Congenital lung malformations, lung tumors and genetics

Federica Pederiva, Vanna Pecile, Luigina De Leo

Riunione TREP Trieste 12 Aprile 2012

Symptomatic pulmonary malformations require emergent surgery

Surgical resection is the standard of care for symptomatic pulmonary malformations

The management of the asymptomatic patients remain controversial

Early surgical excision is recommended in many series to avoid the eventual development of complications:

• recurrent infections

• pneumothoraces

• malignant complications

Ann Thorac Surg 1983 Jul;36(1):108-19.

Primary pulmonary neoplasms of childhood: a review. Hartman GE, Shochat SJ.

4% of pulmonary tumors (sarcomas, PPB, bronchogenic carcinoma, mesenchymoma)

were associated with congenital cystic malformations

• Life long surveillance

• CT scan? CXRs?

• How do you follow a congenital pulmonary

malformations for 70-80 years?

Observations of asymptomatic patients?

About 46 cases of malignancies in children thought to have arisen from congenital pulmonary malformations have been reported: • 7 pleuropulmonary blastoma arising in CCAM • 12 rhabdomyosarcoma: 9 arising in CCAM, 1 in bronchogenic cyst, 1 in localized emphysema, 1 in intralobar sequestration • 27 bronchioloalveolar carcinoma arising in CCAM

About 6 cases of malignancies in adults arisen from congenital pulmonary malformations have been reported: • 1 pleuropulmonary blastoma arising in extralobar sequestration • 2 squamous cells carcinoma: 1 arising in CCAM, 1 in intralobar sequestration • 2 bronchioloalveolar carcinoma arising in CCAM • 1 lymphoepithelioma-like carcinoma arising in pulmonary sequestration

Cytogenetics changes possibly associated with the biology of PPB include: • trisomy 2 • trisomy 8 • loss of chromosome 17p material (possible involvement of p53)

DICER1 has a role in lung development. Its conditional loss in the developing mouse lung results in cystic airways, disruption of branching morphogenesis and mesenchymal expansion that resembles the early stage of PPB

Study to discover somatic mutations in 188 human lung adenocarcinomas → identification of 26 genes mutated (ERBB4, EPHA3, KDR, NTRK) → somatic mutations of tumour suppressor genes (NF1, APC, RB1, ATM) → sequence changes in PTPRD → deletion of LRP1B gene

Karyotype and p53 mutations in 9 CCAM, 2 intralobar sequestrations and 2 PPB → normal karyotypes in CCAM and intralobar sequestrations → clonal abnormalities in PPB → TP53 mutations not found

CCAM is nonneoplastic

Mucinous adenocarcinoma is a mucus-producing lung malignancy expressing MUC5AC selectively and characterized by K-RAS missense mutations Ananlysis of mucins expression and EGFR, KRAS abd HER2 mutations in 41 CPAM and 6 pulmonary sequestrations: → strong and selective expression of MUC5AC → KRAS missense mutations → no mutations in EGFR and HER2 genes

CPAM is a premalignant lesion

To look further insight the biologic and genetic relationship between congenital

pulmonary malformations and lung tumors

Are congenital lung malformations premalignant lesions?

Research study

8 congenital pulmonary malformations: • 5 CPAM • 3 intralobar sequestrations

6/8 had prenatal diagnosis

Pilot study

Evaluation of:

• Molecular karyotype of lung tissue and peripheral

blood of the patient

• Molecular karyotype of peripheral blood of

parents of patient

• p53 gene expression in lung tissue and in

peripheral blood

Evaluation of:

• Molecular karyotype of lung tissue and peripheral

blood of the patient

• Molecular karyotype of peripheral blood of

parents of patient

• p53 gene expression in lung tissue and in

peripheral blood

Not inherited deletions

GENE CHROMOSOME POLYMORPHISM

ZBBX 3 no

FGF13 X yes

Not inherited deletions

ZBBX largely uncharacterized tumor suppressor gene altered in human cancer

FGF13 the protein encoded by the gene is a member of FGF family that is involved in embryonic development, cell growth, tissue repair, tumor growth and invasion

Not inherited nor polymorphic duplications GENE CHROMOSOME

LRP1B 2

EPHA6 3

LRB4 4

EXOC1 4

GABRA2 4

PRDM9 5

ASCC3 6

SUPTH3, MIR586, RUNX2 6

KHDRBS2 6

MIR2053, CSMD3 8

YTHDF3 8

CNBD1 8

PTPRD 9

CNKSN2 X

HMGN5 X

Not inherited nor polymorphic duplications

LRP1B tumor suppressor gene, deleted in non-small cell lung carcinomas (adenocarcinoma, squamous cell carcinoma and large cell carcinoma), confers cancer cells an increased growth and invasive capacity. The duplication inactivated the gene.

EPHA6 mutated in lung cancer. The duplication inactivated the gene

Not inherited not polymorphic duplications

ASCC3 up-regulated in lung cancer. The duplication inactivated the gene.

KHDRBS2 mutated in lung adenocarcinoma. The duplication inactivated the gene.

PTPRD a candidate tumor suppressor gene deleted or mutated in lung adenocarcinoma. The duplication inactivated the gene.

Evaluation of:

• Molecular karyotype of lung tissue and peripheral

blood of the patient

• Molecular karyotype of peripheral blood of

parents of patient

• p53 gene expression in lung tissue and in

peripheral blood

• transition C→G in exon 4 in lung tissue of 7/8 patients

p53 gene

• transition C→G in exon 4 in peripheral blood of 3/4 patients and their parents

• a tumor suppressor gene that contributes to human cancer in different ways

• Duplications and deletions of genes involved in lung tumors pathogenesis were found in the pulmonary tissue of congenital lung malformations

• Further investigation is needed to understand if congenital lung malformations have a genetic tendency to malignant transformation

Preliminary conclusions

• Study groups:

Infants and children receiving a diagnosis of congenital pulmonary malformation during pregnancy or afterwards

Infants and children receiving a diagnosis of pleuropulmonary blastoma

Adults receiving a diagnosis of adenocarcinoma

• Ethics committee approval

Multicentric study

Multicentric study

• Samples collection protocol will be provided to the collaborating centers

• Samples will be sent to the Research Laboratory (Institute for Maternal and Child Health - IRCCS “Burlo Garofolo” – Trieste, Italy) for the experiments

• Collection of samples for 1 year

Multicentric study

• Evaluation of:

Molecular karyotype of lung tissue and peripheral blood of the patient

Molecular karyotype of peripheral blood of parents of patient

p53 gene expression in lung tissue and in peripheral blood

DICER 1 gene mutations

EGFR, HER2, KRAS mutations

Thank you