Cellular oncogenes and suppressor genes as prognostic markers in cancer

doi:10.1016/0009-9120(93)80007-H

Clinical Biochemistry

Volume 26, Issue 6, December 1993, Pages 439-447

https://doi.org/10.1016/0009-9120(93)80007-H Get rights and content

Activation of cellular or c-oncogenes and loss of function of suppressor genes appears to be the key event in the formation of most human cancers. Altered forms of these genes or their protein products have the potential to provide a new generation of cancer markers. As cancer markers, the most useful application of c-oncogenes and suppressor genes so far, has been in providing prognostic information. The correlation of N-myc gene amplification with poor prognosis in neuroblastoma was one of the first examples of prognostic data supplied by a c-oncogene. Most, but not all investigators, find that either amplification or increased expression of c-erbB-2 gene correlates with poor prognosis in breast cancer. Other potential prognostic markers in breast cancer include amplification of the c-myc gene, and increased expression of both EGFR and p53 protein. Although c-oncogenes and suppressor genes have the potential to supply prognostic information in a broad range of cancers, many of the results are still preliminary with conflicting conclusions.

References (95)

AlitaloK et al.
Myc oncogenes: Activation and amplification
Biochim Biophys Acta
(1987)
Roux-DossetoM et al.
c-Myc gene amplification in selected node-negative breast cancer patients correlates with high rate of early relapse
Eur J Cancer
(1992)
RiouG et al.
C-myc proto-oncogene expression in early carcinoma of the uterine cervix
Lancet
(1987)
HaubruckH et al.
ras p21: Effects and regulation
Biochim Biophys Acta
(1991)
Bar-SagiD et al.
Microinjection of the ras oncogene protein into PC12 cells induce morphological differentation
Cell
(1985)
LupuR et al.
The role of erbB-2 and its ligands in growth control of malignant breast epithelium
J Steroid Biochem
(1992)
LevineAJ et al.
Tumor suppressor genes: The p53 and retinoblastoma sensitivity genes and gene products
Biochim Biophys Acta
(1990)
FinlayCA et al.
The p53 protooncogene can act as a suppressor of transformation
Cell
(1989)
ScheffnerM et al.
The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes degradation of p53
Cell
(1990)
BarnesDM et al.
Abnormal expression of wild type p53 protein in normal cells of a cancer family patient
Lancet
(1992)

SunX-F et al.

Prognostic significance of cytoplasmic p53 oncoprotein in colorectal adenocarcinoma

Lancet

(1992)

BishopJM

Molecular themes in oncogenesis

Cell

(1991)

WeinbergR

Tumor suppressor genes

Science

(1991)

WeinbergRA

The integration of molecular genetics into cancer management

Cancer

(1992)

PennL et al.

c-Myc: Evidence for multiple regulatory functions

Semin Cancer Biol

(1990)

CohnSL et al.

Prolonged N-myc protein half-life in a neuroblastoma cell line lacking N-myc amplification

Oncogene

(1990)

SeegerRC et al.

Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas

N Engl J Med

(1985)

BourhisJ et al.

Combined analysis of DNA ploidy index and N-myc genomic content in neuroblastoma

Cancer Res

(1991)

OngG et al.

Oncoprotein stability after tumour resection

Br J Cancer

(1990)

VarleyJM et al.

Alterations in either c-erbB-2 (neu) or c-myc proto-oncogenes in breast carcinomas correlates with poor short-term prognosis

Oncogene

(1987)

BernsE et al.

c-Myc amplification is a better prognostic factor than Her/neu amplification in primary breast cancer

Cancer Res

(1992)

BorgA et al.

c-Myc amplification is an independent prognostic factor in postmenopausal breast cancer

Int J Cancer

(1992)

JohnsonBE et al.

Myc family oncogene amplification in tumour cell lines established from small cell lung cancer patients and its relationship to clinical status and course

J Clin Invest

(1987)

RiouG

Proto-oncogenes and prognosis in early carcinoma of the uterine cervix

Cancer Surveys

(1988)

ErismanMD et al.

Noncorrelation of the expression of the c-myc oncogene in colorectal carcinoma with recurrence of disease or patient survival

Cancer Res

(1988)

BarbacidM

ras genes

Annu Rev Biochem

(1987)

BosJL

ras oncogenes in human cancers: A review

Cancer Res

(1989)

SantosE et al.

T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes

Nature

(1982)

SlebosR et al.

K-ras oncogene activation is a prognostic marker in adenocarcinoma of the lung

N Engl J Med

(1990)

HaradaM et al.

Prognostic significance of the expression of ras oncogene product in non-small cell carcinoma of the lung

Cancer

(1992)

ClairT et al.

Prognostic significance of the expression of a ras protein with a molecular weight of 21,000 by human breast cancer

Cancer Res

(1987)

WatsonD et al.

The H-ras oncogene product p21 and prognosis in human breast cancer

Breast Cancer Res Treatment

(1990)

DatiC et al.

C-erbB-2 and ras expression levels in breast cancer are correlated and show a cooperative association with unfavorable clinical outcome

Int J Cancer

(1991)

TanakaT et al.

Expression of Ha-ras oncogene products in human neuroblastoma and the significant correlation with a patients prognosis

Cancer Res

(1988)

SmithsA et al.

Genetic alterations during colorectal-tumor development

N Engl J Med

(1988)

ListAF et al.

Biology and pathogenesis of the myelodysplastic syndrome

Semin Oncol

(1992)

MaihleNJ et al.

C-erbB-2 and the epidermal growth factor receptor: A molecule with dual identity

Biochim Biophys Acta

(1988)

LibermanTA et al.

Amplification enhances expression and possible rearrangement of EGF receptors in primary human brain tumors of glial origin

Nature

(1985)

ThompsonDM et al.

The EGF receptor: Structure, regulation and potential role in malignancy

Cancer Surveys

(1985)

KlijnJGM et al.

The clinical significance of epidermal growth factor (EGF-R) in human breast cancer: A review of 5232 patients

Endocr Rev

(1992)

SainsburyJRC et al.

Epidermal growth factor receptor status as a predictor of early relapse and death from breast cancer

Lancet

(1987)

NicholsonS et al.

Epidermal growth factor receptor (EGFr): results of a 6 year follow-up study in operable breast cancer with emphasis on the node negative subgroup

Br J Cancer

(1991)

OwensOJ et al.

Epidermal growth factor receptors (EGFR) in human ovarian cancer

Br J Cancer

(1991)

HarrisAL et al.

Epidermal growth factor receptor: A marker of early relapse in breast cancer and tumor stage progression in bladder cancer; interaction with neu

HendlerFJ et al.

Increased EGF-R1 binding predicts a poor survival in squamous tumors

ShiC et al.

Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts

Nature

(1981)

BargmannCI et al.

The neu oncogene encodes an epidermal growth factor receptor-related protein

Nature

(1986)

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ReviewCellular oncogenes and suppressor genes as prognostic markers in cancer

Biochim Biophys Acta

Eur J Cancer

Lancet

Biochim Biophys Acta

Cell

J Steroid Biochem

Biochim Biophys Acta

Cell

Cell

Lancet

Lancet

Molecular themes in oncogenesis

Cell

Tumor suppressor genes

Science

The integration of molecular genetics into cancer management

Cancer

c-Myc: Evidence for multiple regulatory functions

Semin Cancer Biol

Prolonged N-myc protein half-life in a neuroblastoma cell line lacking N-myc amplification

Oncogene

Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas

N Engl J Med

Combined analysis of DNA ploidy index and N-myc genomic content in neuroblastoma

Cancer Res

Oncoprotein stability after tumour resection

Br J Cancer

Alterations in either c-erbB-2 (neu) or c-myc proto-oncogenes in breast carcinomas correlates with poor short-term prognosis

Oncogene

c-Myc amplification is a better prognostic factor than Her/neu amplification in primary breast cancer

Cancer Res

c-Myc amplification is an independent prognostic factor in postmenopausal breast cancer

Int J Cancer

Myc family oncogene amplification in tumour cell lines established from small cell lung cancer patients and its relationship to clinical status and course

J Clin Invest

Proto-oncogenes and prognosis in early carcinoma of the uterine cervix

Cancer Surveys

Noncorrelation of the expression of the c-myc oncogene in colorectal carcinoma with recurrence of disease or patient survival

Cancer Res

ras genes

Annu Rev Biochem

ras oncogenes in human cancers: A review

Cancer Res

T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes

Nature

K-ras oncogene activation is a prognostic marker in adenocarcinoma of the lung

N Engl J Med

Prognostic significance of the expression of ras oncogene product in non-small cell carcinoma of the lung

Cancer

Prognostic significance of the expression of a ras protein with a molecular weight of 21,000 by human breast cancer

Cancer Res

The H-ras oncogene product p21 and prognosis in human breast cancer

Breast Cancer Res Treatment

C-erbB-2 and ras expression levels in breast cancer are correlated and show a cooperative association with unfavorable clinical outcome

Int J Cancer

Expression of Ha-ras oncogene products in human neuroblastoma and the significant correlation with a patients prognosis

Cancer Res

Genetic alterations during colorectal-tumor development

N Engl J Med

Biology and pathogenesis of the myelodysplastic syndrome

Semin Oncol

C-erbB-2 and the epidermal growth factor receptor: A molecule with dual identity

Biochim Biophys Acta

Amplification enhances expression and possible rearrangement of EGF receptors in primary human brain tumors of glial origin

Nature

The EGF receptor: Structure, regulation and potential role in malignancy

Cancer Surveys

The clinical significance of epidermal growth factor (EGF-R) in human breast cancer: A review of 5232 patients

Endocr Rev

Epidermal growth factor receptor status as a predictor of early relapse and death from breast cancer

Lancet

Epidermal growth factor receptor (EGFr): results of a 6 year follow-up study in operable breast cancer with emphasis on the node negative subgroup

Br J Cancer

Epidermal growth factor receptors (EGFR) in human ovarian cancer

Br J Cancer

Epidermal growth factor receptor: A marker of early relapse in breast cancer and tumor stage progression in bladder cancer; interaction with neu

Increased EGF-R1 binding predicts a poor survival in squamous tumors

Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts

Nature

Review
Cellular oncogenes and suppressor genes as prognostic markers in cancer