Genetic Alteration in PanIN and IDC

In recent years, it has been established that the most likely precursor of ordinary IDC of the pancreas is the high-grade PanIN (PanIN-3) [11]. Some

Table l. Genetic alterations in pancreatic carcinoma

Gene

Locus

Function

Frequency

Caretaker gene

BRCA2

i3q

DNA repair

7%

FANCC, FANCG

9q, 9p

DNA repair

<5%

Oncogenes

k-ras

12

signal transduction

85%~95%

CCNE

i9q

G1/S cell cycle transition

NA

Tumor-suppressor genes

pl6

9p

G1/S cell cycle arrest

98%

p53

i7p

Cell cycle arrest,

50%~75%

apoptosis

DPC4

i8q

TGF-ß/activin pathway

55%

LKBl/STKll

i9p

Serine/threonine kinase

5%

TGF-p/activin receptor

TGF-ß/activin pathway

5%

BAX

i9q

Apoptosis

<5%

FBXW7

4q

G1 cell cycle transition

<5%

Table 2. Frequency of mutations in several of the major pancreatic cancer-associated genes

Type of cancer

K-ras (%)

Cyclin Di (%)

pi6 (%)

p53 (%)

Pancreas

-95

-95

-80

-40

Colon

-60

-60

-20

-60

Esophagus

-60

-40

-95

-60

Liver

-60

-20

-80

-60

Gallbladder

-60

-60

-80

-80

papers indicated that residual PanIN-3 after resection progresses to IDC some years later [12-14]. This evidence suggests that PanIN-3 may be one of the precursor lesions of conventional PC.

The best material for investigating true precursor lesions is an intraductal carcinoma with minimal invasion [15, 16]. However, we rarely encounter such carcinomas. Therefore, most immunohistochemical and molecular analyses on the carcinogenesis and histogenesis of IDC were done by investigating the tumor itself and/or intraductal lesions adjacent to IDC.

Yamano et al. used molecular biology to investigate both intraductal lesions adjacent to IDC and IDC with an excellent microdissection technique [17]. Their loss of heterozygosity (LOH) analysis revealed that IDCs of the pancreas develop from hyperplasia (corresponding to PanIN-1) through severe ductal dysplasia (corresponding to PanIN-3) to invasive carcinoma by a progressive and divergent accumulation of genetic changes. The above reflect the spectrum of intraductal morphological alterations around invasive foci. LOH of 17p and 9p is observed at a high frequency in both invasive and severe ductal dysplastic foci, and a 9p loss may be the earliest event in the transition from hyperplasia to early dysplasia. Other chromosomal alterations including 18q and 6p follow later in the intraductal dys-plastic and invasive stages and confer subclones with a further growth advantage.

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