Fallopian Tube Cancer

Overview

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cancer DNA
  • Cystadenocarcinoma, Serous
  • Mutation
  • Ovarian Cancer
  • Fallopian tube cancer
  • TP53
  • Ubiquitin-Protein Ligases
  • ERBB2
  • Biomarkers, Tumor
  • Virus Integration
  • DNA Mutational Analysis
  • Epithelium
  • Genetic Predisposition
  • Case-Control Studies
  • BRCA1 Protein
  • BRCA1
  • Ploidies
  • Risk Reduction Behavior
  • Breast Cancer
  • Staining and Labeling
  • Carcinoma
  • Hysterectomy
  • Promoter Regions
  • Phenotype
  • Risk Factors
  • Germ-Line Mutation
  • Heterozygote
  • BRCA2
  • Fallopian Tubes
  • Staging
  • Peritoneal Neoplasms
  • Immunohistochemistry
  • Adenocarcinoma
  • Cancer Gene Expression Regulation
  • Precancerous Conditions
  • BRCA2 Protein
  • Ovariectomy
  • Carcinoma in Situ
  • Pedigree
  • p53 Protein
  • Transcription Factors
  • MKI67
Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (6)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
BRCA1 17q21.31 IRIS, PSCP, BRCAI, BRCC1, FANCS, PNCA4, RNF53, BROVCA1, PPP1R53 -BRCA1 mutations in Fallopian Tube Cancer
140
BRCA2 13q13.1 FAD, FACD, FAD1, GLM3, BRCC2, FANCD, PNCA2, FANCD1, XRCC11, BROVCA2 -BRCA2 and Fallopian Tube Cancer
117
TP53 17p13.1 P53, BCC7, LFS1, TRP53 -TP53 and Fallopian Tube Cancer
27
MKI67 10q26.2 KIA, MIB-, MIB-1, PPP1R105 -Ki-67 Antigen and Fallopian Tube Cancer
18
PAX2 10q24 FSGS7, PAPRS -PAX2 and Fallopian tube cancer
8
ERBB2 17q12 NEU, NGL, HER2, TKR1, CD340, HER-2, MLN 19, HER-2/neu -ERRB2 and Fallopian Tube Cancer
3

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Blok F, Roes EM, van Leenders GJ, van Beekhuizen HJ
The lack of clinical value of peritoneal washing cytology in high risk patients undergoing risk-reducing salpingo-oophorectomy: a retrospective study and review.
BMC Cancer. 2016; 16:18 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To assess the clinical value of peritoneal washing cytology (PWC) in women with BRCA1 or BRCA2 mutations and women from a family with hereditary breast and/or ovarian cancer (HBOC) undergoing risk-reducing salpingo-oophorectomy (RRSO) in detecting primary peritoneal cancer (PPC) or occult ovarian/fallopian tube cancer.
METHODS: A retrospective study of patients with known BRCA1 or BRCA2 mutation or HBOC who underwent RRSO at the Erasmus Medical Centre, Rotterdam, The Netherlands between January 2000-2014. Patients with an elevated risk of malignancy prior to the procedure were excluded from primary analysis (elevated CA-125, an ovarian mass, abdominal pain or another gynecological malignancy). A review of the literature was conducted.
RESULTS: Of the 471 patients who underwent RRSO, a total of 267 cytology samples were available for analysis. Four samples showed malignant cells, all four patients were diagnosed with ovarian and/or fallopian tube cancer at histologic examination. A fifth patient, of whom no cytology sample was obtained during RRSO, developed primary peritoneal cancer 80 months post RRSO.
CONCLUSIONS: This study failed to show that cytology is of value during RRSO in detecting primary peritoneal cancer, however 36% of patients with concomitant ovarian or fallopian tube cancer had positive cytology. Therefore, the routine sampling of peritoneal washings during RRSO is not found to be useful to detect subsequent PPC.

Harter P, Johnson T, Berton-Rigaud D, et al.
BRCA1/2 mutations associated with progression-free survival in ovarian cancer patients in the AGO-OVAR 16 study.
Gynecol Oncol. 2016; 140(3):443-9 [PubMed] Related Publications
OBJECTIVE: AGO-OVAR 16 demonstrated that pazopanib maintenance therapy significantly increased progression-free survival (PFS) in patients with ovarian cancer whose disease had not progressed after first-line therapy. In a sub-study, we evaluated the effect of clinically important germline BRCA1 and BRCA2 mutations on PFS.
METHODS: Of 940 AGO-OVAR 16 participants, 664 had BRCA1/2 exon sequencing data (pazopanib, n=335; placebo, n=329). A Cox model was used to test the association between genetic variants and PFS.
RESULTS: Ninety-seven of 664 patients (15%) carried clinically important BRCA1/2 mutations (BRCA1/2 carriers: pazopanib 14%, placebo 16%). Median PFS was longer in BRCA1/2 mutation carriers than in BRCA1/2 non-carriers in the placebo arm (30.3 vs 14.1 months, hazard ratio, 0.48; 95% confidence interval [CI]: 0.29-0.78; P=0.0031); a similar non-significant trend was noted with pazopanib (30.2 vs 17.7 months, hazard ratio, 0.64; 95% CI: 0.40-1.03; P=0.069). Among BRCA1/2 non-carriers, PFS was longer for pazopanib-treated patients than placebo-treated patients (17.7 vs 14.1 months, hazard ratio, 0.77; 95% CI: 0.62-0.97; P=0.024). Among BRCA1/2 carriers, there was no significant PFS difference between treatments, although numbers were small (pazopanib, 46; placebo, 51), resulting in a wide CI (hazard ratio, 1.36; 95% CI: 0.66-2.82).
CONCLUSIONS: Patients with clinically important BRCA1/2 mutations had better prognosis. BRCA1/2 mutation status might be added as strata in future trials in primary ovarian cancer.

Sakamoto I, Hirotsu Y, Nakagomi H, et al.
BRCA1 and BRCA2 mutations in Japanese patients with ovarian, fallopian tube, and primary peritoneal cancer.
Cancer. 2016; 122(1):84-90 [PubMed] Related Publications
BACKGROUND: The contribution of BRCA1 and BRCA2 to ovarian cancer in Japanese patients is still unclear. This study investigated the frequency of germline mutations in BRCA1/2 in Japanese patients with ovarian, peritoneal, or fallopian tube cancer, regardless of their family histories, which were suggestive of hereditary breast and ovarian cancer.
METHODS: Ninety-five unselected women with ovarian cancer who were seen from 2013 to 2015 at Yamanashi Prefectural Central Hospital were enrolled. Analyses of BRCA1/2 gene mutations were performed with next-generation sequencing.
RESULTS: Twelve of the 95 patients (12.6%), including 5 in the BRCA1 (5.3%) and 7 in the BRCA2 (7.4%), had deleterious mutations. Among the 36 cases with a family history, 6 (16.7%) were found to carry mutations in BRCA1 and BRCA2. Notably, 6 of the 59 cases (10.2%) without a family history also had BRCA1/2 germline mutations. There was no statistical difference between the 2 groups (P = .36). The presence of mutations and their clinical relevance were studied. Mutation carriers were diagnosed at advanced stages (100% of positive cases among stage III or IV cases) and had poor prognostic histological subtypes (100% of positive cases had high-grade serous adenocarcinomas).
CONCLUSIONS: In this unselected Japanese population, approximately 13% of the cases with ovarian cancer appeared to be associated with an inherited risk, regardless of a family history. This finding indicates that BRCA1/2 genetic testing should be performed for all patients with ovarian cancers.

Mahdi H, Gockley A, Esselen K, et al.
Outcome of neoadjuvant chemotherapy in BRCA1/2 mutation positive women with advanced-stage Müllerian cancer.
Gynecol Oncol. 2015; 139(3):407-12 [PubMed] Related Publications
OBJECTIVES: To investigate whether patients with germline BRCA1/2 mutations who received neoadjuvant chemotherapy (NAC) for advanced-stage Müllerian cancer (MC) have an improved outcome compared to patients who did not undergo genetic testing.
METHODS: Three hundred and two patients who received NAC for stage III-IV MC were identified from a multi-institutional study involving Cleveland Clinic and Brigham and Women's Hospital for 2000-2014 and 2010-2014 respectively. Patients were divided into 3 cohorts: patients with germline BRCA1/2 mutations (BRCA_mut+; N=30), patients with no genetic testing (BRCA_mut_unk; N=166) and patients with negative genetic testing (BRCA_mut-, N=106).
RESULTS: There were no differences in the clinical characteristics and rates of complete cytoreduction and bowel resection between the three groups. BRCA_mut+ had longer PFS compared to BRCA_mut_unk and BRCA_mut- (19.1 vs. 15.1 vs. 15.7months respectively. However, this difference was not statistically significant (p=0.48). Patients with BRCA2 mutation had non-significant trend toward longer PFS compared to patients with unknown BRCA or BRCA1 mutation (20.2 vs. 15.1 vs. 14.8months respectively, p=0.58). BRCA_mut+ and BRCA_mut- had longer overall survivals (OS) compared to BRCA_mut_unk patients (50.5 vs. 54.1 vs. 36.5months respectively, p=0.009). In multivariable analyses, controlling for age, stage and complete cytoreduction, BRCA_mut_unk was associated with worse PFS (HR 1.44, 95% CI 1.01-2.05, p=0.045) and OS (HR 2.67, 95% CI 1.33-5.36, p=0.006).
CONCLUSIONS: Patients with germline BRCA mutations had improved outcomes with NAC compared to patients with unknown BRCA status. These outcomes were more favorable compared to the outcome of NAC in prior studies.

McDaniel AS, Stall JN, Hovelson DH, et al.
Next-Generation Sequencing of Tubal Intraepithelial Carcinomas.
JAMA Oncol. 2015; 1(8):1128-32 [PubMed] Free Access to Full Article Related Publications
IMPORTANCE: High-grade serous carcinoma (HGSC) is the most prevalent and lethal form of ovarian cancer. HGSCs frequently arise in the distal fallopian tubes rather than the ovary, developing from small precursor lesions called serous tubal intraepithelial carcinomas (TICs, or more specifically, STICs). While STICs have been reported to harbor TP53 mutations, detailed molecular characterizations of these lesions are lacking.
OBSERVATIONS: We performed targeted next-generation sequencing (NGS) on formalin-fixed, paraffin-embedded tissue from 4 women, 2 with HGSC and 2 with uterine endometrioid carcinoma (UEC) who were diagnosed as having synchronous STICs. We detected concordant mutations in both HGSCs with synchronous STICs, including TP53 mutations as well as assumed germline BRCA1/2 alterations, confirming a clonal association between these lesions. Next-generation sequencing confirmed the presence of a STIC clonally unrelated to 1 case of UEC, and NGS of the other tubal lesion diagnosed as a STIC unexpectedly supported the lesion as a micrometastasis from the associated UEC.
CONCLUSIONS AND RELEVANCE: We demonstrate that targeted NGS can identify genetic alterations in minute lesions, such as TICs, and confirm TP53 mutations as early driving events for HGSC. Next-generation sequencing also demonstrated unexpected associations between presumed STICs and synchronous carcinomas, providing evidence that some TICs are actually metastases rather than HGSC precursors.

Howitt BE, Hanamornroongruang S, Lin DI, et al.
Evidence for a dualistic model of high-grade serous carcinoma: BRCA mutation status, histology, and tubal intraepithelial carcinoma.
Am J Surg Pathol. 2015; 39(3):287-93 [PubMed] Related Publications
Most early adnexal carcinomas detected in asymptomatic women with germline BRCA mutations (BRCA) present as serous tubal intraepithelial carcinomas (STIC). However, STICs are found in only ∼40% of symptomatic high-grade serous carcinomas (HGSCs) and less frequently in pseudoendometrioid variants of HGSC. Consecutive cases of untreated HGSC from BRCA and BRCA women with detailed fallopian tube examination (SEE-FIM protocol) were compared. STIC status (+/-) was determined, and tumors were classified morphologically as SET ("SET", >50% solid, pseudoendometrioid, or transitional) or classic predominate ("Classic"). SET tumors trended toward a higher frequency in BRCA versus BRCA women (50% vs. 28%, P=0.11), had a significantly younger mean age than those with classic HGSC in BRCA women (mean 56.2 vs. 64.8 y, P=0.04), and displayed a better clinical outcome in both groups combined (P=0.024). STIC was significantly more frequent in tumors from the BRCA cohort (66% vs. 31%, P=0.017) and specifically the BRCA tumors with classic morphology (83%) versus those with SET morphology (22%, P=0.003). Overall, several covariables-histology, BRCA status, age, coexisting STIC, and response to therapy-define 2 categories of HGSC with differences in precursor (STIC) frequency, morphology, and outcome. We introduce a dualistic HGSC model that could shed light on the differences in frequency of STIC between symptomatic and asymptomatic women with HGSC. This model emphasizes the need for further study of HGSC precursors to determine their relevance to the prevention of this lethal malignancy.

Ning G, Bijron JG, Yamamoto Y, et al.
The PAX2-null immunophenotype defines multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium.
J Pathol. 2014; 234(4):478-87 [PubMed] Free Access to Full Article Related Publications
The oviducts contain high-grade serous cancer (HGSC) precursors (serous tubal intraepithelial neoplasia or STINs), which are γ-H2AX(p) - and TP53 mutation-positive. Although they express wild-type p53, secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer; moreover, both STINs and SCOUTs share a loss of PAX2 expression (PAX2(n) ). We evaluated PAX2 expression in proliferating adult and embryonic oviductal cells, normal mucosa, SCOUTs, Walthard cell nests (WCNs), STINs, and HGSCs, and the expression of genes chosen empirically or from SCOUT expression arrays. Clones generated in vitro from embryonic gynaecological tract and adult Fallopian tube were Krt7(p) /PAX2(n) /EZH2(p) and underwent ciliated (PAX2(n) /EZH2(n) /FOXJ1(p) ) and basal (Krt7(n) /EZH2(n) /Krt5(p) ) differentiation. Similarly, non-ciliated cells in normal mucosa were PAX2(p) but became PAX2(n) in multi-layered epithelium undergoing ciliated or basal (WCN) cell differentiation. PAX2(n) SCOUTs fell into two groups: type 1 were secretory or secretory/ciliated with a 'tubal' phenotype and were ALDH1(n) and β-catenin(mem) (membraneous only). Type 2 displayed a columnar to pseudostratified (endometrioid) phenotype, with an EZH2(p) , ALDH1(p) , β-catenin(nc) (nuclear and cytoplasmic), stathmin(p) , LEF1(p) , RCN1(p) , and RUNX2(p) expression signature. STINs and HGSCs shared the type 1 immunophenotype of PAX2(n) , ALDH1(n) , β-catenin(mem) , but highly expressed EZH2(p) , LEF1(p) , RCN1(p) , and stathmin(p) . This study, for the first time, links PAX2(n) with proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs, and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumour suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2), calcium binding (RCN1), and oncogenesis (stathmin). This shared expression signature between benign and neoplastic entities links normal progenitor cell expansion to abnormal and neoplastic outgrowth in the oviduct and exposes a common pathway that could be a target for early prevention.

Cass I, Walts AE, Barbuto D, et al.
A cautious view of putative precursors of serous carcinomas in the fallopian tubes of BRCA mutation carriers.
Gynecol Oncol. 2014; 134(3):492-7 [PubMed] Related Publications
OBJECTIVE: To compare the frequency and distribution of candidate precursors of serous carcinoma in the fallopian tubes of BRCA mutation carriers to BRCA non-mutation carriers (controls) at risk-reducing bilateral salpingo-oophorectomy (RRSO).
METHODS: 78 BRCA carriers (52 BRCA1, 26 BRCA2) and 23 controls underwent RRSO. Fallopian tubes were serially cross-sectioned, and adnexa were entirely submitted and examined by two gynecologic pathologists blinded to BRCA mutation status. The presence and location of serous tubal intraepithelial carcinoma (STIC), p53 overexpression (≥ 6 consecutively stained nuclei), Ki67 overexpression, atypia/low grade dysplasia and epithelial hyperplasia were compared between BRCA carriers and controls. Patient age was dichotomized: ≤ 50 and >50 years.
RESULTS: 9 (12%) BRCA carriers had occult carcinoma: 8 STIC and 1 stage IC tubal carcinoma with STIC. No occult carcinomas or STIC was seen in controls. STIC involved the distal tube in all cases and was multifocal in three cases. STIC was more common in women >50 (p=0.06). P53 overexpression was common in BRCA carriers (30%) and controls (43%) (p=0.5) and did not correlate with age. Only 5/9 (55%) of STIC exhibited p53 overexpression. 2 patients had Ki67 overexpression: both BRCA1 carriers with STIC. No difference in the frequency of atypia/low grade dysplasia or hyperplasia was observed between BRCA carriers and controls.
CONCLUSIONS: STIC is the dominant precursor of serous fallopian tube carcinoma in BRCA carriers. There is insufficient evidence to support p53 overexpression alone as a putative precursor. Atypia/low grade dysplasia and epithelial hyperplasia are not pre-neoplastic lesions of serous fallopian tube carcinoma.

Hunter SM, Ryland GL, Moss P, et al.
Genomic aberrations of BRCA1-mutated fallopian tube carcinomas.
Am J Pathol. 2014; 184(6):1871-6 [PubMed] Related Publications
Intraepithelial carcinomas of the fallopian tube are putative precursors to high-grade serous carcinomas of the ovary and peritoneum. Molecular characterization of these early precursors is limited but could be the key to identifying tumor biomarkers for early detection. This study presents a genome-wide copy number analysis of occult fallopian tube carcinomas identified through risk-reducing prophylactic oophorectomy from three women with germline BRCA1 mutations, demonstrating that extensive genomic aberrations are already established at this early stage. We found no indication of a difference in the level of genomic aberration observed in fallopian tube carcinomas compared with high-grade serous ovarian carcinomas. These findings suggest that spread to the peritoneal cavity may require no or very little further tumor evolution, which raises the question of what is the real window of opportunity to detect high-grade serous peritoneal carcinoma arising from the fallopian tube before it spreads. Nonetheless, the similarity of the genomic aberrations to those observed in high-grade serous ovarian carcinomas suggests that genetic biomarkers identified in late-stage disease may be relevant for early detection.

Ishikawa H, Kiyokawa T, Utsuno E, et al.
Serous tubal intraepithelial carcinoma in a Japanese woman with a deleterious BRCA1 mutation.
Jpn J Clin Oncol. 2014; 44(6):597-601 [PubMed] Related Publications
Risk-reducing salpingo-oophorectomy for reducing future cancer risk in women with hereditary breast and ovarian cancer syndrome is rarely performed in Japan; therefore, the cancer preventive effect of risk-reducing salpingo-oophorectomy for hereditary breast and ovarian cancer syndrome among the Japanese population remains unclear. Here, we report the first case of serous tubal intraepithelial carcinoma identified through a risk-reducing salpingo-oophorectomy in a Japanese woman with hereditary breast and ovarian cancer syndrome and who had a deleterious germline mutation of E1214X in BRCA1, but not a BRCA2 mutation. A pre-operative examination revealed multiple uterine leiomyomas but no adnexal mass. Robotic-assisted bilateral salpingo-oophorectomy together with hysterectomy was performed. A pathological examination identified serous tubal intraepithelial carcinoma in the right fallopian tube with no dissemination. Serous tubal intraepithelial carcinoma is implicated as an origin of invasive cancer of the fallopian tube with peritoneal dissemination; prophylactic salpingo-oophorectomy is currently the only method to identify this occult cancer. Our case demonstrated that risk-reducing salpingo-oophorectomy can detect occult cancers, including serous tubal intraepithelial carcinoma, thereby preventing future cancer development in the Japanese hereditary breast and ovarian cancer syndrome population.

Staff S, Tolonen T, Laasanen SL, et al.
Quantitative analysis of γ-H2AX and p53 nuclear expression levels in ovarian and fallopian tube epithelium from risk-reducing salpingo-oophorectomies in BRCA1 and BRCA2 mutation carriers.
Int J Gynecol Pathol. 2014; 33(3):309-16 [PubMed] Related Publications
Mutations in BRCA1 and BRCA2 genes confer an increased lifetime risk for breast and ovarian cancer. Increased lifetime ovarian cancer risk among BRCA1/BRCA2 mutation carriers can be substantially decreased by risk-reducing salpingo-oophorectomy (RRSO), which also provides material for molecular research on early pathogenesis of serous ovarian cancer. RRSO studies have suggested fallopian tube as a primary site of serous high-grade ovarian cancer. In this study, the nuclear expression levels of γ-H2AX and p53 using immunohistochemical (IHC) study was quantitatively assessed in ovarian and fallopian tube epithelium derived from RRSOs in 29 BRCA1 and BRCA2 mutation carriers and in 1 patient with a strong family history of breast and ovarian cancer but showing an unknown BRCA status. Both p53 and γ-H2AX nuclear staining levels were significantly higher in BRCA1/2 mutation-positive fallopian tube epithelium compared with the control fallopian tube epithelium (P<0.006 and P=0.011, respectively). Nuclear expression levels of p53 and γ-H2AX were similar between the BRCA1/2 mutation-positive ovarian epithelium and controls. Both γ-H2AX and p53 showed significantly higher nuclear expression levels in BRCA1/2 mutation-positive fallopian tube epithelium compared with BRCA1/2 mutation-positive ovarian epithelium (P<0.0001 and P<0.0001, respectively). BRCA1/2 mutation-positive fallopian tube epithelium showed a positive correlation between the γ-H2AX and p53 nuclear expression levels (Pearson r=0.508, P=0.003). Our results of quantitative nuclear p53 and γ-H2AX expression levels in ovarian and fallopian tube epithelium derived from RRSO in high-risk patients support the previously suggested role of fallopian tube epithelium serving as a possible site of initial serous ovarian carcinogenesis.

Finch AP, Lubinski J, Møller P, et al.
Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation.
J Clin Oncol. 2014; 32(15):1547-53 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The purposes of this study were to estimate the reduction in risk of ovarian, fallopian tube, or peritoneal cancer in women with a BRCA1 or BRCA2 mutation after oophorectomy, by age of oophorectomy; to estimate the impact of prophylactic oophorectomy on all-cause mortality; and to estimate 5-year survival associated with clinically detected ovarian, occult, and peritoneal cancers diagnosed in the cohort.
PATIENTS AND METHODS: Women with a BRCA1 or BRCA2 mutation were identified from an international registry; 5,783 women completed a baseline questionnaire and ≥ one follow-up questionnaires. Women were observed until either diagnosis of ovarian, fallopian tube, or peritoneal cancer, death, or date of most recent follow-up. Hazard ratios (HRs) for cancer incidence and all-cause mortality associated with oophorectomy were evaluated using time-dependent survival analyses.
RESULTS: After an average follow-up period of 5.6 years, 186 women developed either ovarian (n = 132), fallopian (n = 22), or peritoneal (n = 32) cancer, of whom 68 have died. HR for ovarian, fallopian, or peritoneal cancer associated with bilateral oophorectomy was 0.20 (95% CI, 0.13 to 0.30; P < .001). Among women who had no history of cancer at baseline, HR for all-cause mortality to age 70 years associated with an oophorectomy was 0.23 (95% CI, 0.13 to 0.39; P < .001).
CONCLUSION: Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality.

Reade CJ, McVey RM, Tone AA, et al.
The fallopian tube as the origin of high grade serous ovarian cancer: review of a paradigm shift.
J Obstet Gynaecol Can. 2014; 36(2):133-40 [PubMed] Related Publications
Research published over the past 10 years has suggested that most "ovarian cancer," and specifically the high-grade serous carcinoma (HGSC) subtype of ovarian cancer, actually originates in the fallopian tube. In this review, we examine the evidence supporting the tubal origin hypothesis for HGSC, and discuss the clinical implications of our improved understanding of the pathogenesis of ovarian cancer. We searched Medline R and Medline in-process and non-indexed citations from inception to December 15, 2012, to identify all English or French language articles discussing the origins of HGSC. Articles and findings were summarized descriptively. A step-wise transformation from normal epithelium to a lesion with the ability to invade and metastasize has been demonstrated within the fallopian tube. Intraepithelial or early invasive carcinoma of the fallopian tube is frequently identified in BRCA mutation carriers who undergo prophylactic risk-reducing salpingo-oophorectomy. In both BRCA mutation carriers and women from the general population, pre-invasive changes within the fimbriated end of the fallopian tube appear in association with early HGSC. Molecular and genetic studies, as well as in vitro and animal models, have also supported a tubal origin for HGSC. Whether the removal of fallopian tubes (salpingectomy) at the time of pelvic surgery for other reasons will lead to reductions in mortality from ovarian cancer is currently unknown, but it is an important area for future clinical research.

Karst AM, Jones PM, Vena N, et al.
Cyclin E1 deregulation occurs early in secretory cell transformation to promote formation of fallopian tube-derived high-grade serous ovarian cancers.
Cancer Res. 2014; 74(4):1141-52 [PubMed] Free Access to Full Article Related Publications
The fallopian tube is now generally considered the dominant site of origin for high-grade serous ovarian carcinoma. However, the molecular pathogenesis of fallopian tube-derived serous carcinomas is poorly understood and there are few experimental studies examining the transformation of human fallopian tube cells. Prompted by recent genomic analyses that identified cyclin E1 (CCNE1) gene amplification as a candidate oncogenic driver in high-grade serous ovarian carcinoma, we evaluated the functional role of cyclin E1 in serous carcinogenesis. Cyclin E1 was expressed in early- and late-stage human tumor samples. In primary human fallopian tube secretory epithelial cells, cyclin E1 expression imparted malignant characteristics to untransformed cells if p53 was compromised, promoting an accumulation of DNA damage and altered transcription of DNA damage response genes related to DNA replication stress. Together, our findings corroborate the hypothesis that cyclin E1 dysregulation acts to drive malignant transformation in fallopian tube secretory cells that are the site of origin of high-grade serous ovarian carcinomas.

Buza N, Rutherford T, Hui P
Genotyping diagnosis of nongestational choriocarcinoma involving fallopian tube and broad ligament: a case study.
Int J Gynecol Pathol. 2014; 33(1):58-63 [PubMed] Related Publications
A 22 year-old G1P1 woman presented to the emergency room with clinical impression of "ruptured right adnexal mass" and underwent a right salpingo-oophorectomy to rule out ectopic pregnancy. Instead, gross and microscopic examination revealed a pure choriocarcinoma involving the right fallopian tube and broad ligament. On the basis of the patient's age, recent history of delivery, last menstrual period for 10 weeks, large tumor mass, and possible pelvic lymph node metastasis, the patient promptly started to receive 8 cycles of multiagent chemotherapy regimen with a working diagnosis of high-risk gestational choriocarcinoma. Subsequent DNA genotyping analysis showed that the tumor cells had an identical genetic profile to that of the normal tissue of the patient, therefore establishing a final diagnosis of nongestational choriocarcinoma. Six months after the initial presentation, a second surgery was performed to remove a persistent right para-adnexal mass, which showed only necrotic tissue upon microscopic examination. The patient received 1 additional cycle of multiagent chemotherapy. She was alive without evidence of recurrence 26 months after the initial diagnosis.

Pennington KP, Walsh T, Harrell MI, et al.
Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.
Clin Cancer Res. 2014; 20(3):764-75 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain.
EXPERIMENTAL DESIGN: Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway.
RESULTS: Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation.
CONCLUSIONS: Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials.

Anton A, Schott S, Kaip G, et al.
Ki-67 and p53 expression of the fallopian tube mucosa in breast cancer patients with hereditary risk.
Arch Gynecol Obstet. 2014; 289(5):1079-85 [PubMed] Related Publications
PURPOSE: The fallopian tube has been implicated as a site of origin of sporadic and BRCA1-related ovarian cancer. To investigate if Ki-67 or p53 is altered in BRCA1 mutation carriers, we have studied the expression of these markers in morphologically normal mucosa in the fallopian tube and fimbriae.
METHODS: Prophylactic adnexectomy specimens from 24 patients (eight BRCA1 mutation carriers, eight non-mutation carriers, and eight with unknown BRCA1 status), were scored by automated image analysis for the amount of Ki-67 and wild-type p53 expression. All patients had a history of breast cancer and a family history of breast or ovarian cancer.
RESULTS: In the fimbriae, a median of 0.42 % Ki-67 and 0.04 % p53-positive epithelial cells was present, compared to a median of 0.36 % for Ki-67 and 0.05 % for p53 in the fallopian tube. Ki-67 expression decreased significantly with age (r = -0.45, p = 0.028). In contrast, p53 expression was not age-dependent for the whole group of patients (r = 0.25, p = 0.25). Subgroup analysis revealed a difference for p53 expression of the BRCA1 mutation carriers with respect to age (median 0.039 vs. 0.082 % for age less or greater than 50.5 years). Consequently, the p53/Ki-67 ratio showed an age-dependent increase, which was accelerated in the BRCA1-positive patients.
CONCLUSIONS: Ki-67 and p53 expression varies in morphologically normal tubal epithelial cells depending on age and BRCA1 mutation status. This may reflect an altered and age-dependent DNA repair in BRCA1 mutation carriers and may be related to increased risk of ovarian cancer arising in the fallopian tube.

Huang WC, Tsai CC, Wei MC, Kuo KT
Mutation analysis of papillary tubal hyperplasia associated with ovarian atypical proliferative serous tumor and low-grade serous carcinoma.
Am J Obstet Gynecol. 2013; 209(2):e6-8 [PubMed] Related Publications
We present a patient with ovarian atypical proliferative serous tumor and low-grade serous carcinoma, related to KRAS mutation. Bilateral fallopian tubes had papillary tubal hyperplasia, providing additional evidence that it is the putative precursor of low-grade serous tumors. Mutation analysis of papillary tubal hyperplasia has not been done in previous literature.

Chene G, Tchirkov A, Pierre-Eymard E, et al.
Early telomere shortening and genomic instability in tubo-ovarian preneoplastic lesions.
Clin Cancer Res. 2013; 19(11):2873-82 [PubMed] Related Publications
PURPOSE: Genetic instability plays an important role in ovarian carcinogenesis. We investigated the level of telomere shortening and genomic instability in early and preinvasive stages of ovarian cancer, serous tubal intraepithelial carcinoma (STIC), and tubo-ovarian dysplasia (TOD).
EXPERIMENTAL DESIGN: Fifty-one TOD from prophylactic salpingo-oophorectomies with BRCA1 or 2 mutation, 12 STICs, 53 tubo-ovarian high-grade serous carcinoma, and 36 noncancerous controls were laser capture microdissected from formalin-fixed, paraffin-embedded sections, analyzed by comparative genomic hybridization (array CGH) and for telomere length (using quantitative real-time PCR based on the Cawthon's method). TOD and STICs were defined by morphologic scores and immunohistochemical expressions of p53, Ki67, and γH2AX.
RESULTS: TOD showed marked telomere shortening compared with noncancerous controls (P < 10(-7)). STICs had even shorter telomeres than TOD (P = 0.0008). Ovarian carcinoma had shorter telomeres than controls but longer than STICs and dysplasia. In TOD, telomeres were significantly shorter in those with BRCA1 mutation than in those with BRCA2 mutation (P = 0.005). In addition, γH2AX expression in TOD and STIC groups with short telomeres was significantly increased (P < 10(-7)). In dysplastic epithelium, we found subtle genomic alterations, in contrast to more important genomic imbalances in STICs. The total number of genetic alterations was the highest in ovarian cancers.
CONCLUSIONS: These findings suggest that genetic instability occurs in early stages of ovarian tumorigenesis. STICs and noninvasive dysplasia are likely an important step in early serous ovarian neoplasia.

Kessler M, Fotopoulou C, Meyer T
The molecular fingerprint of high grade serous ovarian cancer reflects its fallopian tube origin.
Int J Mol Sci. 2013; 14(4):6571-96 [PubMed] Free Access to Full Article Related Publications
High grade serous ovarian cancer (HGSC), the most lethal and frequent type of epithelial ovarian cancer (EOC), has poor long term prognosis due to a combination of factors: late detection, great metastatic potential and the capacity to develop resistance to available therapeutic drugs. Furthermore, there has been considerable controversy concerning the etiology of this malignancy. New studies, both clinical and molecular, strongly suggest that HGSC originates not from the surface of the ovary, but from the epithelial layer of the neighboring fallopian tube fimbriae. In this paper we summarize data supporting the central role of fallopian tube epithelium in the development of HGSC. Specifically, we address cellular pathways and regulatory mechanisms which are modulated in the process of transformation, but also genetic changes which accumulate during disease progression. Similarities between fallopian tube mucosa and the malignant tissue of HGSC warrant a closer analysis of homeostatic mechanisms in healthy epithelium in order to elucidate key steps in disease development. Finally, we highlight the importance of the cancer stem cell (CSC) identification and understanding of its niche regulation for improvement of therapeutic strategies.

May T, Shoni M, Crum CP, et al.
Low-grade and high-grade serous Mullerian carcinoma: review and analysis of publicly available gene expression profiles.
Gynecol Oncol. 2013; 128(3):488-92 [PubMed] Related Publications
OBJECTIVE: Mullerian low grade serous carcinoma (LGSC) and high grade serous carcinoma (HGSC) have distinct molecular profiles, clinical behavior and treatment response. Our objective was to study the biological profiles of these carcinomas.
METHODS: This study examines publicly available gene expression profiles of LGSC and HGSC to identify differentially expressed genes and key pathways involved in carcinogenesis and chemotherapy response.
RESULTS: Our analysis supports the hypothesis that serous mullerian carcinoma develop through two different pathways yielding two distinct malignancies, namely LGSC and HGSC. Furthermore, genes potentially involved in chemotherapeutic resistance of LGSC were identified. Suppressing the levels of these genes/proteins may increase clinical response to standard chemotherapy in patients with LGSC.
CONCLUSION: In summary, this review shows the molecular profile of LGSC and HGSC through multi-center analysis of gene expression profiles of these tumors. The gene signatures of these neoplasms may potentially be used to develop disease-specific, targeted therapy for LGSC and HGSC.

Mingels MJ, Roelofsen T, van der Laak JA, et al.
Tubal epithelial lesions in salpingo-oophorectomy specimens of BRCA-mutation carriers and controls.
Gynecol Oncol. 2012; 127(1):88-93 [PubMed] Related Publications
OBJECTIVE: A precursor lesion for ovarian carcinoma, tubal intraepithelial carcinoma (TIC), has been identified in BRCA-mutation carriers undergoing prophylactic bilateral salpingo-oophorectomy (pBSO). Other lesions were also identified in fallopian tubes, but different terminology, interpretation, and lack of knowledge of normal epithelium, have hampered to unravel their possible role in carcinogenesis. The aim of this study is to classify tubal epithelial lesions in BRCA-mutation carriers and controls to enable comparison of prevalence, area of localization, and possible malignant potential.
METHODS: Two hundred twenty-six BRCA1/2-mutation carriers were included; ovaries and fallopian tubes, embedded completely, were reviewed. Controls included 105 women who underwent BSO for non-malignant reasons. Tubal epithelial lesions included the following categories: hyperplasia, minor epithelial atypia, TIC, and invasive carcinoma.
RESULTS: Tubal neoplasia was identified in 7.1% (invasive carcinoma, 0.9%; TIC, 6.2%) of BRCA-mutation carriers compared to none in controls (p=0.004, Fisher's exact test). Hyperplasia and minor epithelial atypia were identified in 41.6% BRCA-mutation carriers and compared to 58.1% in controls (p=0.005, Pearson's chi square). Invasive carcinoma and TIC showed preference for the fimbrial ends (p=0.027, Pearson's chi square), while hyperplasia and minor epithelial atypia displayed more variation in localization.
CONCLUSIONS: Invasive tubal carcinoma and TIC were limited to BRCA-mutation carriers, whereas hyperplasia and minor epithelial atypia were commonly found in both BRCA-mutation carriers and controls. It is suggested that hyperplasia and minor atypia represent variations of normal tubal epithelium instead of premalignant lesions. Furthermore, total salpingectomy is strongly recommended as most but not all TIC occurred in the fimbriae.

Foulkes WD
Epigenetic modification and cancer: mark or stamp?
Endocr Relat Cancer. 2012; 19(2):C23-7 [PubMed] Related Publications
Hypotheses are built upon data, but data require hypotheses before they can be understood. The development of the 'two-hit' hypothesis of carcinogenesis was a key event in cancer genetics because it provided a testable model of how tumours develop. In this commentary on 'Promoter hypermethylation patterns in Fallopian tube epithelium of BRCA1 and BRCA2 germline mutation carriers' by Bijron et al. published in the February 2012 issue of Endocrine-Related Cancer, the need for new grammar and some new hypotheses in epigenetics is discussed. Meanwhile, data suggesting an important role of epigenetic modification in the cause, progression and treatment of cancer continues to accumulate.

Bijron JG, van der Groep P, van Dorst EB, et al.
Promoter hypermethylation patterns in fallopian tube epithelium of BRCA1 and BRCA2 germ line mutation carriers.
Endocr Relat Cancer. 2012; 19(1):69-81 [PubMed] Related Publications
BRCA1/2 germ line mutation carriers have a high risk of developing fallopian tube carcinoma (FTC), thought to occur through different early (p53 signatures) and later (dysplasia, intra-epithelial carcinoma) premalignant stages. Promoter hypermethylation of tumour suppressor genes is known to play a key role in (early) carcinogenesis. However, little is known about methylation in normal and (pre)malignant fallopian tube tissue. We identified 14 areas of p53 accumulation in the fallopian tubes of BRCA mutation carriers. Cells from these areas were harvested together with cells from adjacent benign appearing areas. An age-matched non-BRCA sporadic control group (n=13) and eight sporadic FTCs were included as negative and positive controls respectively. Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 70 tumour suppressor genes in all samples. We observed a gradual increase in methylation from sporadic control tissue (median cumulative methylation index (CMI) 568.19) through normal tissue and from areas of p53 accumulation in BRCA carriers (median CMI 687.54 and 676.72) to FTC (median CMI 780.97). Furthermore, the methylation percentage of many individual tumour suppressor genes differed significantly between these groups, gradually increasing as for CMI. Between areas with and without p53 accumulation in BRCA mutation carriers no significant differences were found. In this paper, we have shown that BRCA mutation carriers display increased methylation of tumour suppressor genes in their non-malignant fallopian tube epithelium, closer to methylation levels in FTC than to normal sporadic tissue. Methylation could, therefore, play an important role in the increased risk of gynaecological malignancies in BRCA mutation carriers.

Chêne G, Raoelfils I, Cayre A, et al.
[Don't forget fallopian tubes! A morphologic and immunohistochemical study about Fallopian tubes with genetic risk (BRCA mutation)].
Gynecol Obstet Fertil. 2012; 40(1):14-8 [PubMed] Related Publications
OBJECTIVES: The objective of this study was to describe morphologic and immunohistochemical features of precursor tubal lesions in prophylactically removed Fallopian tubes.
PATIENTS AND METHODS: Hundred and forty-seven bilateral salpingectomies (genetic predisposition or group A: n=57; and control group or group B: n=90) were reviewed by two pathologists blinded to clinical data. Seven epithelial cytological and architectural features were studied to compare the degree of tubal epithelial abnormalities between the two groups. Immunohistochemical expression patterns of Ki67 and p53 were also evaluated.
RESULTS: Serous tubal intraepithelial lesions (STIL) have been identified in group A with stronger expression for Ki67 and p53 (especially in BRCA 1 group) than in group B.
DISCUSSION AND CONCLUSION: The current results show the importance of salpingo-oophrectomy in BRCA mutation carriers and the complete histopathological sampling of the Fallopian tubes.

Walsh T, Casadei S, Lee MK, et al.
Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.
Proc Natl Acad Sci U S A. 2011; 108(44):18032-7 [PubMed] Free Access to Full Article Related Publications
Inherited loss-of-function mutations in BRCA1 and BRCA2 and other tumor suppressor genes predispose to ovarian carcinomas, but the overall burden of disease due to inherited mutations is not known. Using targeted capture and massively parallel genomic sequencing, we screened for germ-line mutations in 21 tumor suppressor genes in genomic DNA from women with primary ovarian, peritoneal, or fallopian tube carcinoma. Subjects were consecutively enrolled at diagnosis and not selected for age or family history. All classes of mutations, including point mutations and large genomic deletions and insertions, were detected. Of 360 subjects, 24% carried germ-line loss-of-function mutations: 18% in BRCA1 or BRCA2 and 6% in BARD1, BRIP1, CHEK2, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, or TP53. Six of these genes were not previously implicated in inherited ovarian carcinoma. Primary carcinomas were generally characterized by genomic loss of normal alleles of the mutant genes. Of women with inherited mutations, >30% had no family history of breast or ovarian carcinoma, and >35% were 60 y or older at diagnosis. More patients with ovarian carcinoma carry cancer-predisposing mutations and in more genes than previously appreciated. Comprehensive genetic testing for inherited carcinoma is warranted for all women with ovarian, peritoneal, or fallopian tube carcinoma, regardless of age or family history. Clinical genetic testing is currently done gene by gene, with each test costing thousands of dollars. In contrast, massively parallel sequencing allows such testing for many genes simultaneously at low cost.

Kuhn E, Kurman RJ, Vang R, et al.
TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma--evidence supporting the clonal relationship of the two lesions.
J Pathol. 2012; 226(3):421-6 [PubMed] Free Access to Full Article Related Publications
Serous tubal intraepithelial carcinomas (STICs) have been proposed to be the most likely precursor of ovarian, tubal and 'primary peritoneal' (pelvic) high-grade serous carcinoma (HGSC). As somatic mutation of TP53 is the most common molecular genetic change of ovarian HGSC, occurring in more than 95% of cases, we undertook a mutational analysis of 29 pelvic HGSCs that had concurrent STICs to demonstrate the clonal relationship of STICs and HGSCs. In addition, we correlated the mutational data with p53 immunostaining to determine the role of p53 immunoreactivity as a surrogate for TP53 mutations in histological diagnosis. Somatic TP53 mutations were detected in all 29 HGSCs analysed and the identical mutations were detected in 27 of 29 pairs of STICs and concurrent HGSCs. Missense mutations were observed in 61% of STICs and frameshift/splicing junction/nonsense mutations in 39%. Interestingly, there were two HGSCs with two distinctly different TP53 mutations each, but only one of the mutations was detected in the concurrent STICs. Missense mutations were associated with intense and diffuse (≥ 60%) p53 nuclear immunoreactivity, while most of the null mutations were associated with complete loss of p53 staining (p < 0.0001). Overall, this p53 staining pattern yielded a sensitivity of 87% and a specificity of 100% in detecting TP53 missense mutations. In conclusion, the above findings support the clonal relationship of STIC and pelvic HGSC and demonstrate the utility of p53 immunostaining as a surrogate for TP53 mutation in the histological diagnosis of STIC. In this regard, it is important to appreciate the significance of different staining patterns. Specifically, strong diffuse staining correlates with a missense mutation, whereas complete absence of staining correlates with null mutations.

D'Adda T, Pizzi S, Bottarelli L, et al.
Metaplastic papillary tumor of the salpinx: report of a case using microsatellite analysis.
Int J Gynecol Pathol. 2011; 30(6):532-5 [PubMed] Related Publications
Metaplastic papillary tumor (MPT) of the salpinx is a rare lesion found in the lumen of fallopian tubes during the postpartum period. This lesion is very small and is composed microscopically of papillae lined by stratified epithelium. Similar to serous borderline ovarian tumors (BOTs), epithelial elements of MPT show a budding, abundant, dense, and eosinophilic cytoplasm, bland nuclei or with mild atypia. It is not clear whether this lesion is a papillary metaplastic proliferation or a small atypical proliferative (borderline) serous tumor associated with pregnancy. Owing to its rarity, MPT has never been investigated in molecular studies and compared with ovarian serous neoplasms. In this study, a case of tubal MPT was molecularly examined and compared with 4 BOTs and with 2 low-grade ovarian carcinomas, using microsatellite analysis with 13 markers at 8 chromosomal regions involved in ovarian carcinogenesis. The tubal MPT and one of the BOTs showed no alterations in the investigated chromosomal regions. The remaining 3 BOTs showed only single allelic imbalances. Instead, low-grade serous carcinomas showed a higher frequency of alterations, including allelic imbalance at chr10q23, 1p36, 9p22, and 17. In conclusion, this study provides, for the first time, molecular data on an MPT of the fallopian tube, indicating that this entity might share both morphologic and molecular similarities with a subset of minimally altered BOTs, termed atypical proliferative serous tumors, which behave in a benign manner. However, in our opinion, further molecular studies should be conducted on other cases of MPTs to confirm this hypothesis.

George SH, Greenaway J, Milea A, et al.
Identification of abrogated pathways in fallopian tube epithelium from BRCA1 mutation carriers.
J Pathol. 2011; 225(1):106-17 [PubMed] Related Publications
The discovery of occult invasive and intra-epithelial tubal carcinomas in BRCA1 mutation carriers undergoing prophylactic surgery has implicated the fallopian tube epithelium as the source of serous cancer. However, little is known of the early molecular events of serous oncogenesis, or why cancers in BRCA1 mutation carriers are found preferentially in tissues which are responsive to reproductive hormones. We hypothesize that molecular alterations present in morphologically normal tubal epithelium from BRCA1 heterozygotes reflect the earliest events in serous carcinogenesis and may be markers of increased cancer risk as well as targets for risk reduction. Genetic profiling of microdissected tubal epithelium from histologically normal BRCA1 mutation carriers and controls was performed. We sought to define a signature which differentiated BRCA1 mutant tubal epithelium from women with low risk of developing ovarian cancer. Molecular differences between the follicular and luteal phases were prominent and, by using filtering techniques and a two-way ANOVA without a False Discovery Rate correction, we identified 440 probe sets with a more than two-fold change in gene expression related to BRCA1 mutation status. Using gene ontology and known associations to cancer pathways, we selected five genes for further analysis by qPCR and immunohistochemistry, and were able to demonstrate statistically significant differentiation of BRCA1 and control cases in an independent set of cases. The altered expression profiles in histologically normal tubal epithelium from BRCA1 heterozygotes suggest that these cells may respond differently to microenvironmental stresses.

Yates MS, Meyer LA, Deavers MT, et al.
Microscopic and early-stage ovarian cancers in BRCA1/2 mutation carriers: building a model for early BRCA-associated tumorigenesis.
Cancer Prev Res (Phila). 2011; 4(3):463-70 [PubMed] Free Access to Full Article Related Publications
Risk-reducing salpingo-oophorectomy (RRSO) is the cornerstone of ovarian cancer prevention in BRCA1/2 mutation carriers. Occult fallopian tube and ovarian cancers have been reported in a small percentage of BRCA1/2 mutation carriers undergoing RRSO. Here, we review our single-institution experience with RRSO in BRCA1/2 mutation carriers to characterize cases of microscopic cancers in these patients. At the time of RRSO, 7.9% of BRCA1 mutation carriers were diagnosed with microscopic fallopian tube or ovarian cancers and no cases were diagnosed in BRCA2 mutation carriers. The majority of the microscopic cancers include cases that were confined to the fallopian tubes, although there were also cases involving ovaries only or peritoneal washings only. This suggests that the site of origin may be in the ovary, fallopian tube, or peritoneum for BRCA-associated serous cancers. However, an analysis of early-stage (stages I and II) ovarian and fallopian tube cancers diagnosed in BRCA1/2 mutation carriers confirms that the ovary is a preferred site for tumor growth with 11 of 14 early-stage cancers having a dominant ovarian mass. Overall, these data suggest that cancer initiation may occur in the ovary, fallopian tube, or peritoneum, but tumor growth and progression are favored in the ovary. We present an updated model for BRCA1/2 mutation-associated ovarian and fallopian tube carcinogenesis, which may aid in identifying improved prevention strategies for high-risk women who delay or decline RRSO.

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