Association of <i>BRCA1</i> Mutations With Occult Primary Ovarian Insufficiency: A Possible Explanation for the Link Between Infertility and Breast/Ovarian Cancer Risks

Oktay, Kutluk; Kim, Ja Yeon; Barad, David H.; Babayev, Samir

doi:10.1200/jco.2009.24.2057

Cited by 327 publications

(270 citation statements)

References 27 publications

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“…While not included in Table 2, publications have discussed a possible link between infertility and the BRCA-1 mutation, which is a well-documented risk factor for the development of breast cancer. Oktay, Phillips, and Wang showed in three separate studies that BRCA-1 mutations were associated with low anti-mullerian hormone (AMH) levels and low ovarian response rates [37][38][39]. This subset of women, as expected, is at higher risk to develop breast cancer in the future.…”

Section: Infertility and Gynecologic Malignancymentioning

confidence: 81%

“…Patients with BRCA-1 mutations have well-documented lower AMH levels and low ovarian response rates to ART, but no convincing evidence exists to date to show that these women have decreased natural fertility [37][38][39]. It is important to note that the studies which discussed BRCA-1 mutations did not show correlations between low AMH and poor ovarian response in women with BRCA-2 mutations.…”

Section: Discussionmentioning

confidence: 99%

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Female infertility, infertility-associated diagnoses, and comorbidities: a review

Hanson

Johnstone

Dorais

et al. 2016

J Assist Reprod Genet

216

145

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Purpose The purpose of the study is to evaluate existing literature for possible associations between female infertility, infertility-associated diagnoses, and the following areas of disease: psychiatric disorders, breast cancer, ovarian cancer, endometrial cancer, cardiovascular disease, and metabolic dysfunction. Methods The design of the study is a literature review. The patients were women included in 26 selected studies due to a diagnosis of infertility or a reproductive disorder associated with infertility. This study has no interventions, and the main outcome measure is the association between female infertility or a related diagnosis and psychiatric disorders, breast cancer, ovarian cancer, endometrial cancer, cardiovascular disease, and metabolic dysfunction. Results Female infertility and related reproductive disorders may have ramifications for women beyond reproductive health. An analysis of publications shows that women with infertility had higher rates of psychiatric disorders and endometrial cancer than the general population [1][2][3][4][5][6][7][8][9][10]. Data is conflicting about whether infertile women are at increased risk for breast cancer and ovarian cancer [7,8,[10][11][12][13][14][15][16][17][18][19][20]. A generalized diagnosis of infertility was not clearly associated with an increased risk of cardiovascular disease or metabolic dysfunction, but women with infertility related to polycystic ovarian syndrome (PCOS) do appear more likely to develop cardioCapsule There is a growing body of literature addressing the impact of female infertility on long-term health. This review evaluates 26 studies, investigating possible correlations between infertility and psychiatric illness, breast cancer, ovarian cancer, endometrial cancer, cardiovascular disease, and metabolic dysfunction. Overall, higher rates of psychiatric illness and endometrial cancer were seen in infertile women. It is unclear whether infertility results in increased rates of breast cancer and ovarian cancer, and data are conflicting regarding correlations between generalized infertility and cardiovascular disease and metabolic dysfunction. This study summarizes current literature and can guide practitioners in counseling infertile patients.

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Section: Infertility and Gynecologic Malignancymentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Female infertility, infertility-associated diagnoses, and comorbidities: a review

Hanson

Johnstone

Dorais

et al. 2016

J Assist Reprod Genet

216

145

View full text Add to dashboard Cite

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“…No difference in the FMR1 genotype distribution is present among the two groups ( Figure 2): among BRCA mutation carriers, 22 (51.2%) were norm, 18 (41.9%) were het and 3 (6.9%) were hom, while in non-carriers 53 (51%) were norm, 40 (38.5%) were het and 11 (10.5%) were hom (w 2 …”

Section: Resultsmentioning

confidence: 98%

“…2 Impairment of functional ovarian reserve is associated with another genetic trait, the polymorphic CGG repeat of the Fragile X Mental Retardation 1 (FMR1) gene. 3 Female FMR1 premutation carriers (55-200 CGG repeats) are at increased risk of primary ovarian insufficiency (FXPOI).…”

Section: Introductionmentioning

confidence: 99%

The FMR1 CGG repeat test is not a candidate prescreening tool for identifying women with a high probability of being carriers of BRCA mutations

et al. 2013

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The identification of women with a high probability of being carriers of pathogenic BRCA mutation is not straightforward and a major improvement would be the availability of markers of mutations that could be directly evaluated in individuals asking for genetic testing. The FMR1 gene testing was recently proposed as a candidate prescreening tool because an association between BRCA pathogenic mutations and FMR1 genotypes with 'low alleles' (CGG repeat number o26) was observed. To confirm this hypothesis, we evaluated the distribution of FMR1 alleles and genotypes between BRCA mutation carriers and non-carriers in a cohort of 147 Italian women, free of cancer or affected by breast and/or ovarian cancer, who were tested for the presence of BRCA mutation in a clinical setting. The distribution of FMR1 CGG repeat numbers in the two groups was similar (lower allele median/mean were 30/27.4 and 30/27.9, respectively; Mann-Whitney test P ¼ 0.997) and no difference in the FMR1 genotype distribution was present (v 2 ¼ 0.503, d.f. ¼ 2, P ¼ 0.78). This result is in contrast with literature data and suggests that FMR1 genetic testing is not a candidate BRCA prescreening tool. European Journal of Human Genetics (2014) 22, 280-282; doi:10.1038/ejhg.2013 published online 25 September 2013 Keywords: FMR1; BRCA; HBOC; mutation screening INTRODUCTIONThe decision to offer testing for BRCA mutations is challenging in many women in whom an inherited predisposition to breast/ovarian cancer is suspected, because of the associated costs, but also for the difficult interpretation of test results when genetic variants of uncertain significance are detected. Although several tools have been developed to help in this decision, their performance is unsatisfactory. 1 A major improvement would be the availability of markers of pathogenic BRCA mutations that could be directly evaluated in individuals candidate to (or asking for) genetic testing.A low ovarian response rate was observed in BRCA1 mutationpositive women with breast cancer undergoing in vitro fertilization, suggesting an association between BRCA1 mutation and occult primary ovarian insufficiency. 2 Impairment of functional ovarian reserve is associated with another genetic trait, the polymorphic CGG repeat of the Fragile X Mental Retardation 1 (FMR1) gene. 3 Female FMR1 premutation carriers (55-200 CGG repeats) are at increased risk of primary ovarian insufficiency (FXPOI). However, an increased risk of ovarian insufficiency was also reported in women with CGG repeat numbers still within the conventional normal range (o55 CGG repeats) but lower (o26 CGG repeats) or higher (35-55 CGG repeats) of the range of CGG repeats associated with normal folliculogenesis (26-34 CGG repeats). [4][5][6] Recently, Weghofer et al 7 have investigated whether BRCA mutations and FMR1 ovarian genotypes are interdependent: in Austrian women carrying a BRCA mutation they observed almost exclusively the presence of genotypes containing at least one FMR1 allele with a CGG repeat number below 26 (so calle...

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“…However, this association is very controversial, and studies show contradictory results by means of parity, age at menopause, and AMH levels ( Table 2). Low performance in IVF was reported in only one small study which evaluated young breast cancer patients undergoing COH prior to cancer treatment [50]. Four of 12 BRCA1 carriers displayed poor ovarian response compared to only two of 68 non-carriers and untested patients.…”

Section: Brca Mutation and Ivf Performancementioning

confidence: 97%

IVF for fertility preservation in breast cancer patients—efficacy and safety issues

Shapira

Raanani

Meirow

2015

J Assist Reprod Genet

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Background Potential risks on future fertility have become a dominant issue in consultation and management of newly diagnosed young cancer patients. Several fertility preservation strategies are currently available. Of those, ovarian stimulation followed by IVF and embryo cryopreservation is the most established one and is especially applicable in reproductive aged breast cancer patients. Aim The aim of this study is to provide a comprehensive review on ovarian stimulation and IVF for fertility preservation in newly diagnosed breast cancer patients. Methods Review of relevant literature is available through PubMed and Google scholar. Results The use of IVF for fertility preservation in breast cancer patients raises dilemmas regarding efficacy and safety of controlled ovarian stimulation. Among these are the suggested role of malignancy and BRCA mutation in reducing ovarian response to stimulation, strategies designated to protect against hyper-estrogenic state associated with stimulation (co-treatment with tamoxifen or letrozole), and possible adjustments to accommodate oncologic-related time constraints. Conclusion Ovarian stimulation followed by IVF forms an important fertility preservation strategy for newly diagnosed young breast cancer patients, though live born rates following thawed embryo transfer in these patients are still lacking. Recent advances in controlled ovarian stimulation protocols provide practical options for some of the challenges that breast cancer patients present.

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Association of BRCA1 Mutations With Occult Primary Ovarian Insufficiency: A Possible Explanation for the Link Between Infertility and Breast/Ovarian Cancer Risks

Cited by 327 publications

References 27 publications

Female infertility, infertility-associated diagnoses, and comorbidities: a review

Female infertility, infertility-associated diagnoses, and comorbidities: a review

The FMR1 CGG repeat test is not a candidate prescreening tool for identifying women with a high probability of being carriers of BRCA mutations

IVF for fertility preservation in breast cancer patients—efficacy and safety issues

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