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

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.

- 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.