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DICER1-related Pleuropulmonary Blastoma Cancer Predisposition Syndrome

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Cyclophosphamide

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Liposomal doxorubicin

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Ifosfamide

Dactinomycin

Isophosphamide mustard

Type I PPB is an early manifestation of this malignant disease, cured in some cases by surgery. Surgical guidelines are presented. It is unknown whether adjuvant chemotherapy improves cure rates for individuals with Type I PPB. If the treating physicians select adjuvant chemotherapy treatment, chemotherapy options include a 22-week regimen: 4 courses of vincristine, actinomycin D and cyclophosphamide (VAC) followed by 3 courses of vincristine and actinomycin D (VA). Therapy decisions are the responsibility of the treating institution.

Types II and III PPB are aggressive sarcomas. Surgery and chemotherapy are necessary in all cases. Surgical guidelines are presented. Many children with Types II or III PPB receive a single-arm multi-agent chemotherapy neo-adjuvant/adjuvant regimen of IVADo (ifosfamide, vincristine, actinomycin, doxorubicin) for 36 weeks. Second and possible 3rd look surgery may be considered for local control. Radiation therapy may be considered. Specific therapy decisions are the responsibility of the treating institution.

Type Ir (regressed) PPB is a unique, purely cystic tumor which lacks a primitive cell component. The International PPB/DICER1 Registry will enroll and follow participants with Type Ir PPB, regardless of age.

PPB and the associated conditions found in PPB families suggest a familial tendency to formation of tumors. The International PPB/DICER1 Registry for PPB, DICER1 and Associated Conditions study will enroll and follow participants who have the DICER1 gene mutations or conditions associated with PPB or DICER1.

Kris Ann P Schultz, MD

Paige HR Mallinger, MS

Anne K Harris, MPH

Pleuropulmonary blastoma (PPB) is a rare malignant neoplasm of the lung presenting in early childhood. Type I PPB is a purely cystic lesion, Type II is a partially cystic, partially solid tumor, Type III is a completely solid tumor. Treatment of children with PPB is at the discretion of the treating institution. This study builds off of the 2009 study and will also seek to enroll individuals with DICER1-associated conditions, some of whom may present only with the DICER1 gene mutation, which will help the Registry understand how these tumors and conditions develop, their clinical course and the most effective treatments.

PPB is a rare cancer of the lung presenting in early childhood, mostly commonly from birth to age \~72 months. PPB occurs within the lung or between the lung and the chest wall. There are three primary forms of PPB called Types I, II, and III PPB. PPB is related to an underlying change/mutation in a gene called DICER1 which impacts gene expression and cell growth. DICER1 mutations may also lead to the development of other tumors in children and adults.

The International PPB/DICER1 Registry offers information based on previous data from Registry participants and the medical literature and collaborative efforts with international rare tumor groups.

Retrospective and real-time central pathology review is encouraged. Therapy decisions remain at the discretion of the treating institution.

Children with Type I PPB require surgery and sometimes chemotherapy. Therapy decisions are the responsibility of the treating institution. Surgical guidelines are presented. It is unknown whether adjuvant chemotherapy improves cure rates for Type I PPB patients. Chemotherapy options include a 22-week regimen: 4 courses of vincristine, actinomycin D and cyclophosphamide (VAC) followed by 3 courses of vincristine and actinomycin D (VA).

Children with Types II and III PPB, require surgery, chemotherapy and sometimes radiation therapy. Many children with Types II or III PPB receive a single-arm multi-agent chemotherapy neo-adjuvant/adjuvant regimen of IVADo (ifosfamide, vincristine, actinomycin, doxorubicin) for 36 weeks. Second and possible 3rd look surgery may be considered for local control. Radiation therapy may be considered.

Tumor tissue, blood, urine, and cerebral spinal fluid (the latter only if a lumbar puncture is performed for clinical purposes) collected from enrolled individuals.

International PPB/DICER1 Registry

International Pleuropulmonary Blastoma/DICER1 Registry (for PPB, DICER1 and Associated Conditions)

The primary endpoint for statistical analysis will be time from start treatment to an event, defined as the occurrence of progression or recurrence of PPB, occurrence of a second malignant neoplasm, or death from any cause that is at least possibly related to the original disease or treatment.

The investigators will assess overall response to chemotherapy among participants with radiographically measurable tumor following initial surgery or biopsy.

The investigators will assess overall survival and time to death from any cause among participants.

Chemotherapy and surgery may have adverse effects on the quality of life outcomes. Multiple factors may impact quality of life for participants.This study will allow the investigators to assess the quality of life outcomes in participants with DICER1-related tumors and will compare outcomes to those with more common childhood cancers.

Chemotherapy and surgery may have adverse effects on cardiac outcomes. This study will allow the investigators to assess the cardiac outcomes as measured by ejection fraction and shortening fraction via echocardiogram of participants with DICER1-related tumors, and compare outcomes to those with more common childhood cancers.

Chemotherapy and surgery may have adverse effects on pulmonary outcomes. This study will allow the investigators to assess the pulmonary outcome of participants as ascertained by pulmonary function testing (forced vital capacity (FVC), FEV1(forced expiratory volume in 1 second)/FVC) with DICER1-related tumors, and compare outcomes to those with more common childhood cancers.

This protocol will include individuals with germline DICER1 mutations and will calculate incidence rates of specific neoplasms in this population

Washington University School of Medicine

ResourcePath, LLC

Beijing Children's Hospital

University of Cambridge

Emory University

Dana-Farber Cancer Institute

Phoenix Children's Hospital

Allina Health System

University of California, San Francisco

M.D. Anderson Cancer Center

University of Texas

Kaiser Permanente

UC Davis Children's Hospital

KK Women's and Children's Hospital

Louisiana State University Health Sciences Center Shreveport

Children's Healthcare of Atlanta

Dayton Children's Hospital

Akron Children's Hospital

Starship Children's Hospital of New Zealand

Ann & Robert H Lurie Children's Hospital of Chicago

Children's Hospitals and Clinics of Minnesota

Disease Susceptibility

Disease Attributes

People without pathogenic DICER1 germline variation

People with pathogenic DICER1 germline variation or history of DICER1-associated tumors

NCI Family Study Referrals

Douglas R Stewart, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Douglas Stewart, M.D.

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.

Study Description:

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. In 2009, Hill and colleagues identified heterozygous germline disease-associated variants 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 DICER1-related tumor risks (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 disease-associated variants in these patients and their family members. This will also allow us to identify DICER1 disease-associated variant-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 disease-associated variant 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 patients with PPB and other DICER1-related tumors 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 and other DICER1-related tumors.
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-related tumor risk.

Endpoints:

Primary endpoints: include all cancers, with specific attention to those currently thought to be part of the DICER1-related tumor risk.

Secondary endpoints: include non-malignant health issues.

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

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

To evaluate various parameters related to psychosocial and behavioral issues resulting from being a member of a family at increased risk of PPB.

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.

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.

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.

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.

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.

Secondary endpoints will include characterization of other known or suspected DICER1-related non-tumor health issues such as dysmorphic features, thyroiditis, dental problems, dysmorphology, ophthalmologic abnormalities and pneumothorax. Characterization of individuals and families with DICER1-related non-tumor phenotypes permits identification of people at risk.

National Cancer Institute (NCI)

Study title	NCT ID	Conditions	Eligibility	Organization
International PPB/DICER1 Registry	NCT03382158	Pleuropulmonary... Sertoli-Leydig ... DICER1 Syndrome Cystic Nephroma Wilms Tumor Pineoblastoma Renal Sarcoma Nodular Hyperpl... Nasal Chondrome... Ciliary Body Me... Neuroblastoma Pituitary Cance... Embryonal Rhabd... Ovarian Sarcoma Gynandroblastom... Thyroid Carcino... Embryonal Rhabd... Embryonal Rhabd... Embryonal Rhabd...	-	Children's Hospitals and Clinics of Minnesota
International PPB/DICER1 Registry	NCT03382158	Pleuropulmonary... Sertoli-Leydig ... DICER1 Syndrome Cystic Nephroma Wilms Tumor Pineoblastoma Renal Sarcoma Nodular Hyperpl... Nasal Chondrome... Ciliary Body Me... Neuroblastoma Pituitary Cance... Embryonal Rhabd... Ovarian Sarcoma Gynandroblastom... Thyroid Carcino... Embryonal Rhabd... Embryonal Rhabd... Embryonal Rhabd...	-	Children's Hospitals and Clinics of Minnesota
DICER1-related Pleuropulmonary Blastoma Cancer Predisposition Syndrome: A Natural History Study	NCT01247597	Pleuropulmonary... Cystic Nephroma Ovarian Sertoli... Ocular Medulloe... Nasal Chondrome...	-	National Institutes of Health Clinical Center (CC)

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