Download Losses of FHIT and p16 in oral carcinogenesis – a FISH

Losses of FHIT and p16 in oral
carcinogenesis –
a FISH based study
Johannes Bier
background – „leukoplakia“ 1/2
• oral leukoplakia main epithelial lesion of the mucosa of
the mouth (prevalence: 2.3%)
• heterogeneous group with varying risk
• premalignant epithelial precursor lesion of OSCC (3-8%
transform into cancer)
• whitish patches
• several grades: hyperplasia, low/high grade dysplasia,
CIS, invasive cancer
• mainly due to carcinogens, i.e. nicotine, alcohol, but also
idiopathic
background – „leukoplakia“ 2/2
• no standardized regime for treatment
• follow-up with biopsy and histopathology currently gold
standard
• molecular biological techniques to be future proposals ?
• no specific markers to predict malignant transformation
yet
• LOH and polyploidy ?
so what?
there are hints...
• molecular progression model for oral carcinogenesis:
accumulation of genetic changes (Califano et al.,1996)
(adopted from Fearon & Vogelstein 1990: colon cancer)
• studies on LOH proposed 3p and 9p to be important for
progression (Rosin et al., 2000; Mao et al.,1996)
• greater probability of progression into OSCC
3p and 9p...
• 3p14 alias FHIT (fragile histidine triade), 9p21 alias p16
• both tumor suppressor genes
• considered to indicate transition from hyperplasia to
dysplasia
FISH what?!
leukoplakia with hyperplasia – probes for FHIT
centromere
gene
FISH what?!
invasive carcinoma – probes for FHIT
centromer
gene
results - deletion FHIT / p16
100
9
19
75
50
25
115
percentage of cells with deletion 9p (p16)
percentage of cells with deletion 3p (FHIT)
100
75
20
50
25
0
0
control
(infant)
control hyperplasia dysplasia
(adult)
cis
OSCC
normal
epithelium
of OSCC
patients
control
(infant)
control hyperplasia dysplasia
(adult)
cis
OSCC
normal
epithelium
of OSCC
patients
results - polysomy FHIT / p16
100
30
75
6
33
64
50
70
63
25
62
percentage of cells with polysomy 9p (p16)
percentage of cells with polysomy 3p (FHIT)
100
75
27
56
50
13
25
10
18
64
0
33
6
88
94
control
(infant)
55
68
0
control hyperplasia dysplasia
(adult)
cis
OSCC
normal
epithelium
of OSCC
patients
control
(infants)
control hyperplasia dysplasia
(adults)
cis
OSCC
normal
epithelium
of OSCC
patients
discussion
• already >90% of hyperplasia deletion for FHIT 
Califano et al. = 20%
• our threshold: 25% / 13%  LOH studies 50%
• FHIT earlier event than p16; results underline role of
FHIT regarding cell cycle regulation
• possibility to distinguish deletion – amplification
• hyperplasia does not show polysomy 3p or 9p
• polysomy 3 indicator of increasing oral carcinogenesis