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Pleuropulmonary Blastoma

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Neuroepithelioma

D. Ashley Hill, MD

Kris Ann Schultz, MD

Pleuropulmonary Blastoma (PPB) is a rare lung tumor which develops in childhood. The underlying genetic factors which contribute to the development and progression of PPB are not defined. We are working to identify the genetic factors which may contribute to the development of this rare tumor.

Studies of inherited cancer syndromes have provided unique opportunities to uncover and explain important cellular pathways with broad relevance to both sporadic cancers and human development. This proposal studies the cancer predisposition syndrome originally described as a familial form of pleuropulmonary blastoma (PPB). PPB is a rare, aggressive lung cancer that affects young children. Children with PPB and/or their family members are at increased risk for a number of rare conditions, including Wilms tumor, rhabdomyosarcoma, brain tumors, ovarian tumors and nodular hyperplasia of the thyroid gland. In 2009, we mapped a PPB locus and identified germline, loss of function mutations in one copy of DICER1 as the genetic basis of this syndrome. DICER1 encodes a protein that performs the final critical step in maturation of microRNAs (miRNAs). miRNAs are an important form of gene regulation. The syndrome's varied nature is likely attributable to the various roles of miRNAs during different developmental and/or functional circumstances. This study focuses on defining the full phenotype of this cancer predisposition syndrome including penetrance, expressivity in children and adults, pathologic classification of disease and spectrum of predisposing DICER1 mutations. Improved understanding of the clinical and genetic features of this cancer predisposition syndrome is essential to facilitate early diagnosis when the diseases are most curable, and to create genetic counseling and educational materials to guide medical care.

We are collecting blood samples or saliva samples. When available, we also collect tumor samples from prior surgical procedures.

Elucidating the Genetic Basis of the Pleuropulmonary Blastoma (PPB) Familial Cancer Syndrome

Sequence data deposited in ClinVar upon publication. Publication of all final results in NIHMS

Ashley Hill

MD, Professor of Pathology

Carcinoma

Thyroid Neoplasms

Thyroid Diseases

Thyroid Nodule

Hyperplasia

Goiter, Nodular

Neuroblastoma

Hamartoma

Neuroectodermal Tumors, Primitive, Peripheral

Head and Neck Neoplasms

Nodular Regenerative Hyperplasia

Pituitary Cancer

Gynandroblastoma

DICER1-related Pleuropulmonary Blastoma Cancer Predisposition Syndrome

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Infective Agents

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Vincristine

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)

Digestive System Diseases

Carcinoma, Renal Cell

Liver Neoplasms

Medulloblastoma

Hepatoblastoma

Renal Cell Carcinoma

Medulloblastoma, Childhood

DNA analysis

cytogenetic analysis

gene expression analysis

gene rearrangement analysis

mutation analysis

polymerase chain reaction

polymorphism analysis

laboratory biomarker analysis

medical chart review

Dana A. Hill, MD

RATIONALE: The identification of gene mutations in young patients with pleuropulmonary blastoma syndrome may allow doctors to better understand the genetic processes involved in the development of some types of cancer, and may also help doctors identify patients who are at risk for cancer.

PURPOSE: This research study studies gene mutations in samples from young patients with pleuropulmonary blastoma syndrome at risk for developing cancer.

OBJECTIVES:

* To determine if DICER1 mutations contribute to tumor pathogenesis in cystic nephromas and cystic partially differentiated nephroblastomas outside of families with pleuropulmonary blastoma (PPB) syndrome.

OUTLINE: Archived DNA samples are analyzed for DICER1 mutation by qPCR and directly sequenced using BigDye Terminator chemistry. Results are then compared against the single nucleotide polymorphism (SNP) database.

Gene Mutation in Samples From Young Patients With Pleuropulmonary Blastoma Syndrome at Risk for Developing Cancer

Investigation of DICER1 in Cystic Nephroma and Cystic Partially Differentiated Nephroblastoma

Children's Oncology Group

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Elucidating the Genetic Basis of the Pleuropulmonary Blastoma (PPB) Familial Cancer Syndrome	NCT00565903	Pleuropulmonary... Cystic Nephroma Sertoli-Leydig ... Medulloepitheli... Embryonal Rhabd... Goiter Sarcoma Pineoblastoma Pituitary Tumor... Wilms Tumor		1 Day - 95 Years	Children's National Research Institute
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)
Elucidating the Genetic Basis of the Pleuropulmonary Blastoma (PPB) Familial Cancer Syndrome	NCT00565903	Pleuropulmonary... Cystic Nephroma Sertoli-Leydig ... Medulloepitheli... Embryonal Rhabd... Goiter Sarcoma Pineoblastoma Pituitary Tumor... Wilms Tumor		1 Day - 95 Years	Children's National Research Institute
Gene Mutation in Samples From Young Patients With Pleuropulmonary Blastoma Syndrome at Risk for Developing Cancer	NCT01353300	Brain and Centr... Hereditary Wilm... Kidney Cancer Liver Cancer Neuroblastoma Pleuropulmonary... Sarcoma	DNA analysis cytogenetic ana... gene expression... gene rearrangem... mutation analys... polymerase chai... polymorphism an... laboratory biom... medical chart r...	- 120 Years	Children's Oncology Group

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