The Genetics of PPB

Genetic Study in PPB: A New Scientific Study of PPB Causes

The International PPB Registry in collaboration with the National Institute of Health is conducting a major study of genetic inheritance in PPB patients and their families. We ask that all PPB patients and their families consider participating. Visit for more information.

The PPB Family Tumor and Dysplasia Syndrome

Pleuropulmonary blastoma (OMIM #601200) is a genetic and familial disease in approximately 33% of kindreds affected by a PPB. This is the PPB Family Tumor and Dysplasia Syndrome; it may be manifested in the patient or family or both (see especially Registry Publications: Priest 1996; Boman 2006; Priest 2009, Hill Science 2009).

The conditions most prominent in this syndrome are as follows. The most frequently observed conditions are in bold; DICER1 mutations (marked in the following by "D1 +") are being described in PPB-associated examples of many of these conditions (DICER1 mutation paper involving Registry authors: Registry Publications: Hill Science 2009; Bahubeshi 2010; Rio Frio 2011; Slade 2011).

PPB – may be bilateral or multifocal, may be more than one PPB in a family (D1 +)

Lung cysts – (when other family members’ cysts have been available for pathologic study, they are Type I or Type Ir PPB) (D1 +)

Renal neoplasia: Cystic nephroma – observed in 9-10% of PPB patients or kindreds. Wilms tumor also occurs with PPB but much less frequently than CN. Both CN and WT in the context of PPB have been shown to have DICER1 mutations. (See Registry Publications Boman et al 2006; Bahubeshi 2010) (D1 +)

Dysplasias – such as, intestinal hamartomatous polyps (from esophagus to rectum, but often ileal and leading to intussusception); cystic hepatic hamartoma

Nasal chondromesenchymal hamartoma – a rare sinonasal chondro-stromal tumor has been observed in 5 PPB patients. (Registry Publications Priest, 2010) (D1 +)

Ciliary-body medulloepithelioma – an extremely rare intra-ocular tumor has been observed in 4 PPB kindreds (Registry Publications Priest Br J Ophthalmol in press 2011) (D1 +)

Any childhood cancer – including rhabdomyosarcoma (D1 +), other sarcomas, neuroblastoma, medulloblastoma and other CNS tumors. Some unusual leukemias in heavily affected families appear related to PPB

Gonadal tumors – especially ovarian Sertoli-Leydig cell tumors (D1 +) and other sex-cord stromal tumors (D1 +), ovarian dysgerminoma, testicular seminoma (D1 +) and perhaps germ cell tumors (see Registry Publications: Rio Frio 2011: abstract Schultz 2010)

Uterine cervix sarcoma botryoides – this very rare neoplasm of teenage and young adult women has occurred with PPB and with PPB-related conditions. (D1 +)

Nodular thyroid hyperplasia (D1 +) and differentiated thyroid carcinomas (D1 +) Although nodular thyroid hypersplasia (multinodular goiter) is common in the general population, its inclusion the the PPB family Tumor and Dysplasia Syndrome is supported by genetic studies. (See Registry Publications Rio Frio 2011; Slade 2011)

A few children with PPB have had what appear to be treatment-related second malignant neoplasms, but despite their apparent propensity to neoplasia, the frequency of treatment-related neoplasms in PPB survivors does not appear to be different from other childhood cancer survivors.

Much remains to be learned about the implications of DICER1 mutations for PPB and the associated conditions in the PPB Family Tumor and Dysplasia Syndrome. PPB families have many phenotypically normal obligate carriers. The inheritance pattern suggests an autosomal dominant susceptibility with reduced penetrance. The extent to which DICER1 mutations are found in familial PPB and in apparently sporadic PPB must be defined. Additional PPB patients and families are under study by the Registry and our collaborators to explore further the implications of DICER1 mutation. Referrals of PPB families are appreciated.

The PPB Registry intends to establish a CLIA-approved laboratory to offer clinical tests for use by physicians and genetic counselors when PPB patients and their families seek such testing.

Biology Summary: Dicer, Drosha, and Silencing RNA

DICER1 codes for DICER1 protein - a key enzyme in the production of micro-RNA (miRNA) and short interfering RNA (siRNA), known collectively as small silencing RNAs. DICER1 is a cytoplasmic endoribonuclease III enzyme discovered in 2001(Bernstein; Nature 2001; 409:363); DICER1 cleaves ~70 nucleotide stem-loop precursor molecules yielding miRNA and siRNA (typically ~22 nucleotides). Small silencing RNAs are non-coding cytoplasmic RNAs and are critical regulators of messenger RNA (mRNA) by interfering with (silencing, quenching, suppressing) mRNA. More than 95% of cytoplasmic RNA does not code for protein synthesis (Nelson; Brain Pathol 2008; 18:130). The importance of non-coding RNAs in controlling mRNA expression by suppression has been elaborated since ~1992 (Bernstein; RNA 2001; 7:1509). The many unique small silencing RNAs target specific mRNAs and guide them to an effector complex known as the “RNA-induced silencing complex” (RISC). In addition to DICER1’s role cleaving precursors into small RNAs, DICER participates with RISC in suppressing mRNA expression by either degrading it or preventing its transcription.

“Drosha” enzyme is another critical endoribonuclease III required for production of small non-coding RNAs. Drosha was discovered in 2003 (Lee; Nature 2003; 425: 415). Located in the nucleus, it processes early small RNA precursors. Drosha products are then actively transported to the cytoplasm where DICER acts.

DICER1 and Drosha and the small RNA mRNA-silencing activities are highly conserved across plant and animal species. This gene-regulating schema is now considered essential for normal development and function of cells and is being implicated in disease (Alvarez-Garcia; Development 2005; 132: 4653). The PPB Family Tumor and Dysplasia Syndrome is the first human disease in which DICER1 malfunction is implicated.