Skip to main content
Gut logoLink to Gut
. 2001 Jul;49(1):82–86. doi: 10.1136/gut.49.1.82

Genomic homogeneity in fibrolamellar carcinomas

Y Sirivatanauksorn 1, V Sirivatanauksorn 1, N Lemoine 1, R Williamson 1, B Davidson 1
PMCID: PMC1728372  PMID: 11413114

Abstract

BACKGROUND—Fibrolamellar carcinoma (FLC) is a variant of hepatocellular carcinoma (HCC) with distinctive clinical and histological features. To date there have been few studies on the genotypic aspects of FLC and no previous attempts have been made to use the arbitrarily primed-polymerase chain reaction (AP-PCR) technique to detect genetic alterations in this disease.
AIM—The aim of this study was to assess the degree of genomic heterogeneity of FLC using the AP-PCR technique.
METHODS—A total of 50 tissue samples of primary and metastatic FLCs from seven patients were microdissected. AP-PCR amplification of each genomic DNA sample was carried out using two arbitrary primers.
RESULTS—DNA fingerprints of the primary FLCs and all their metastatic lesions (both synchronous and metachronous disease) were identical in an individual patient. The fingerprints were different between tumours of different patients. No evidence of intratumour heterogeneity was observed.
CONCLUSIONS—Such genomic homogeneity in FLCs may explain their indolent growth. The absence of clonal evolution, which is present in other tumours (particularly HCCs), may explain the distinct behaviour in this tumour. The tumorigenic pathway and degree of somatic genomic changes in this disease may be less complex than in HCC.


Keywords: fibrolamellar carcinoma; hepatocellular carcinoma; DNA fingerprint; arbitrarily primed-polymerase chain reaction; laser capture microdissection

Full Text

The Full Text of this article is available as a PDF (178.5 KB).

Figure 1  .

Figure 1  

Laser capture microdissection (LCM) of a fibrolamellar carcinoma (FLC) nodule. As no coverslip is used in LCM, the reduction in refractive index means that most light passing through the tissue is scattered which can obscure cellular detail at high magnifications. (A) A 10 µm thick paraffin embedded section of FLC tissue stained with haematoxylin and eosin. The tumour cells are separated into nests and sheets by dense lamellar bands of collagen. (B) Selected tumour cells transferred to the film of the vial caps. (C) The residual tissue section after laser capture.

Figure 2  .

Figure 2  

Arbitrarily primed-polymerase chain reaction (AP-PCR) analysis of primary fibrolamellar carcinomas (FLC) and their metastatic lesions from patient No 1. Autoradiograms of polyacrylamide gel electrophoresis of 33P labelled DNA fragments amplified by AP-PCR. Genomic DNA from each sample was amplified with the AR3 (A) and ZF3 (B) primers. P, primary FLC; Ov, left ovarian mass; Ap, appendiceal nodule; LNP, infrapancreatic lymph nodes; LNIVC, inferior vena cava lymph nodes; LO1/LO2, lesser omentum nodules; Peri, peritoneum; (number of sectors is represented at the top).

Figure 3  .

Figure 3  

Arbitrarily primed-polymerase chain reaction (AP-PCR) analysis of primary fibrolamellar carcinomas (FLC) and their metastatic lesions from patient No 6. Autoradiograms of polyacrylamide gel electrophoresis of 33P labelled DNA fragments amplified by AP-PCR. Genomic DNA from each sample was amplified with the AR3 (A) and ZF3 (B) primers. P, primary FLC; LN, lymph nodes metastases; (number of sectors is represented at the top).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Achille A., Biasi M. O., Zamboni G., Bogina G., Magalini A. R., Pederzoli P., Perucho M., Scarpa A. Chromosome 7q allelic losses in pancreatic carcinoma. Cancer Res. 1996 Aug 15;56(16):3808–3813. [PubMed] [Google Scholar]
  2. Berman M. A., Burnham J. A., Sheahan D. G. Fibrolamellar carcinoma of the liver: an immunohistochemical study of nineteen cases and a review of the literature. Hum Pathol. 1988 Jul;19(7):784–794. doi: 10.1016/s0046-8177(88)80261-2. [DOI] [PubMed] [Google Scholar]
  3. Collier N. A., Weinbren K., Bloom S. R., Lee Y. C., Hodgson H. J., Blumgart L. H. Neurotensin secretion by fibrolamellar carcinoma of the liver. Lancet. 1984 Mar 10;1(8376):538–540. doi: 10.1016/s0140-6736(84)90934-6. [DOI] [PubMed] [Google Scholar]
  4. Craig J. R., Peters R. L., Edmondson H. A., Omata M. Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinico-pathologic features. Cancer. 1980 Jul 15;46(2):372–379. doi: 10.1002/1097-0142(19800715)46:2<372::aid-cncr2820460227>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  5. Ding S. F., Delhanty J. D., Bowles L., Dooley J. S., Wood C. B., Habib N. A. Infrequent chromosome allele loss in fibrolamellar carcinoma. Br J Cancer. 1993 Feb;67(2):244–246. doi: 10.1038/bjc.1993.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ding S. F., Habib N. A., Dooley J., Wood C., Bowles L., Delhanty J. D. Loss of constitutional heterozygosity on chromosome 5q in hepatocellular carcinoma without cirrhosis. Br J Cancer. 1991 Dec;64(6):1083–1087. doi: 10.1038/bjc.1991.468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ehrenfried J. A., Zhou Z., Thompson J. C., Evers B. M. Expression of the neurotensin gene in fetal human liver and fibrolamellar carcinoma. Ann Surg. 1994 Oct;220(4):484–491. doi: 10.1097/00000658-199410000-00007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Giercksky H. E., Thorstensen L., Qvist H., Nesland J. M., Lothe R. A. Comparison of genetic changes in frozen biopsies and microdissected archival material from the same colorectal liver metastases. Diagn Mol Pathol. 1997 Dec;6(6):318–325. doi: 10.1097/00019606-199712000-00003. [DOI] [PubMed] [Google Scholar]
  9. Honda K., Sbisà E., Tullo A., Papeo P. A., Saccone C., Poole S., Pignatelli M., Mitry R. R., Ding S., Isla A. p53 mutation is a poor prognostic indicator for survival in patients with hepatocellular carcinoma undergoing surgical tumour ablation. Br J Cancer. 1998 Mar;77(5):776–782. doi: 10.1038/bjc.1998.126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ionov Y., Peinado M. A., Malkhosyan S., Shibata D., Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993 Jun 10;363(6429):558–561. doi: 10.1038/363558a0. [DOI] [PubMed] [Google Scholar]
  11. Kohno T., Morishita K., Takano H., Shapiro D. N., Yokota J. Homozygous deletion at chromosome 2q33 in human small-cell lung carcinoma identified by arbitrarily primed PCR genomic fingerprinting. Oncogene. 1994 Jan;9(1):103–108. [PubMed] [Google Scholar]
  12. Macintosh C. A., Stower M., Reid N., Maitland N. J. Precise microdissection of human prostate cancers reveals genotypic heterogeneity. Cancer Res. 1998 Jan 1;58(1):23–28. [PubMed] [Google Scholar]
  13. Mise K., Tashiro S., Yogita S., Wada D., Harada M., Fukuda Y., Miyake H., Isikawa M., Izumi K., Sano N. Assessment of the biological malignancy of hepatocellular carcinoma: relationship to clinicopathological factors and prognosis. Clin Cancer Res. 1998 Jun;4(6):1475–1482. [PubMed] [Google Scholar]
  14. Okano A., Hajiro K., Takakuwa H., Kobashi Y. Fibrolamellar carcinoma of the liver with a mixture of ordinary hepatocellular carcinoma: a case report. Am J Gastroenterol. 1998 Jul;93(7):1144–1145. doi: 10.1111/j.1572-0241.1998.00348.x. [DOI] [PubMed] [Google Scholar]
  15. Orsatti G., Greenberg P. D., Rolfes D. B., Ishak K. G., Paronetto F. DNA ploidy of fibrolamellar hepatocellular carcinoma by image analysis. Hum Pathol. 1994 Sep;25(9):936–939. doi: 10.1016/0046-8177(94)90015-9. [DOI] [PubMed] [Google Scholar]
  16. Paradinas F. J., Melia W. M., Wilkinson M. L., Portmann B., Johnson P. J., Murray-Lyon I. M., Williams R. High serum vitamin B12 binding capacity as a marker of the fibrolamellar variant of hepatocellular carcinoma. Br Med J (Clin Res Ed) 1982 Sep 25;285(6345):840–842. doi: 10.1136/bmj.285.6345.840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Payne C. M., Nagle R. B., Paplanus S. H., Graham A. R. Fibrolamellar carcinoma of liver: a primary malignant oncocytic carcinoid? Ultrastruct Pathol. 1986;10(6):539–552. doi: 10.3109/01913128609007211. [DOI] [PubMed] [Google Scholar]
  18. Peinado M. A., Malkhosyan S., Velazquez A., Perucho M. Isolation and characterization of allelic losses and gains in colorectal tumors by arbitrarily primed polymerase chain reaction. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10065–10069. doi: 10.1073/pnas.89.21.10065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pinna A. D., Iwatsuki S., Lee R. G., Todo S., Madariaga J. R., Marsh J. W., Casavilla A., Dvorchik I., Fung J. J., Starzl T. E. Treatment of fibrolamellar hepatoma with subtotal hepatectomy or transplantation. Hepatology. 1997 Oct;26(4):877–883. doi: 10.1002/hep.510260412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Raaphorst F. M., Tami J., Sanz I. E. Cloning of size-selected human immunoglobulin heavy-chain rearrangements from third complementarity-determining region fingerprint profiles. Biotechniques. 1996 Jan;20(1):78-82, 84, 86-7. doi: 10.2144/96201st02. [DOI] [PubMed] [Google Scholar]
  21. Reubi J. C., Waser B., Schaer J. C., Laissue J. A. Neurotensin receptors in human neoplasms: high incidence in Ewing's sarcomas. Int J Cancer. 1999 Jul 19;82(2):213–218. doi: 10.1002/(sici)1097-0215(19990719)82:2<213::aid-ijc11>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  22. Reuland P., Aicher K. P., Brambs H. J., Enderle G., Feine U., Gärtner H. V., Weber P. Incidental finding of a hepatic lesion: differential diagnostic problems for fibrolamellar hepatic carcinoma. J Nucl Med. 1994 Aug;35(8):1342–1346. [PubMed] [Google Scholar]
  23. Saitoh Y., Bruner J. M., Levin V. A., Kyritsis A. P. Identification of allelic loss on chromosome arm 6p in human astrocytomas by arbitrarily primed polymerase chain reaction. Genes Chromosomes Cancer. 1998 Jul;22(3):165–170. doi: 10.1002/(sici)1098-2264(199807)22:3<165::aid-gcc1>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
  24. Saul S. H., Titelbaum D. S., Gansler T. S., Varello M., Burke D. R., Atkinson B. F., Rosato E. F. The fibrolamellar variant of hepatocellular carcinoma. Its association with focal nodular hyperplasia. Cancer. 1987 Dec 15;60(12):3049–3055. doi: 10.1002/1097-0142(19871215)60:12<3049::aid-cncr2820601232>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  25. Sirivatanauksorn Y., Sirivatanauksorn V., Bhattacharya S., Davidson B. R., Dhillon A. P., Kakkar A. K., Williamson R. C., Lemoine N. R. Evolution of genetic abnormalities in hepatocellular carcinomas demonstrated by DNA fingerprinting. J Pathol. 1999 Nov;189(3):344–350. doi: 10.1002/(SICI)1096-9896(199911)189:3<344::AID-PATH430>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
  26. Sirivatanauksorn Y., Sirivatanauksorn V., Bhattacharya S., Davidson B. R., Dhillon A. P., Kakkar A. K., Williamson R. C., Lemoine N. R. Genomic heterogeneity in synchronous hepatocellular carcinomas. Gut. 1999 Nov;45(5):761–765. doi: 10.1136/gut.45.5.761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Soreide O., Czerniak A., Bradpiece H., Bloom S., Blumgart L. Characteristics of fibrolamellar hepatocellular carcinoma. A study of nine cases and a review of the literature. Am J Surg. 1986 Apr;151(4):518–523. doi: 10.1016/0002-9610(86)90117-0. [DOI] [PubMed] [Google Scholar]
  28. Starzl T. E., Iwatsuki S., Shaw B. W., Jr, Nalesnik M. A., Farhi D. C., Van Thiel D. H. Treatment of fibrolamellar hepatoma with partial or total hepatectomy and transplantation of the liver. Surg Gynecol Obstet. 1986 Feb;162(2):145–148. [PMC free article] [PubMed] [Google Scholar]
  29. Welsh J., McClelland M. Fingerprinting genomes using PCR with arbitrary primers. Nucleic Acids Res. 1990 Dec 25;18(24):7213–7218. doi: 10.1093/nar/18.24.7213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Welsh J., McClelland M. Genomic fingerprints produced by PCR with consensus tRNA gene primers. Nucleic Acids Res. 1991 Feb 25;19(4):861–866. doi: 10.1093/nar/19.4.861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Welsh J., Pretzman C., Postic D., Saint Girons I., Baranton G., McClelland M. Genomic fingerprinting by arbitrarily primed polymerase chain reaction resolves Borrelia burgdorferi into three distinct phyletic groups. Int J Syst Bacteriol. 1992 Jul;42(3):370–377. doi: 10.1099/00207713-42-3-370. [DOI] [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES