上皮肿瘤和融合基因Epithelial Neoplasms

and Fusion GenesHongying Zhang (张红英 )1, Andre M. Oliveira2

1Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China （中国四川省成都市四川大学华西医院病理科） ;

2Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

Introduction• Recurrent chromosomal rearrangements with

the formation of fusion genes（融合基因） have been traditionally associated with hematologic and mesenchymal tumors （血液肿瘤和间叶肿瘤） but only rarely in epithelial neoplasms（上皮肿瘤）

• This view has cultivated the erroneous impression that the oncogenic mechanisms present in these tumors are fundamentally different from those found in epithelial neoplasms

• One of the reasons more fusion genes have been found in hematologic malignancies is because these tumors are more often karyotyped

• There may not be any fundamental tissue-specific differences in the genetic mechanisms by which neoplasia is initiated

Nat Genet 2004;36:331-4.

Introduction

• Review and discuss the chromosomal rearrangements and fusion genes in epithelial neoplasms– Head and neck– Thyroid– Kidney– Breast– Prostate– Lung

Pleomorphic Adenoma

• PLAG1 fusion genes (8q12) (40%)– CTNNB1-PLAG1-most common

• t(3;8)(p21;q12)

• HMGA2 fusion genes (12q13-15)(8%)– HMGA2-FHIT– HMGA2-NFIB– HMGA2-WIF1

HAS2–PLAG1 andCOL1A2–PLAG1 have been seen in lipoblastoma

HMGA2 is involved in avariety of neoplasms

The PLAG1 or HMGA2 gene fusions have been identified only in pleomorphicadenomas (among salivary gland neoplams).

Mucoepidermoid Carcinoma• MECT1-MAML2 fusion

gene(55%)– Associated with a better clinical

outcome– Also been identified in Warthin

tumor

• EWSR1-POU5F1 fusion gene-less common– Associated with the less well-

differentiated tumors SKY and IHC analysis

Genes Chromosomes Cancer 2006;45:470–81.

Papillary Thyroid Carcinoma

• RET fusion genes(35%)– CCDC6-RET-associated with classic

histology– NCOA4-RET-associated with

previous radiation therapy

• NTRK1 fusion genes (5%)– TPM3-NTRK1, TPR-NTRK1, TFG-

NTRK1

• BRAF fusion genes (1%)– AKAP9-BRAF

Follicular Thyroid Carcinoma

• PPARG1 fusion genes– PAX8-PPARG1 fusion* (30%)

– CREB3L2-PPARG1 fusion (3%)

Science 2000;289:1357-60.

t(2;3)(q13;p25)

rearrangement of the PPARG1 locus (3p25)

rearrangement of the PAX8 locus (2q13)

NH2 COOH

• The fusion gene is not specific for carcinomas

• Some follicular adenomas may be early follicular carcinomas without capsular or vascular invasion

• Some reported adenomas were actually poorly sampled carcinomas

• Some follicular adenomas can evolve into carcinomas

• The PAX8-PPARG1 fusion was significantly associated with vascular invasion

• FVPTCs with PAX8-PPARG1 fusion should be classified in the group of FTC rather than as a variant of PTC

Midline Carcinoma of Children and Young Adults (NUT Midline

Carcinoma)

Am J Surg Pathol 2008;32:828–834.

Images were kindly provided by Dr French, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

t(15;19)(q13;p13)

BRD4-NUT fusion

rearrangement of the BRD4 locus

immunoreactivity with antibody to NUT

Renal Cell Carcinoma (RCC)• TFE3 fusion genes (25-

35% of paediatric RCC)– ASPL-TFE3 fusion gene

• Also been described in alveolar soft part sarcoma

– PRCC-TFE3 fusion gene

• Alpha-TFEB fusion gene rearrangement of the TFE3 locus

Xp11.2 rearrangementF/28 yrs

Breast Carcinoma

• ETV6-NTRK3 fusion gene in secretary breast carcinoma (SBC) (12/13 cases)

Cancer Cell 2002;2:367-76.

Cancer Cell 2002;2:367-76.

t(12;15)(p13;q25)

ETV6-NTRK3 fusion

F/6 yrs

Also encountered in cellular mesoblastic nephroma and infantile fibrosarcoma

secretary breast carcinoma (SBC)

– a relative higher incidence in children and young adults– low histological grade– a more favourable prognosis

ETV6 rearrangement

• This fusion is a hallmark of ACC

Proc Natl Acad Sci U S A 2009;106:18740-4.

• t(6;9)(q22–23;p23–24) in adenoid cystic carcinomas (ACC) of the breast and head and neck

• MYB-NFIB fusion (11 of 11 cases)

Prostate Carcinoma

• TMPRSS2 fusion genes– TMPRSS2-ERG fusion gene (55%)– TMPRSS2-ETV1 fusion gene (25%)

Science 2005;310:644-8.

Lung Carcinoma

• EML4-ALK in non-small-cell lung carcinomas (NSCLCs) (<7%)– The majority of them belong to

adenocarcinomas– This fusion appears to be

associated with young age– Predominantly seen in non- or

light-smokers

• Two additional alternate ALK fusion genes– TFG-ALK– KIF5B-ALK

ALK immunoreactivity

rearrangement of the ALK locus

Provided by Drs Boland and Yi, Mayo Clinic, Rochester, MN, USA

chimeric protein

Conclusions• The formation of fusion genes is a universal

oncogenic mechanism observed in a variety of human neoplasms

• The use of traditional gene mapping techniques and novel bioinformatic approaches have led to the identification of several novel fusion genes in epithelial neoplasms

• The identification of fusion genes in epithelial neoplasia has open new avenues for the diagnosis, prognosis and therapy of epithelial neoplasms