Genetic predisposition in gynecologic cancers

doi:10.1053/j.seminoncol.2016.08.005

Seminars in Oncology

Volume 43, Issue 5, October 2016, Pages 543-547

https://doi.org/10.1053/j.seminoncol.2016.08.005 Get rights and content

Abstract

This review article discusses the diagnosis and management of hereditary ovarian cancer and hereditary uterine cancer. The key recommendations highlighted are: All women with high grade non-mucinous epithelial ovarian cancer should be offered at least BRCA1 and BRCA2 genetic testing. The care of women with BRCA-associated ovarian cancer should be tailored to their mutation status. Risk-reducing bilateral salpingo-oophorectomy is recommended for women with BRCA1/2 mutations. Women with endometrial cancer should be assessed for the possibility of Lynch syndrome. Individuals with Lynch syndrome should undergo screening colonoscopy every 1–2 years. Lynch syndrome causes a high risk of endometrial cancer, and women with Lynch syndrome should consult with a gynecologic specialist to formulate a plan for managing this risk.

Section snippets

Diagnosis

During the last decade, compelling evidence has accumulated that women with epithelial ovarian cancer are at high enough risk to have a germline BRCA1 or BRCA2 mutation that genetic testing is recommended whether or not there is a family history of cancer [1]. The term “ovarian cancer” is understood to also include fallopian tube cancer and primary peritoneal cancer, particularly given the recent recognition that some, but not all, ovarian cancers appear to originate in the fallopian tube [2],

Management of ovarian cancer patients with a hereditary predisposition

For the BRCA-positive ovarian cancer patient, a new class of targeted therapies called PARP inhibitors has been shown to be particularly effective. Several studies in advanced and recurrent ovarian cancer patients have demonstrated that these drugs are preferentially effective in BRCA-associated ovarian cancers [19], [20], [21]. In December 2014, the US Food and Drug Administration (FDA) approved the use of olaparib for use in women with a BRCA mutation who had relapsed ovarian cancer, after

Diagnosis

In contrast to the relatively high percentage of ovarian cancer that is hereditary, only 2%–3% of all endometrial cancers are hereditary (see Fig. 1). Nearly all hereditary endometrial cancer is attributable to Lynch syndrome. Lynch syndrome is caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. MSH2 can also be indirectly inactivated via large deletion of the 3′ end of its neighbor EPCAM, although it is not yet clear whether the phenotypic consequences of EPCAM

Conclusion

Key recommendations for genetic predisposition in gynecologic cancers are listed in Table 1.

Conflicts of interest

None.

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Inherited rare and common variants in PTCH1 and PTCH2 contributing to the predisposition to reproductive cancers
2022, Gene
Citation Excerpt :
These cancers are sometimes grouped together, but little is known about their common genetic etiology. Current understanding of the genetic predisposition to these cancers centers around BRCA1 and BRCA2 and their partners in the homologous recombination repair pathway (Daniels and Lu, 2016; Wang, 2016). It is clear that rare, deleterious variants of BRCA1 and BRCA2 are associated with greater risks of breast, ovarian, and prostate cancers (Thompson and Easton, 2002; Antoniou et al., 2003; Kote-Jarai et al., 2011).
PTCH1 and PTCH2 are associated with nevoid basal cell carcinoma syndrome and basal cell carcinoma. We determined the prevalence of their common and rare variants in 877 patients with various reproductive cancers and 296 healthy subjects. Using targeted next-generation sequencing, we found significantly statistical associations of the minor alleles at seven common variants of PTCH1 and PTCH2 with a decreased risk of reproductive cancers (P = 9.69 × 10⁻¹²). Among these variants, two haplotype blocks in high linkage disequilibrium were consisted of rs2277184, rs2066829 and rs2236405 sites at PTCH1 and rs3795720, rs11573590 and rs11211040 sites at PTCH2. Single marker and haplotype-based analysis consistently revealed a decreased risk of reproductive cancers especially breast and prostate cancers in the subjects carrying the minor alleles, and on the contrary, an increased risk for major alleles. Healthy control subjects showed a higher rate of rare variants than that of cancer patients (P = 0.017). Notably, two frameshift variants (p.Ser391* and p.Cys101Alafs*48) of PTCH2 with deleterious effects were found in only four cancer patients. Higher frequencies of variants of PTCH genes might have a protective role against the development of reproductive cancers, whereas rare deleterious variants of PTCH2 might predispose a carrier to reproductive cancers.
Epithelial ovarian cancer
2022, Genomic and Precision Medicine: Oncology, Third Edition
Over the past decade, medicine has witnessed an explosion of new insights into the genomic events important for determining a woman’s susceptibility to ovarian cancer. Many of these insights also play a key role in determining clinical ovarian cancer outcomes. This chapter reviews our rapidly evolving understanding of these events. It places particular emphasis on those insights, such as our understanding of inherited syndromes of breast and ovarian cancer, that have dramatically expanded options for ovarian cancer prevention and treatment.
Hereditary ovarian tumour syndromes: current update on genetics and imaging
2021, Clinical Radiology
Citation Excerpt :
Annual transvaginal ultrasound starting at 30–35 years of age, endometrial biopsy, CA-125 testing, and prophylactic hysterectomy and bilateral salpingo-oophorectomy after childbearing (prior to the fifth decade), are recommended potential strategies for cancer risk reduction in LS, although there are no clinical studies to confirm their efficacy.39,40 Oral contraceptives have not been shown to be beneficial in reducing the risk of gynaecological cancers in LS.41 Several hereditary syndromes are characterised by the development of distinct yet uncommon non-epithelial ovarian neoplasms with pathognomic histopathological features that suggest the diagnosis (Table 2).
Hereditary ovarian tumour syndromes are a diverse group of hereditary syndromes characterised by the development of specific histotypes of ovarian neoplasms. While BRCA syndromes are exclusively associated with high-grade serous carcinomas, patients with Lynch syndrome show a preponderance of endometrioid subtype of ovarian and endometrial carcinomas. Distinct non-epithelial phenotypes, such as sex cord stromal tumours with annular tubules, Sertoli–Leydig cell tumours, and small cell carcinoma of the hypercalcaemic type occur in patients with Peutz–Jeghers, DICER1, and rhabdoid tumour predisposition syndromes, respectively. Gorlin–Goltz syndrome is characterised by the development of bilateral, multiple ovarian fibromas in 14–24% of patients. Ovarian steroid cell tumours and broad ligament papillary cystadenomas are characteristically found in women with von Hippel–Lindau syndrome. Recent studies have allowed the characterisation of tumour genetics and associated oncological pathways that contribute to tumourigenesis. Implications of the diagnosis of these syndromes on screening, management, and prognosis are discussed.
Inherited cancer syndromes in 220 Italian ovarian cancer patients
2019, Cancer Genetics
Citation Excerpt :
Identification of inherited conditions involving OCs has been traditionally performed through detailed pedigree analysis and germline molecular testing, and more recently through universal screening on colorectal and endometrial cancer samples for LS [7,8]. Considering the epidemiological, clinical and prognostic characteristic of OCs, the identification of an inherited condition might represent an useful strategic model of prevention, which includes benefits not only for the actual patients, but also for the potentially affected family members, who can be detected by cascade testing [5,9]. The aim of this retrospective study was to describe germline and somatic genetic strategies in a series of consecutive patients affected by OCs, who were tested to identify inherited conditions.
A subsets of ovarian carcinomas (OCs) are related to inherited conditions including Hereditary Breast and Ovarian Cancers (HBOC) and Lynch Syndrome (LS). The identification of inherited conditions using genetic testing might be a strategic model for cancer prevention that include benefits for the ovarian cancer patients and for their family members.
We describe a retrospective Italian experience for the identification of inherited conditions in 232 patients affected by OCs using both somatic and germline analyses.
Immunohistochemical and microsatellite analyses performed on OCs identified 20 out of 101 MMR defective cancers and 15 of these were from patients carriers of the MMR germline pathogenetic variants.
BRCA1 and BRCA2 testing offered to 198 OC patients revealed 67 (34%) pathogenetic variant carriers of BRCA1/2 genes. Interestingly LS patients revealed a mean age of OC onset of 45.4 years, which was significantly lower than the mean age of OCs onset of HBOC patients.
Somatic and germline analyses offered to OC patients has proved to be an efficient strategy for the identification of inherited conditions involving OC also in absence of suggestive family histories. The identification of LS and HBOC syndromes through OC patients is an effective tool for OC prevention.
Role of bioactive lipofishins in prevention of inflammation and colon cancer
2019, Seminars in Cancer Biology
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Cancer is a multistep process caused by accumulated errors in the genes that control cellular processes [1–10].
Many clinical conditions exist in which it is desirable to stimulate or suppress the immune system, and many different drugs are able to do this. It is also well known that nutrition may affect human health and immune responses. Nutritional factors are crucial components of the diet and essential for normal growth and development of both vertebrate and invertebrate organisms. Many of these components have been shown to play different roles in the immune response and, under different circumstances, they can significantly modulate the immune system to create an effective response. Diet and its components are known to play an important factor in the process of inflammation and in turn on the health effects related to inflammation, such as cancer and cardiovascular diseases. Previous research so far has mainly looked at the effect of specific food stuffs or nutrients on inflammation and health outcomes. The aims of the present review was a) to underline the fact that diet as a whole plays an important role in modifying inflammation and health outcomes related to inflammation, aging, and colon cancer; b) to show the in vitro cytotoxic effect of LipoFishins (E-Congerine 10423^®; AntiGan™) obtained from the Atlantic Conger conger marine organism present on the Galician coast, against different human tumor cell lines; c) to show the in vivo effect of E-Congerine-10423^® on colonic inflammation induced in mice by seven weeks’ exposure to 2% of dextran sulfate sodium (DSS); and d) to show the effect of E-Congerine-10423^® (AntiGan™) on tumor markers (TMs) in healthy subjects and in patients with different types of cancer at the time of diagnosis. Preliminary data in a limited number of cases indicate that about 50% of the patients show a reduction in the levels of tumor markers (TM), and this response was much more evident in patients with cancer, when TM values are above normal range. Finally, all the above mentioned results suggest that diet has a major role in controlling inflammation and thereby plays an important role in the development or prevention of various chronic diseases, hence public health steps should be taken to modify the individual’s whole diet and to promote the intake of specific natural compounds.
Women's preferences for cancer risk management strategies in Lynch syndrome
2019, Gynecologic Oncology
Citation Excerpt :
Potential strategies for reducing endometrial and ovarian cancer risk include endometrial biopsy, transvaginal ultrasound, CA125 testing, prophylactic hysterectomy with bilateral salpingo-oophorectomy in women who have completed childbearing [8]. While oral contraceptives have demonstrated a 50% decrease in endometrial cancer risk in the general population, they have not yet been proven to be efficacious in women with Lynch syndrome [9] and may only be appropriate in a select group of women [10]. Colonoscopy is a cost-effective screening strategy in LS; however, transvaginal ultrasounds alone have not been effective in identifying early cases of endometrial cancer [11,12].
We assessed preferences for cancer risk management strategies for Lynch syndrome (LS) in LS-affected women.
Women with LS aged ≥25 years evaluated 9 cancer risk management strategies using a visual analog scale (VAS) and modified standard gamble (SG). For the VAS, women ranked each strategy ranging from 0 (least preferred) to 100 (most preferred). VAS scores were calculated by dividing the corresponding number by 100. Scores closer to 1.0 reflected more favorable strategies. For the SG, participants were asked to specify their expected threshold of lifetime risk of endometrial or colorectal cancer, ranging from 0 to 100%, at which they would consider undertaking each strategy. Strategies included chemoprevention, cancer screening, and preventive surgery. Cancer worry and perceived cancer risk measures were collected on a subset of participants.
Sixty-one women completed preference assessments. By VAS, annual combined screening was the most preferred, followed by annual screenings and chemoprevention with oral contraceptives. By SG, women were the most willing to endorse oral contraceptives and biannual screening strategies at the lowest threshold of lifetime risk followed by annual screening strategies. Surgical interventions were the least preferred strategies using both VAS and SG. Women with a family history of gynecologic or colorectal cancer were less likely to consider prevention or screening options compared to women without a family history. Cancer worry was higher among women with a positive family history of LS cancer.
Understanding women's preferences may facilitate optimal use and adherence to cancer risk management strategies.

View all citing articles on Scopus

: Supported by the NIH/NCI Clinical Cancer Support Grant under award number P30CA016672.

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Genetic predisposition in gynecologic cancers

Abstract

Section snippets

Diagnosis

Management of ovarian cancer patients with a hereditary predisposition

Diagnosis

Conclusion

Conflicts of interest

Gynecol Oncol

Gynecol Oncol

Lancet Oncol

Lancet Oncol

Eur J Cancer

Am J Obstet Gynecol

Genet Med

Gynecol Oncol

Gynecol Oncol

Gastroenterology

Gynecol Oncol

Microscopic and early-stage ovarian cancers in BRCA1/2 mutation carriers: building a model for early BRCA-associated tumorigenesis

Cancer Prev Res

Cancer : principles & practice of oncology. Primer of the molecular biology of cancer

Inherited mutations in women with ovarian carcinoma

JAMA Oncol

BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group

J Clin Oncol

Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing

Proc Natl Acad Sci U S A

BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases

Cancer

Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer

Br J Cancer

American Society of Clinical Oncology Policy Statement Update: genetic and genomic testing for cancer susceptibility

J Clin Oncol

Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer

J Natl Cancer Inst

Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population

J Clin Oncol

BRIP1 as an ovarian cancer susceptibility gene: ready for the clinic?

J Natl Cancer Inst

Germline sequence variants and ovarian cancer: known-knowns and known-unknowns

JAMA Oncol

DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors

JAMA

Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz-Jeghers syndrome and four with adenoma malignum of the cervix

Cancer