Clonality and allelotype analyses of focal nodular hyperplasia compared with hepatocellular adenoma and carcinoma

doi:10.3748/wjg.15.4695

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Gastroenterol. Oct 7, 2009; 15(37): 4695-4708
Published online Oct 7, 2009. doi: 10.3748/wjg.15.4695

Table 1 Clinicopathological features of 12 FNH lesions and data of immunohistochemistry, clonality and LOH assays

Case numbers	Age (yr)/gender	Lesion codes	Lesion sizes (cm)	Ki-67-LI (%)	p53-LI (%)	Clonality by XCIA	No. of LOH
01	40/F	01¹	5.0	1.6	0	PC²	0
02	30/F	02	2.5	0.5	0	PC²	0
		03	7.0	0.8	0	PC²	0
03	22/M	04³	5.2	0.7	0	NT	0
04	44/M	05¹	1.2	0.5	0	NT	0
05	31/F	06¹	4.7	0.3	0	PC²	0
06	43/F	07	3.2	1.0	0	PC²	NT
07	44/F	08¹	2.0	0.8	0	PC⁴	NT
08	53/F	09⁵	4.8	1.0	0	PC²	NT
09	23/F	10¹^,⁵	4.5	1.2	0	PC⁴	NT
10	46/F	11¹^,⁵	5.3	0.8	0	PC³	NT
		12¹	1.5	0.9	0	PC⁴	NT

¹Some small preneoplastic foci, composed of clear cells, identified in surrounding liver parenchyma;

²Tested on phosphoglycerate kinase (PGK) locus;

³Nodules of altered hepatocytes (NAH) isolated from FNH by microdissection for LOH detection;

⁴Noninformative at PGK locus and the data obtained by the assay on androgen receptor (AR) locus;

⁵NAH isolated from FNH by microdissection for clonality assessment by XCIA. FNH: Focal nodular hyperplasia; Ki-67-LI: Ki-67 antigen-labeling indices; p53-LI: p53 protein-labeling indices by DO-7; XCIA: X-chromosomal inactivation assay; LOH: Loss of heterozygosity; F: Female; M: male; PC: Polyclonality; NT: Not tested for its origin from a male patient.

Table 2 Clinicopathological features of 12 HCAs and 22 HCCs, with data of clonality and LOH assays

Case numbers	Age (yr)/gender	Lesion codes	Lesion sizes (cm)	Lesion types	Ki-67-LI (%)	p53-LI (%)	Clonality by XCIA	No. of LOH	Chromosomal arms affected by LOH
11	36/F	HCA01	3.5	HCA	1.3	0	MC¹	3	8p, 11p, 16q
12	57/F	HCA02	3.0	HCA²	1.3	0	MC¹	1	17p
13	28/M	HCA03	7.3	HCA, SCC²	2.5	0	NT	4	11p, 13q, 17p
14	52/M	HCA04	8.5	HCA	1.1	0	NT	3	11p, 17p
15	31/F	HCA05	7.0	HCA	3.1	0	MC¹	4	11p, 13q
16	29/F	HCA06	1.0	HCA²	2.0	0	MC¹	NT	NT
		HCA07	12.0	HCA²	1.8	0	MC¹	5	1p, 13q, 17p
17	30/F	HCA08	1.0	HCA, SCC²	1.5	0	MC³	1	13q
18	29/F	HCA09	5.0	HCA	0.9	0	MC¹	4	6q, 11p, 13q, 17p
19	37/F	HCA10	5.0	HCA	1.3	0	MC³	2	13q, 17p
20	33/F	HCA11	2.0	HCA²	2.3	0	MC¹	NT	NT
21	40/F	HCA12	1.5	HCA²	2.0	0	MC³	NT	NT
22	31/F	HCC01	2.2	HCC, G1	2.0	10	NT	11	8p, 11p, 13q, 16q, 17p
23	46/M	HCC02	4.1	HCC, G1	65.0	0	NT	7	6q, 13q, 16q, 17p
24	42/M	HCC03	3.0	HCC, G1	2.5	0	NT	10	6q, 8p, 13q, 17p
25	51/M	HCC04	5.3	HCC, G1	8.2	80	NT	5	8p, 11p, 13q, 16q, 17p
26	49/M	HCC05	2.0	HCC, G1	2.0	0	NT	2	1p, 11p
27	27/M	HCC06	2.5	HCC, G1	1.2	0	NT	2	8p, 11p
28	56/M	HCC07	3.3	HCC, G1	1.5	0	NT	0	None
29	38/F	HCC08	8.3	HCC, G1	18.0	0	MC¹	NT	NT
30	64/F	HCC09	3.6	HCC, G1	5.5	0	MC³	NT	NT
31	53/F	HCC10	9.5	HCC, G2	8.5	0	NT	3	8p
32	33/M	HCC11	8.0	HCC, G2	5.2	0	NT	5	6q, 11p, 17p
33	48/F	HCC12	5.2	HCC, G2	35.0	0	NT	4	6q, 8p, 16q
34	44/F	HCC13	4.2	HCC, G2	65.0	80	NT	12	8p, 11p, 13q, 16q, 17p
35	29/F	HCC14	3.6	HCC, G2	0.9	0	NT	2	1p, 11p
36	61/F	HCC15	4.5	HCC, G2	3.7	0	NT	6	6q, 13q, 16q, 17p
37	48/M	HCC16	5.0	HCC, G2	1.4	0	NT	3	6q, 11p, 17p
38	39/M	HCC17	4.0	HCC, G2	1.5	0	NT	0	None
39	39/M	HCC18	5.0	HCC, G2	1.2	0	NT	0	None
40	50/M	HCC19	2.0	HCC, G2	2.0	0	NT	8	8p, 11p, 13q, 17p
41	51/M	HCC20	7.4	HCC, G2	12.2	0	NT	1	11p
42	55/F	HCC21	2.5	HCC, G2	28.5	0	MC³	NT	NT
43	77/F	HCC22	5.6	HCC, G2	16.2	0	MC³	NT	NT

¹Noninformative at PGK locus and the data obtained by the assay on AR locus;

²Some small preneoplastic foci, composed of clear cells, identified in surrounding liver parenchyma;

³Tested on PGK locus. HCA: Hepatocellular adenoma; HCC: Hepatocellular carcinoma; MC: Monoclonality; NT: Not tested for its origin from a male patient (for HCA) or its evidently malignant phenotypes; SCC: Small-cell change.

Table 3 Sequences of primers for nested PCR-based LOH assays

Markers (locations)	External primer pairs¹	Internal primer pairs¹
D1S199 (1p36.13)	CCTGGGCAACATAGCAG	GGTGACAGAGTGAGACCCTG
	TGACATCTTCCTCCACCTC	CAAAGACCATGTGCTCCGTA
D1S2843 (1p36.12)	AGAAGGTCGGGCACAAA	GGGCTGGGCATTACACAAC
	TTCATCACCCACCCAAAA	ATCAAATTGGCTTCTCACCG
D1S513 (1p35.2)	AGCTGAGACCCTGCCTTG	AGCTGAGACCCTGCCTTG
	AATGCCTGCTGTATGAAA	AGCCTTCAGAGCCTGCC
D4S406 (4q31.21)	TCCCAGTTTACAACCACA	CTGGTTTTAAGGCATGTTTG
	GAAGGTGGCTAACTAAAA	TCCTCAGGGAGGTCTAAT
D4S426 (4q35.2)	CAAGTAATACAATATGGTAA	ATACACTGCATCCATATATACAAGG
	ATACACTGCATCCATATATACAAGG	ACATTGTGAAATGACCACAG
D6S437 (6q25.3)	TTACTGACTTCTTGAAAGGGTG	TGTCCTGGTGGAGGCA
	ACACGCCATCACAGGAAC	GGTACAGTGTTTGACCCTAAGA
D6S305 (6q26)	AAAGCTGAGAAGCCATTCA	CACCAGCGTTAGAGACTGC
	GCAAATGGAGCATGTCACT	GCAAATGGAGCATGTCACT
D6S1008 (6q27)	GCTACTTCAGCAGGGTT	AAGAAAGACTAGAGAGACAGACAGC
	AATGACCACGAGTTCTTC	ATCATTTGCCCATTTACCAA
D6S297 (6q27)	CAAGAAGTGTCTCTAAAGATAAGG	CAAGAAGTGTCTCTAAAGATAAGG
	GCAAGATGTAGAAGGAGA	CAACCAACCACGGTATATG
D8S277 (8p23.1)	GTTCCCTATGGCTAAAG	CCAGGTGAGTTTATCAATTCCTGAG
	AGTTTGCCTCCAGAAA	TGAGAGGTCTGAGTGACATCCG
D8S1754 (8p22)	TTTGGGTAAGATACTTTAAGCG	CAGGGAAGTCTCGGTTTG
	AAATAGTCGGGTCGGGAG	TCAGGGACACGATTCAGC
D8S1827 (8p22)	AGAAATAGCCAAAGAAGC	GACAGAATCATGTGGCCTTT
	CTGGGAAGGTCAGCAGATTG	TTTTGTAAAATGTAAAATTGGCTTT
D8S261 (8p22)	GAGGCTACTAACAACGTG	TGCCACTGTCTTGAAAATCC
	TATTACAGTGGTTATGGC	TATGGCCCAGCAATGTGTAT
D8S258 (8p21.3)	ACAATAATGATGAGGCCAGAA	CTGCCAGGAATCAACTGAG
	CAGCCAATACGCAGGAGC	TTGACAGGGACCCACG
D8S298 (8p21.3)	CTAGTTATTATGCAGAGGTGACATC	AGGCTTACACCCATGGACC
	GAGGCTGGTTAGCATCACG	ACGCAGCACACAACATCAT
D8S1771 (8p21.2)	GGGGTGGGTGTAGATATT	TTTACAAGAACCACCTGCC
	TTGATTCTTTGCTGATGC	GATATAAAACATGACTTTGCTACCC
D8S1772 (8q22.1)	TTGATGCTCCTCTGTTGC	GATCTGAGCCTTCCTACTGTC
	AAGTCCTCCCTTTGCTGA	TGCCTTTTGGTGAATGG
D8S522 (8q24.12)	TATAGCAAATATGTTCACG	GAAAACAAAACAGGCTCC
	CCATCTTGGCTCCTC	TGACCAAACAACTAGACACC
D11S1301 (11p13)	GCCACAGCACTCCAG	GGCAACAGAGTGAGACTCA
	GACAACCTCCCTCACC	GTGTTCTTTATGTGTAGTTC
D11S2008 (11p13)	ATTCAGGAGCACAGAACA	CATCCATCTCATCCCATCAT
	GCATCCATACGGAAAGTC	TTCACCCTACTGCCAACTTC
D11S907 (11p13)	GCTTATTGTCCATACCCAAA	GCTTATTGTCCATACCCAAA
	GAAAAGCAAAGGCATCGT	AAAGNACCTTAATTTCAGGC
D13S164 (13q12.3)	GGCGATCCACCCACCTT	GCTGTGATTGCACCACC
	TGCCACGCACCTGTAGTCC	ATTACAGGCGTGACACACC
D13S289 (13q12.3)	AGGGCGTCACCGTGTT	CTGGTTGAGCGGCATT
	GACTGAGGCAGGAGGATTG	TGCAGCCTGGATGACA
D13S260 (13q12.3)	AATGGATCTGCTTGC	AGATATTGTCTCCGTTCCATGA
	ATCACTCCAAATGTAAAT	CCCAGATATAAGGACCTGGCTA
D13S171 (13q12.3)	CAGATACAGACATTTTGGAA	CCTACCATTGACACTCTCAG
	GCTCTACAGCATTGACCT	TAGGGCCATCCATTCT
D13S267 (13q13.1)	AGCTAATGGCCTGAAAGG	GGCCTGAAAGGTATCCTC
	AGAGGTCAAAGAGGAAGA	TCCCACCATAAGCACAAG
D13S220 (13q13.2)	AATCACCTCCCACCAG	CCAACATCGGGAACTG
	AGGGGTTCCTTCATCC	TGCATTCTTTAAGTCCATGTC
D13S219 (13q13.3)	CTGGATGAAAAGGAAC	AAGCAAATATGCAAAATTGC
	TTATCTCATTCAGTTGCT	TCCTTCTGTTTCTTGACTTAACA
D13S218 (13q13.3)	TTCTCATAAGAAATCCCC	GATTTGAAAATGAGCAGTCC
	TTTCATATCCCTGTTCAA	GTCGGGCACTACGTTTATCT
D13S325 (13q14.11)	ATGCAGCTTAAGTCCTTT	TCCTTTAAGTGTCTAGAGAGGAGG
	CTGTGCTATCTCCTCCAA	TCTCTCTCAGAAGTTTGGAAGC
D13S291 (13q14.11)	GTCTGACGGGAAACAGC	ATGGCCAGACTTCCCACT
	CACAAACAGAATCAACCCT	CCAGGCTCACATGCTAACA
D13S126 (13q14.2)	AGCCTCCCAAAGTGCTA	TCACCAGTAAAATGCTATTGG
	AGTCATCTGGTCCCTCAAT	GTGATTTTCAAATTTGCTCTG
D13S118 (13q14.2)	TGTAAATAGCTTAGTTG	GAAATAGTATTTGGACCTGGG
	CTACTGACATTTGCTC	CCACAGACATCAGAGTCCTT
D13S153 (13q14.2)	AACTTGGCTGCGATGATAAGAA	AGCATTGTTTCATGTTGGTG
	CCTGAGGTATTGACGAAGGGTC	CAGCAGTGAAGGTCTAAGCC
D13S284 (13q14.3)	CCAGCTCGTGTTCATTT	AAAATCAGGTGGAAACAGAAT
	GTACATTTTATAGATTCATAGAGTC	AAAGGCTAACATCGAAGGGA
D13S137 (13q14.3)	GATGGTGGGTGGGACTT	CAGGAGGGATGGACTCACTTC
	GGAATATGTGGAGGATTTATCTCTG	TTTCCTCATTCTTTCCCAATTG
D13S321 (13q21.1)	TAAATGCAATCTGAAT	TACCAACATGTTCATTGTAGATAGA
	CATAGCAAGACTCTGTC	CATACACCTGTGGACCCATC
D13S119 (13q21.1)	TCTCATTCCCATAACAT	TTATTGCCTTTGTAGATCATTG
	5' AGAGGAAAGATAGAACAA	AAGACTTTGAATGAAATTCCC
D13S170 (13q31.1)	AGCTATTATGTAACCAAT	TTGCACTGTGGAGATAAACACATAG
	TGTTGTTCTAAGCCAC	TCACATTGTCTTTTAAGGCAGGAG
D13S71 (13q31.3)	ACGCTCCTTCGTGGTG	GTATTTTTGGTATGCTTGTGC
	GTGCCTCTGTTTCTCCTATT	CTATTTTGGAATATATGTGCCT
D16S514 (16q21)	TGACACGCAATTTACCCT	CTATCCACTCACTTTCCAGG
	AATCACATTTTCCCACTG	TCCCACTGATCATCTTCTC
D16S402 (16q22.1)	GAGGCAAAGAGGTATCCA	TTTTGTAACCATGTACCCCC
	CCCACTCATTCCTGTCCC	ATTTATAGGGCCATGACCAG
D16S3029 (16q23.1)	AGGGTGTTGAGGTGTCTG	ATAGAGTTGGGCTGCATAGA
	ATAGGGTCTGCTGGGTT	CTTTCCTGAAATTGGAAGTGA
D16S3040 (16q23.2)	TATGTTGGTGGATGATTT	TACTCCGGCAAGGACG
	5' GTCAAGGAACACTGAACT	GCTGCCTAGCACATGG
D16S422 (16q24.3)	ACAGCCACCTCTATTCA	CAGTGTAACCTGGGGGC
	AACATTTTACTATATCTTACTTTCG	CTTTCGATTAGTTTAGCAGAATGAG
D16S3121 (16q24.3)	AAGTCACTGGGCTAACAAGG	CATGTTGTACATCGTGATGC
	TGGGTCCTGAGGTCACAAA	AGCTTTTATTTCCCAGGGGT
D16S303 (16q24.3)	GCAGGTTATGGATGTGAGTTTGTT	GATCAGTGCTCGTTTTTTTTGGTTTGG
	TTCGGAAGGCTGAGGCAGTA	CAACAAGAGCGAAACTCGGTCTCAA
D17S643 (17p13.3)	TGCCGTTCTCAGGTGGTT	CTTCCTTGTCTCTAAACAGTCCTTT
	TTCCTCCCTGCATGGATT	GTAGTCCCAGGGAGCTGGAAGT
D17S849 (17p13.3)	TACAATACTGCTGCAATAAG	CAATTCTGTTCTAAGATTATTTTGG
	TACAATAACATCAGGAAACA	CTCTGGCTGAGGAGGC
D17S926 (17p13.3)	GAAGTGGGAAGATTGCTT	GCAGTGGGCCATCATCA
	ATCCTCTGAACCGTATTT	CCGCAGAAGGCTGTTGT
D17S695 (17p13.3)	AGCCTGGGCAACAAGAGC	CTGGGCAACAAGAGCAAAATTC
	CAGCCAACGGGCGTCATT	TTTGTTGTTGTTCATTGACTTCAGTCT
D17S1840 (17p13.3)	GGCAACGTGGTGAAACCC	GCCTGGGCGACAGAGTGA
	ACCAGGACCGGCTGCTCT	TGGGGCAGACTTGGTCCTT
D17S1529 (17p13.3)	GTTAGCCTCTTCCTTGGACATTC	TTGTTTCTATCCACGCAGGC
	ATCATTCCGTTTCACCTTTGG	GATGGCTGTGCTTGCTGGTA
D17S1574 (17p13.3)	CTTCTTCTGCGTCAGGTATG	TCACTTATCGGCATCTGATCC
	CCAAAGTGCTGGGATTA	CTGATGTGCCTTTTGTGTGTG
D17S831 (17p13.3)	GCCCAAATCAGAAGCAAG	CGCCTTTCCTCATACTCCAG
	GACATCCATTGGCACCAC	GCCAGACGGGACTTGAATTA
D17S654 (17p13.3)	GGGGTACGCCTTTCCTCA	GACCTAGGCCATGTTCACAGCC
	GGTTGGCAAGACCACTGTTAGA	GACATCCATTGGCACCACCCCAA
D17S796 (17p13.2)	GAGCAGCTAGGATCAAGGG	CAATGGAACCAAATGTGGTC
	AGAACGGCAAACAACGAA	AGTCCGATAATGCCAGGATG
β-actin²	CTGTGCCCATCTACGAGG	AGAGATGGCCACGGCTGCTT
	AAAGGGTGTAACGCAACTAA	ATTTGCGGTGGACGATGGAG

¹Nucleotide sequences were written in a 5' to 3' direction, with the forward and reverse primers for each reaction presented at the upper and lower lines, respectively;

²Amplified as an internal control with a product of 406 bp.

Table 4 Nonrandom X-chromosomal inactivation revealed in NAH microdissected from 3 FNH and their inactivation patterns

Origin of lesions	No. of NAH tested	No. with signals	No. with MC (%)	No. of lesions with
				Upper band	Lower band
FNH09	38	34	14 (41.2)	12	2
FNH10	6	6	2 (33.3)	0	2
FNH11	12	12	5 (41.7)	0	5
Total	56	52	21 (40.4)	12	9

Table 5 LOH profiles of 13 NAH microdissected from an FNH lesion (FNH04)

Lesion codes	Diameters (mm)¹	Numbers of LOH	Loci affected²
NAH57	3.8	6	D6S437, D8S298, D13S118, D13S153, D16S3029, D16S3040
NAH58	3.5	5	D8S298, D11S1301, D11S2008, D13S321, D16S3121
NAH59	1.8	2	D13S164, D17S1840
NAH60	2.7	2	D11S1301, D13S321
NAH61	3.8	6	D11S2008, D13S118
NAH62	3.2	4	D8S298, D13S164, D13S321, D17S1840
NAH63	2.8	5	D1S513, D8S298, D13S118, D13S153, D17S695
NAH64	3.8	5	D6S1008, D13S218, D16S514, D16S3040, D17S926
NAH65	3.2	5	D1S513, D8S298, D11S907, D13S164, D13S126
NAH66	2.0	1	D6S1008
NAH67	2.1	4	D8S298, D11S1301, D11S907, D16S422
NAH68	2.4	3	D13S164, D13S126, D13S321
NAH69	2.8	5	D6S437, D8S298, D13S118, D13S321, D17S926

¹The largest diameters as measured in cross sections of the lesions under a microscope;

²The markers written in underlined characters represent loci affected in high frequencies (≥ 30%) in NAH.

Citation: Cai YR, Gong L, Teng XY, Zhang HT, Wang CF, Wei GL, Guo L, Ding F, Liu ZH, Pan QJ, Su Q. Clonality and allelotype analyses of focal nodular hyperplasia compared with hepatocellular adenoma and carcinoma. World J Gastroenterol 2009; 15(37): 4695-4708
URL: https://www.wjgnet.com/1007-9327/full/v15/i37/4695.htm
DOI: https://dx.doi.org/10.3748/wjg.15.4695