GnRH and LHR gene variants predict adverse outcome in premenopausal breast cancer patients.
BACKGROUND
Breast cancer development and progression are dependent on estrogen activity. In premenopausal women, estrogen production is mainly regulated through the hypothalamic-pituitary-gonadal (HPG) axis.


METHODS
We have investigated the prognostic significance of two variants of genes involved in the HPG-axis, the GnRH (encoding gonadotropin-releasing hormone) 16Trp/Ser genotype and the LHR (encoding the luteinizing hormone receptor) insLQ variant, in retrospectively collected premenopausal breast cancer patients with a long follow-up (median follow-up of 11 years for living patients).


RESULTS
Carriership was not related with breast cancer risk (the case control study encompassed 278 premenopausal cases and 1,758 premenopausal controls). A significant adverse relationship of the LHR insLQ and GnRH 16Ser genotype with disease free survival (DFS) was observed in premenopausal (hormone receptor positive) breast cancer patients. In particular, those patients carrying both the GnRH 16Ser and LHR insLQ allele (approximately 25%) showed a significant increased risk of relapse, which was independent of traditional prognostic factors (hazard ratio 2.14; 95% confidence interval 1.32 to 3.45; P = 0.002).


CONCLUSIONS
We conclude that the LHR insLQ and GnRH 16Ser alleles are independently associated with shorter DFS in premenopausal patients. When validated, these findings may provide a lead in the development of tailored treatment for breast cancer patients carrying both polymorphisms.
Piersma
Djura
D
Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands.
Themmen
Axel P N
AP
Look
Maxime P
MP
Klijn
Jan G M
JG
Foekens
John A
JA
Uitterlinden
André G
AG
Pols
Huibert A P
HA
Berns
Els M J J
EM
D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D016022:Case-Control Studies; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics*; D006801:Humans; D015412:Mastectomy, Segmental; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017697:Premenopause; D011960:Receptors, Estrogen; D011974:Receptors, LH / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate; D013629:Tamoxifen / Q000627:therapeutic use; D016896:Treatment Outcome
D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D011974:Receptors, LH; D013629:Tamoxifen; D007987:Gonadotropin-Releasing Hormone
Oncol Rep. 2002 Sep-Oct;9(5):1127-32
12168084
J Endocrinol. 2002 Apr;173(1):1-11
11927379
J Clin Endocrinol Metab. 2003 Apr;88(4):1653-7
12679452
Mutat Res. 2003 Sep;544(1):9-41
12888106
Hum Mutat. 2003 Oct;22(4):261-74
12955713
J Clin Endocrinol Metab. 2004 Jun;89(6):2763-9
15181055
J Clin Endocrinol Metab. 1977 Feb;44(2):356-60
320223
Nature. 1985 Jan 17-23;313(5999):231-3
2982100
J Clin Endocrinol Metab. 1990 May;70(5):1233-8
2186053
Mol Cell Endocrinol. 1995 Jun;111(2):113-23
7556872
Cancer. 1996 Jan 1;77(1):97-103
8630946
Int J Cancer. 1997 May 16;71(4):595-9
9178813
Biometrics. 1997 Dec;53(4):1253-61
9423247
Osteoporos Int. 1998;8(5):404-9
9850346
Breast Cancer Res Treat. 2004 Oct;87(3):255-64
15528968
JAMA. 2004 Dec 22;292(24):2991-6
15613667
J Clin Oncol. 2005 Mar 10;23(8):1736-50
15755982
Oncologist. 2006 Feb;11(2):111-25
16476832
J Cancer Res Clin Oncol. 2006 May;132(5):275-86
16435142
J Clin Endocrinol Metab. 2006 Apr;91(4):1470-6
16464948
Nat Rev Cancer. 2006 Nov;6(11):886-93
17036039
J Natl Cancer Inst. 2000 Jun 7;92(11):903-11
10841825
Lancet. 2000 May 27;355(9218):1869-74
10866443
J Natl Cancer Inst. 2000 Jul 19;92(14):1126-35
10904085
Gynecol Oncol. 2000 Aug;78(2):194-202
10926802
N Engl J Med. 2001 Jan 25;344(4):276-85
11172156
J Clin Oncol. 2001 Jan 15;19(2):343-53
11208825
Cancer Res. 2002 Feb 15;62(4):1036-44
11861379
Bone. 2003 Feb;32(2):185-90
12633791