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Ovarian cancer and infertility: a genetic link?
Ovarian cancer and infertility: a genetic link? J J Nieto, K J Rolfe, A B MacLean, P Hardiman A genetic mechanism may be responsible for the increased incidence of ovarian cancer in some infertile women (ie, those who failed to conceive despite treatment).
The results of studies showing an increased risk of ovarian cancer in women previously treated for infertility,1,2 have been interpreted as evidence of a causal relationship between the drugs used to induce ovulation and ovarian cancer. However, interpretation of these studies is complicated by the confounding effect of infertility, which is itself a risk factor for ovarian cancer. Alternatively, one could postulate that infertility and epithelial ovarian cancer are consequences of a common underlying genetic abnormality. It is known that mutations of BRCA1 and BRCA2 genes are responsible for most cases of familial ovarian cancer3 and it has been suggested that there are several more common mutations that could allow for an unknown proportion of sporadic ovarian cancers. If some of these mutations were also responsible for infertility, the incidence of ovarian cancer would be increased not only in infertile women but also in their first-degree relatives. To explore this hypothesis, we did a retrospective casecontrol study of ovarian cancer in first-degree relatives of women with a past history of infertility. 672 women entered the study; 137 with a history of ovulatory infertility (53 nulliparous and 84 parous) and 535 controls (227 nulliparous and 308 parous). Women in the control group had ovarian ultrasound scans for a variety of reasons such as uterine myomas, and postmenopaual or perimenopausal bleeding of non-malignant origin. The prevalence of ovarian cancer in first-degree relatives of infertile women was 1·45% compared with 0·74% in relatives of fertile women (RR 1·95 [95% CI 0·36–10·55]). This difference was confined to relatives of women who did not conceive despite treatment (RR compared with fertile controls 14·8 [1·36–160]); there was no difference in prevalence between relatives of infertile women who ultimately conceived and fertile controls. The difference between ovarian cancer prevalence in first-degree relatives of women with voluntary nulliparity (who had not been exposed to fertility drugs) and fertile controls was not significant (RR 7·00 [0·82–59·6]). Our results suggest that first-degree relatives of infertile women have an increased risk of developing ovarian cancer but that this increase is restricted to the relatives of infertile women without children. However, there was no increased prevalence of epithelial ovarian cancer in relatives of multiparous women, regardless of their fertility. Interestingly, in the study by Whittemore,1 the increased risk of ovarian cancer was confined to infertile women who never conceived. Our results could also suggest a trend towards an increased prevalence of ovarian cancer in relatives of women with voluntary nulliparity, but it is difficult to interpret these data because an unknown proportion of the women in this group could have had untreated infertility whereas the remainder were potentially fertile. We suggest that there is a common genetic abnormality underlying infertility and ovarian cancer, and that this abnormality is restricted to a subgroup of women with infertility, who remain childless in spite of treatment. A larger study is planned to confirm these findings.
3
Ponder BAJ. The inheritied contribution to ovarian cancer. In: Ovarian Cancer 4. Leake R, Blackett A, Sharp F, eds. London: Chapman and Hall, 1996: 75–80.
Department of Obstetrics and Gynaecology, Royal Free and University College Medical School, Royal Free Campus, London NW3 2PF, UK (J J Nieto MRCOG, K J Rolfe BSc , Prof A B MacLean FRCOG, P Hardiman MRCOG) Correspondence to: Dr J J Nieto
Antibodies to lipopolysaccharides of Escherichia coli serogroups O5 and O165 in healthy adults Claire Jenkins, Henrik Chart The observation that over 50% of healthy blood donors have serum antibodies to the lipopolysaccharide of Escherichia coli O5 and O165 influences the serodiagnosis of infection with verocytotoxin-producing E coli.
Verocytotoxin-producing strains of Escherichia coli (VTEC) O157 are the main cause of haemolytic ureamic syndrome and renal failure in the UK, although VTEC belonging to other serogroups may also cause human disease. Infection with E coli O157 frequently results in the production of serum antibodies to the O157 lipopolysaccharide antigens and serology remains the method of choice for providing evidence of infection when this organism is not cultured from faeces of patients. Examining patients’ sera for antibodies to the lipopolysaccharide of E coli serogroups other than O157 showed that antibodies were most frequently detected to the lipopolysaccharide of E coli belonging to serogroups that have been isolated from patients only rarely, with 51 strains isolated by the Laboratory of Enteric Pathogens in the period 1981–95.2 A study involving 20 sera from healthy blood donors and 14 children, which did not contain antibodies to the lipopolysaccharide of E coli O157, showed that 11 blood donors but none of the children carried antibodies to the lipopolysaccharide of E coli O5 and O165. One blood donor had antibodies to the lipopolysaccharide of E coli O5 only. Although patients have been shown to possess antibodies to these lipopolysaccharide types,1–3 patients have not been shown to have antibodies to the lipopolysaccharide of both O5 and O165. The reasons for 55% of apparently healthy adults having antibodies to the lipopolysaccharide of E coli O5 and O165 are not known. The incidence of these bacteria in the gut of healthy people has not been determined, and the antibodies to these lipopolysaccharide types may result from shared epitopes with other bacteria. The lipopolysaccharide of E coli O5 has been shown to contain repeating tetrasaccharide units containing repeats of 2-acetamido-2-deoxy-D-galactose, D-galactose, D-ribose, and 3-acetamido-3,6-dideoxy-Dglucose, with the structure -[-4)--D-Galp-(1-3)-␣-DGalpNAc-(1-4)--D-Quinp3NAc-(1-3)--D-Ribf-(1-]-.4 Parts of this carbohydrate structure have been detected in Hafnia alvei, Acinetobacter baumannii, Proteus penneri, and probably occurs in other bacteria.5 The fact that a high proportion of healthy blood donors carry antibodies to the lipopolysaccharide of E coli O5 and O165, draws into question the results of previous serology that speculated that the patients’ serum antibodies to these two lipopolysaccharide types were indicative of infection with E coli O5 or O165. 1
1
2
Whittemore AS, Harris R, Intyre J. Characteristics relating to ovarian cancer risk: collaboraive analysis of 12 US case-control studies. Am J Epidemiol 1992; 136: 1184–203. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumours in a cohort of infertile women. N Engl J Med 1994; 331: 771–76.
THE LANCET • Vol 354 • August 21, 1999
Chart H, Rowe B. Serological identification of infection by Vero cytotoxin producing Escherichia coli in patients with haemolytic uraemic syndrome. Serodiagn Immunother Infect Dis 1990; 4: 413–18. 2 Chart H, Cheasty T, Rowe B. Serological identification of infection of Verocytotoxin-producing E coli. Letts Appl Microbiol 1996; 23: 322–24. 3 Jenkins C, Chart H. Serodiagnosis of infection with verocytotoxinproducing Escherichia coli. J Appl Microbiol 1999; 86: 569–75.
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The results of studies showing an increased risk of ovarian cancer in women previously treated for infertility,1,2 have been interpreted as evidence of a causal relationship between the drugs used to induce ovulation and ovarian cancer. However, interpretation of these studies is complicated by the confounding effect of infertility, which is itself a risk factor for ovarian cancer. Alternatively, one could postulate that infertility and epithelial ovarian cancer are consequences of a common underlying genetic abnormality. It is known that mutations of BRCA1 and BRCA2 genes are responsible for most cases of familial ovarian cancer3 and it has been suggested that there are several more common mutations that could allow for an unknown proportion of sporadic ovarian cancers. If some of these mutations were also responsible for infertility, the incidence of ovarian cancer would be increased not only in infertile women but also in their first-degree relatives. To explore this hypothesis, we did a retrospective casecontrol study of ovarian cancer in first-degree relatives of women with a past history of infertility. 672 women entered the study; 137 with a history of ovulatory infertility (53 nulliparous and 84 parous) and 535 controls (227 nulliparous and 308 parous). Women in the control group had ovarian ultrasound scans for a variety of reasons such as uterine myomas, and postmenopaual or perimenopausal bleeding of non-malignant origin. The prevalence of ovarian cancer in first-degree relatives of infertile women was 1·45% compared with 0·74% in relatives of fertile women (RR 1·95 [95% CI 0·36–10·55]). This difference was confined to relatives of women who did not conceive despite treatment (RR compared with fertile controls 14·8 [1·36–160]); there was no difference in prevalence between relatives of infertile women who ultimately conceived and fertile controls. The difference between ovarian cancer prevalence in first-degree relatives of women with voluntary nulliparity (who had not been exposed to fertility drugs) and fertile controls was not significant (RR 7·00 [0·82–59·6]). Our results suggest that first-degree relatives of infertile women have an increased risk of developing ovarian cancer but that this increase is restricted to the relatives of infertile women without children. However, there was no increased prevalence of epithelial ovarian cancer in relatives of multiparous women, regardless of their fertility. Interestingly, in the study by Whittemore,1 the increased risk of ovarian cancer was confined to infertile women who never conceived. Our results could also suggest a trend towards an increased prevalence of ovarian cancer in relatives of women with voluntary nulliparity, but it is difficult to interpret these data because an unknown proportion of the women in this group could have had untreated infertility whereas the remainder were potentially fertile. We suggest that there is a common genetic abnormality underlying infertility and ovarian cancer, and that this abnormality is restricted to a subgroup of women with infertility, who remain childless in spite of treatment. A larger study is planned to confirm these findings.
3
Ponder BAJ. The inheritied contribution to ovarian cancer. In: Ovarian Cancer 4. Leake R, Blackett A, Sharp F, eds. London: Chapman and Hall, 1996: 75–80.
Department of Obstetrics and Gynaecology, Royal Free and University College Medical School, Royal Free Campus, London NW3 2PF, UK (J J Nieto MRCOG, K J Rolfe BSc , Prof A B MacLean FRCOG, P Hardiman MRCOG) Correspondence to: Dr J J Nieto
Antibodies to lipopolysaccharides of Escherichia coli serogroups O5 and O165 in healthy adults Claire Jenkins, Henrik Chart The observation that over 50% of healthy blood donors have serum antibodies to the lipopolysaccharide of Escherichia coli O5 and O165 influences the serodiagnosis of infection with verocytotoxin-producing E coli.
Verocytotoxin-producing strains of Escherichia coli (VTEC) O157 are the main cause of haemolytic ureamic syndrome and renal failure in the UK, although VTEC belonging to other serogroups may also cause human disease. Infection with E coli O157 frequently results in the production of serum antibodies to the O157 lipopolysaccharide antigens and serology remains the method of choice for providing evidence of infection when this organism is not cultured from faeces of patients. Examining patients’ sera for antibodies to the lipopolysaccharide of E coli serogroups other than O157 showed that antibodies were most frequently detected to the lipopolysaccharide of E coli belonging to serogroups that have been isolated from patients only rarely, with 51 strains isolated by the Laboratory of Enteric Pathogens in the period 1981–95.2 A study involving 20 sera from healthy blood donors and 14 children, which did not contain antibodies to the lipopolysaccharide of E coli O157, showed that 11 blood donors but none of the children carried antibodies to the lipopolysaccharide of E coli O5 and O165. One blood donor had antibodies to the lipopolysaccharide of E coli O5 only. Although patients have been shown to possess antibodies to these lipopolysaccharide types,1–3 patients have not been shown to have antibodies to the lipopolysaccharide of both O5 and O165. The reasons for 55% of apparently healthy adults having antibodies to the lipopolysaccharide of E coli O5 and O165 are not known. The incidence of these bacteria in the gut of healthy people has not been determined, and the antibodies to these lipopolysaccharide types may result from shared epitopes with other bacteria. The lipopolysaccharide of E coli O5 has been shown to contain repeating tetrasaccharide units containing repeats of 2-acetamido-2-deoxy-D-galactose, D-galactose, D-ribose, and 3-acetamido-3,6-dideoxy-Dglucose, with the structure -[-4)--D-Galp-(1-3)-␣-DGalpNAc-(1-4)--D-Quinp3NAc-(1-3)--D-Ribf-(1-]-.4 Parts of this carbohydrate structure have been detected in Hafnia alvei, Acinetobacter baumannii, Proteus penneri, and probably occurs in other bacteria.5 The fact that a high proportion of healthy blood donors carry antibodies to the lipopolysaccharide of E coli O5 and O165, draws into question the results of previous serology that speculated that the patients’ serum antibodies to these two lipopolysaccharide types were indicative of infection with E coli O5 or O165. 1
1
2
Whittemore AS, Harris R, Intyre J. Characteristics relating to ovarian cancer risk: collaboraive analysis of 12 US case-control studies. Am J Epidemiol 1992; 136: 1184–203. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumours in a cohort of infertile women. N Engl J Med 1994; 331: 771–76.
THE LANCET • Vol 354 • August 21, 1999
Chart H, Rowe B. Serological identification of infection by Vero cytotoxin producing Escherichia coli in patients with haemolytic uraemic syndrome. Serodiagn Immunother Infect Dis 1990; 4: 413–18. 2 Chart H, Cheasty T, Rowe B. Serological identification of infection of Verocytotoxin-producing E coli. Letts Appl Microbiol 1996; 23: 322–24. 3 Jenkins C, Chart H. Serodiagnosis of infection with verocytotoxinproducing Escherichia coli. J Appl Microbiol 1999; 86: 569–75.
649