Molecular analysis distinguishes metastatic disease from second cancers in patients with retinoblastoma.

The pediatric ocular tumor retinoblastoma readily metastasizes, but these lesions can masquerade as histologically similar pediatric small round blue cell tumors. Since 98% of retinoblastomas have RB1 mutations and a characteristic genomic copy number "signature", genetic analysis is an appealing adjunct to histopathology to distinguish retinoblastoma metastasis from second primary cancer in retinoblastoma patients. Here, we describe such an approach in two retinoblastoma cases.

Identification of clinically relevant mosaicism in type I hereditary haemorrhagic telangiectasia.

Background: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder affecting the vascular system, characterised by epistaxis, arteriovenous malformations and mucocutaneous and gastrointestinal telangiectases. Mutations in two genes, ENG and ACVRL1, account for the majority of cases. Almost all cases of HHT show a family history of HHT-associated symptoms; few cases are de novo.

Detection of mosaic RB1 mutations in families with retinoblastoma.

The RB1 gene mutation detection rate in 1,020 retinoblastoma families was increased by the use of highly sensitive allele specific-PCR (AS-PCR) to detect low-level mosaicism for 11 recurrent RB1 CGA>TGA nonsense mutations. For bilaterally affected probands, AS-PCR increased the RB1 mutation detection sensitivity from 92.6% to 94.

Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma.

Retinoblastoma clinical observations revealed the role of tumor suppressor genes in human cancer, Knudson's 'two-hit' model of cancer induction. We now demonstrate that loss of both RB1 tumor suppressor gene alleles initiates quiescent RB1(-/-) retinomas with low level genomic instability and high expression of the senescence-associated proteins p16(INK4a) and p130. Although retinomas can remain unchanged throughout life, highly proliferative, clonal and aneuploid retinoblastomas commonly emerge, exhibiting altered gene copy number and expression of oncogenes (MYCN, E2F3, DEK, KIF14 and MDM4) and tumor suppressor genes (CDH11, p75(NTR)) and reduced expression of p16(INK4a) and p130.