp KA, Suarez BK, Whelan AJ, Williams G, Bracamontes D, Messinger Y, Goodfellow PJ. DICER1 mutations in familial pleuropulmonary blastoma. Science. 2009 Aug 21;325(5943):965. doi: 10.1126/science.1174334. Epub 2009 Jun 25.

Manivel JC, Priest JR, Watterson J, Steiner M, Woods WG, Wick MR, Dehner LP. Pleuropulmonary blastoma. The so-called pulmonary blastoma of childhood. Cancer. 1988 Oct 15;62(8):1516-26. Review.

Hill DA, Jarzembowski JA, Priest JR, Williams G, Schoettler P, Dehner LP. Type I pleuropulmonary blastoma: pathology and biology study of 51 cases from the international pleuropulmonary blastoma registry. Am J Surg Pathol. 2008 Feb;32(2):282-95. doi: 10.1097/PAS.0b013e3181484165. Review.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Vasta LM, Khan NE, Higgs CP, Harney LA, Carr AG, Harris AK, Schultz KAP, McMaster ML, Stewart DR. Hematologic indices in individuals with pathogenic germline DICER1 variants. Blood Adv. 2021 Jan 12;5(1):216-223. doi: 10.1182/bloodadvances.2020002651.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01247597
• Other Study ID Numbers: 110034; 11-C-0034
• First Posted: November 24, 2010
• Last Update Posted: April 12, 2021
• Last Verified: February 8, 2021

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Thyroid Cancer; Germline DICER1 Mutation; MicroRNA Biogenesis; Pleuropulmonary Blastoma; PPB

Additional relevant MeSH terms:

Hamartoma; Pulmonary Blastoma; Neuroectodermal Tumors, Primitive; Leydig Cell Tumor; Sertoli-Leydig Cell Tumor; Disease Susceptibility; Disease Attributes; Pathologic Processes; Neoplasms; Neoplasms, Complex and Mixed; Neoplasms by Histologic Type; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Sex Cord-Gonadal Stromal Tumors; Neoplasms, Gonadal Tissue; Testicular Neoplasms; Endocrine Gland Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Endocrine System Diseases; Testicular Diseases; Gonadal Disorders; Ovarian Neoplasms