Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies

Lee, Alice W.; Rosenzweig, Stacey; Wiensch, Ashley; Ramus, Susan J.; Menon, Usha; Gentry‐Maharaj, Aleksandra; Ziogas, Argyrios; Anton‐Culver, Hoda; Whittemore, Alice S.; Sieh, Weiva; Rothstein, Joseph H.; McGuire, Valerie; Wentzensen, Nicolas; Bandera, Elisa V.; Qin, Bo; Terry, Kathryn L.; Cramer, Daniel W.; Titus, Linda; Schildkraut, Joellen M.; Berchuck, Andrew; Goode, Ellen L.; Kjær, Susanne K.; Jensen, Allan; Jordan, Susan J.; Ness, Roberta B.; Modugno, Francesmary; Moysich, Kirsten B.; Thompson, Pamela J.; Goodman, Marc T.; Carney, Michael E.; Chang‐Claude, Jenny; Rossing, Mary Anne; Harris, Holly R.; Doherty, Jennifer A.; Risch, Harvey A.; Khoja, Lilah; Alimujiang, Aliya; Phung, Minh Tung; Brieger, Katharine K; Mukherjee, Bhramar; Pharoah, Paul; Wu, Anna H.; Pike, Malcolm C.; Webb, Penelope M.; Pearce, Celeste Leigh

doi:10.1093/jnci/djaa099

Cited by 11 publications

(13 citation statements)

References 37 publications

(64 reference statements)

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“…Three large observational studies have previously looked into differential effects of childbirths on ovarian cancer histological subtypes 7,21,22 . All three studies found protective effects of childbirth on the risk of each major subtype of ovarian cancer subtype (ie, serous, mucinous, endometrioid and clear‐cell ovarian cancer), which also was found in our study.…”

Section: Discussionsupporting

confidence: 86%

Pregnancy duration and ovarian cancer risk: A 50‐year nationwide cohort study

Husby

Wohlfahrt

Melbye

2022

Intl Journal of Cancer

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A woman's reproductive history is strongly associated with her risk of ovarian cancer.However, it is unclear how pregnancies of different duration impact a woman's ovarian cancer risk, and therefore, what part of a pregnancy explains the protective effect. Using a cohort of all Danish women followed from 1968 to 2018, with prospectively registered information on reproductive history (eg, gestational duration of pregnancies, tubal ligation and resection and hormonal pharmaceutical use), we investigated the effect of pregnancy duration on ovarian cancer risk. We adjusted for potential confounders, such as age at pregnancy and time since pregnancy, using loglinear Poisson regression to isolate the effect of pregnancy duration on ovarian cancer risk. Among 2.5 million Danish women with 4.4 million pregnancies, a pregnancy was associated with a reduction of ovarian cancer risk of 21% (95% CI, 14%-28%), 26% (95% CI, 21%-31%), 12% (95% CI, 7%-17%) and 3% (95% CI, À5% to 11%) compared to one less, for the first, second, third and fourth pregnancy, respectively (P < .001 for heterogeneity), with similar effects of induced abortions, spontaneous abortions and childbirths. Sensitivity analysis of age at pregnancy, time since pregnancy and other potential confounders did not change these findings. The reduced ovarian cancer risk associated with pregnancy is primarily driven by the first three pregnancies, with similar effects of induced abortion, spontaneous abortions and childbirth, suggesting that mainly exposure to early pregnancy factors, and not pregnancy duration, protect against ovarian cancer.

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Section: Discussionsupporting

confidence: 86%

Pregnancy duration and ovarian cancer risk: A 50‐year nationwide cohort study

Husby

Wohlfahrt

Melbye

2022

Intl Journal of Cancer

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“…Some studies have observed that the risk of ovarian cancer decreases with the number of pregnancies. 23 , 24 We intended to analyze the relationship between the number of pregnancies and BRCA mutations in the patients with ovarian cancer. Accordingly, 8 women (4.1%) never had a pregnancy, 94 women (48.2%) had 1–3 pregnancies, 34 women (17.4%) had 4–5 pregnancies, 14 women (7.2%) had >5 pregnancies, and the remaining 45 (23.1%) were unknown.…”

Section: Resultsmentioning

confidence: 99%

The Features of BRCA1 and BRCA2 Germline Mutations in Hakka Ovarian Cancer Patients: BRCA1 C.536 A>T Maybe a Founder Mutation in This Population

Luo

Huang

et al. 2022

IJGM

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Objective To investigate the frequencies of BRCA1 and BRCA2 mutations in Chinese Hakka patients with ovarian cancer. Methods The protein coding regions and exon intron boundary regions of the BRCA gene were sequenced using genomic DNA isolated from the lymphocytes of patients with next-generation sequencing. The patients’ family history and clinical records were collected. Results A total of 195 patients with ovarian cancer were included in the study, and 52 distinct variants of the BRCA gene were identified. It was found that 64 patients (64/195, 32.8%) had BRCA gene mutations, including 32 patients (50.0%) with BRCA1 mutation, 27 patients (42.2%) with BRCA2 mutation, and 5 patients (7.8%) with both mutations. Furthermore, 22 pathogenic mutations were detected in 26 patients, 2 likely pathogenic variants in 2 patients, 12 variants of uncertain significance in 20 patients, and 16 likely benign variants in 24 patients. The mutations were mainly found to occur in exons 8, 14, and 17 of BRCA1 and exons 10, 11, 14, and 15 of BRCA2 . The results showed that the BRCA genes possess different mutation hotspots in different ethnic groups. In addition, recurrent mutations were noted in many patients. BRCA1 c.536 A>T, considered a founder mutation, was identified in 10 patients (15.63%, 10/64), followed by BRCA1 c.2635 G>T (6.25%, 4/64) and BRCA2 c.2566 T>C (6.25%, 4/64). Conclusion The BRCA1 c.536 A>T could be considered to be a founder mutation in this ovarian cancer population. This recurrent BRCA1 mutation has rarely been observed in other ethnic groups. Our findings are expected to provide valuable data for clinical consultation and for designing individualized treatment for ovarian cancer.

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“…The risk reduction observed in incomplete pregnancy (duration approximately 4-8 weeks) was similar in magnitude to the reduction observed with oral contraceptive use for 1 year (∼8% risk reduction per year of oral contraceptive use) ( 24 , 26 ), suggesting that factors present in pregnancy other than hormonal changes contribute to the protective effect of pregnancy. Another recent pooled study also showed a 16% reduction in ovarian cancer risk in women ever having an incomplete pregnancy ( 46 ), and another recent study reported that the reduced risk of ovarian cancer associated with term pregnancy was similar to the reduction with incomplete pregnancy including abortions ( 47 ). Taken together, these studies suggested that the incessant ovulation hypothesis may not be able to completely explain the mechanism underlying the protective effect of pregnancies.…”

Section: Evidence Of Flaws In the Altered Endocrine Balance Hypothesismentioning

confidence: 86%

“…A number of studies recently reported that women with incomplete pregnancies, such as spontaneous miscarriage or induced abortion, also have a reduced risk of developing ovarian and endometrial cancer despite progesterone levels only rising modestly compared with full term pregnancies ( 20 , 26 , 46 ). In a pooled analysis of 11 cohort and 29 case–control studies, incomplete pregnancies were found to reduce the risk of endometrial cancer, and to further reduce the risk by 7% to 9% for each additional incomplete pregnancy ( 26 ).…”

Section: Evidence Of Flaws In the Altered Endocrine Balance Hypothesismentioning

confidence: 99%

Understanding How Pregnancy Protects Against Ovarian and Endometrial Cancer Development: Fetal Antigens May Be Involved

et al. 2022

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It is well-known that many factors including infertility, obesity, type 2 diabetes, and family history of cancer increase the risk of developing endometrial and ovarian cancer. However, multiparous women are known to have a lower risk of developing either ovarian or endometrial cancer than non-parous women. The lack of ovulation and shifting of sex hormonal balance, with decreased estrogen levels and increased progesterone levels during pregnancy, has traditionally been thought to be the major contributor to this decreased risk. However, in reality, the mechanisms underlying this phenomenon are relatively unknown. Increasing evidence suggests that endocrine factors are unlikely to completely explain the protective effect of pregnancies, and that multiple other non-endocrine mechanisms including fetal antigens and the newly proposed dormant cells hypothesis may also be involved. In this review, we summarise recent evidence and describe the potential underlying mechanisms that may explain how pregnancy protects against the development of ovarian and endometrial cancers in women’s later life.

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Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies

Cited by 11 publications

References 37 publications

Pregnancy duration and ovarian cancer risk: A 50‐year nationwide cohort study

Pregnancy duration and ovarian cancer risk: A 50‐year nationwide cohort study

The Features of BRCA1 and BRCA2 Germline Mutations in Hakka Ovarian Cancer Patients: BRCA1 C.536 A>T Maybe a Founder Mutation in This Population

Understanding How Pregnancy Protects Against Ovarian and Endometrial Cancer Development: Fetal Antigens May Be Involved

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