RESUMO
BACKGROUND: Repeat leiomyoma occurrence or even reintervention is common after myomectomy. Little is known about the factors related to repeat interventions. OBJECTIVES: This study aimed to determine the frequency of leiomyoma-related reintervention after an initial laparoscopic or abdominal myomectomy and to analyze both clinical and molecular risk factors for reinterventions. Another objective was to define the frequency of clonally related tumors from repeat operations. STUDY DESIGN: This retrospective cohort study included 234 women who had undergone laparoscopic or abdominal myomectomy in 2009-2014. Information on repeat leiomyoma-related interventions as well as on other clinical factors was collected from medical records after a median follow-up time of 11,4 years (range 7,9-13,8 years) after the index procedure. The effect of clinical risk factors on the risk of reintervention was analyzed by the Kaplan-Meier estimator and the Cox proportional hazards model. For molecular analyses, we examined the mutation profiles of 133 formalin-fixed paraffin-embedded leiomyoma samples from 33 patients with repeat operations. We screened the tumors for the three primary leiomyoma driver alterations-MED12 mutations, HMGA2 overexpression, and FH-deficiency-utilizing Sanger sequencing and immunohistochemistry. To further assess the clonal relationship of the tumors, we executed whole-exome sequencing for 52 leiomyomas from 21 patients who exhibited the same driver alteration in tumors obtained from multiple procedures. RESULTS: Reintervention rate at 11,4 years after myomectomy was 20% (46/234). Number of leiomyomas removed at the index myomectomy was a risk factor (hazard ratio 1.21; 95% confidence interval 1.09-1.34). Age at index myomectomy (hazard ratio 0.94; 95% confidence interval 0.89-0.99) and postoperative parity (hazard ratio 0.23; 95% confidence interval 0.09-0.60) were protective factors. Molecular characterization of tumors from index and non-index operations confirmed a clonal relationship of the tumors in 3/33 (9%) patients. None of the leiomyomas harboring a MED12 mutation -the most common leiomyoma driver- were confirmed clonally related. FH-deficiency was detected in repeat leiomyomas from 3/33 (9%) patients. All these patients harbored a germline FH mutation, which is distinctive for the hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Finally, we identified three (3/33; 9%) patients with two tumors each displaying somatic mutations in a recently identified novel leiomyoma driver gene, YEATS4. All YEATS4 mutations were different and thus the tumors were not clonally related. CONCLUSION: Our study shows that reintervention is common after surgical myomectomy. Uterine leiomyomas typically develop independently, but some share a clonal origin. Repeat leiomyoma occurrence may be due to genetic predisposition, such as a germline FH mutation. Distinct somatic YEATS4 mutations identified in multiple leiomyomas from the same patient indicate a possible role for YEATS4 in repeat leiomyomas.
RESUMO
OBJECTIVE: To assess the risk stratification of clinicopathologically and molecularly classified endometrial cancer based on estrogen receptor (ER) and L1 cell adhesion molecule (L1CAM) expression. METHODS: This was a retrospective study of patients who underwent primary treatment at a single tertiary center. Carcinomas were classified into 5 clinicopathological risk groups, as per European guidelines. Immunohistochemistry and polymerase-ϵ sequencing were conducted for molecular classification and determination of ER and L1CAM expression. RESULTS: Data from 1044 patients were analyzed. The median follow-up was 67.5 months. In univariable analyses, ER expression correlated with improved disease-specific survival (DSS) in the "no specific molecular profile" (NSMP) (P < 0.001) and mismatch repair deficient (MMRd) (P = 0.002) subgroups. Negative L1CAM expression was associated with enhanced DSS in the NSMP subgroup alone (P < 0.001). ER (hazard ratio [HR] 0.18), but not L1CAM, exhibited prognostic significance within NSMP when controlling for parameters available at the time of diagnosis (tumor histotype, grade, age). ER and L1CAM were not independently associated with DSS within NSMP when controlling for parameters available after surgery (clinicopathological risk groups, age, adjuvant therapy). However, in high-risk-advanced-metastatic cases, both ER (HR 0.26) and L1CAM (HR 3.9) independently correlated with DSS. Similarly, within MMRd, ER was associated with improved DSS in high-risk-advanced-metastatic carcinomas (HR 0.42). CONCLUSION: The prognostic significance of ER and L1CAM varies across clinicopathological risk groups and molecular subgroups of endometrial cancer. Notably, risk assessment for high-risk-advanced-metastatic NSMP and MMRd subtype carcinomas can be refined by ER status.
RESUMO
OBJECTIVE: Prognostic stratification of endometrial cancer involves the assessment of stage, uterine risk factors, and molecular classification. This process can be further refined through annotation of prognostic biomarkers, notably L1 cell adhesion molecule (L1CAM) and hormonal receptors. Loss of asparaginase-like protein 1 (ASRGL1) has been shown to correlate with poor outcome in endometrial cancer. Our objective was to assess prognostication of endometrial cancer by ASRGL1 in conjunction with other available methodologies. STUDY DESIGN: This was a retrospective study of patients who underwent primary treatment at a single tertiary center. Tumors were molecularly classified by the Proactive Molecular Risk Classifier for Endometrial Cancer. Expression of ASRGL1, L1CAM, estrogen receptor, and progesterone receptor was determined by immunohistochemistry. ASRGL1 expression intensity was scored into four classes. RESULTS: In a cohort of 775 patients, monitored for a median time of 81 months, ASRGL1 expression intensity was related to improved disease-specific survival in a dose-dependent manner (P < 0.001). Low expression levels were associated with stage II-IV disease and presence of uterine factors, i.e. high grade, lymphovascular space invasion, and deep myometrial invasion (P < 0.001 for all). Among the molecular subgroups, low expression was most prevalent in p53 abnormal carcinomas (P < 0.001). Low ASRGL1 was associated with positive L1CAM expression and negative estrogen and progesterone receptor expression (P < 0.001 for all). After adjustment for stage and uterine factors, strong ASRGL1 staining intensity was associated with a lower risk for cancer-related deaths (hazard ratio 0.56, 95 % confidence interval 0.32-0.97; P = 0.038). ASRGL1 was not associated with the outcome when adjusted for stage, molecular subgroups, L1CAM, and hormonal receptors. When analyzed separately within the different molecular subgroups, ASRGL1 showed an association with disease-specific survival specifically in "no specific molecular profile" subtype carcinomas (P < 0.001). However, this association became nonsignificant upon controlling for confounders. CONCLUSIONS: Low ASRGL1 expression intensity correlates with poor survival in endometrial cancer. ASRGL1 contributes to more accurate prognostication when controlled for stage and uterine factors. However, when adjusted for stage and other biomarkers, including molecular subgroups, ASRGL1 does not improve prognostic stratification.
RESUMO
OBJECTIVE: To assess the stage distribution and stage-related disease-specific survival rates for endometrial cancer using the FIGO (the International Federation of Gynecology & Obstetrics) 2009 and 2023 staging systems. Further, we sought to evaluate the prognostic utility of additional covariates beyond the FIGO 2023 stage. METHODS: Endometrial carcinomas were molecularly classified by the Proactive Molecular Risk Classifier for Endometrial Cancer and staged according to FIGO 2009 and 2023 criteria. Disease-specific survival was calculated as the time from surgery to death from endometrial cancer. RESULTS: Data from 604 patients were analyzed. Median follow-up time was 81 months. A total of 118 stage shifts (19.5%) occurred between the FIGO 2009 and FIGO 2023 systems, with upshifts accounting for 107 (90.7%) of these changes. Within the FIGO 2023 system, molecular classification resulted in restaging of 69 patients (11.4%). Shifts that could alter adjuvant therapy decisions were identified in 23 patients (3.8%). The FIGO 2023 system effectively categorized endometrial cancers into prognostic subgroups. The FIGO 2023 stage, tumor size, positive peritoneal cytology, and mismatch repair deficiency were associated with disease-specific survival in a multivariable analysis, whereas age and adjuvant therapy were not. CONCLUSION: The FIGO 2023 staging system for endometrial cancer appears highly prognostic. Prognostic assessment of the patients can be further enhanced by readily accessible covariates. A stage shift between the FIGO 2009 and 2023 systems occurs in about one-fifth of patients. The implementation of molecular classification within the FIGO 2023 system bears implications for decisions regarding adjuvant therapy.
RESUMO
To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.
Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Ovarianas , Polimorfismo de Nucleotídeo Único , Humanos , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Carcinoma Epitelial do Ovário/genética , Transcriptoma , Fatores de Risco , Genômica/métodos , Estudos de Casos e Controles , MultiômicaRESUMO
BACKGROUND: Endometriosis is a common, chronic disease among fertile-aged women. Disease course may be highly invasive, requiring extensive surgery. The etiology of endometriosis remains elusive, though a high level of heritability is well established. Several low-penetrance predisposing loci have been identified, but high-risk susceptibility remains undetermined. Endometriosis is known to increase the risk of epithelial ovarian cancers, especially of endometrioid and clear cell types. Here, we have analyzed a Finnish family where four women have been diagnosed with surgically verified, severely symptomatic endometriosis and two of the patients also with high-grade serous carcinoma. RESULTS: Whole-exome sequencing revealed three rare candidate predisposing variants segregating with endometriosis. The variants were c.1238C>T, p.(Pro413Leu) in FGFR4, c.5065C>T, p.(Arg1689Trp) in NALCN, and c.2086G>A, p.(Val696Met) in NAV2. The only variant predicted deleterious by in silico tools was the one in FGFR4. Further screening of the variants in 92 Finnish endometriosis and in 19 endometriosis-ovarian cancer patients did not reveal additional carriers. Histopathology, positive p53 immunostaining, and genetic analysis supported the high-grade serous subtype of the two tumors in the family. CONCLUSIONS: Here, we provide FGFR4, NALCN, and NAV2 as novel high-risk candidate genes for familial endometriosis. Our results also support the association of endometriosis with high-grade serous carcinoma. Further studies are required to validate the findings and to reveal the exact pathogenesis mechanisms of endometriosis. Elucidating the genetic background of endometriosis defines the etiology of the disease and provides opportunities for expedited diagnostics and personalized treatments.
Assuntos
Carcinoma , Endometriose , Neoplasias Ovarianas , Humanos , Feminino , Idoso , Endometriose/genética , Predisposição Genética para Doença , Sequenciamento do Exoma , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologiaRESUMO
BACKGROUND: Endometrial carcinomas can be classified into four molecular subgroups - mismatch repair deficient (MMRd), p53 abnormal (p53abn), polymerase-ϵ (POLE) ultramutated, and 'no specific molecular profile' (NSMP). Retrospective data imply that the response to adjuvant therapies may depend on the molecular subgroup. These findings emphasize the need for adjuvant therapy trials where patients are randomized to treatment arms separately within each molecular subgroup. PRIMARY OBJECTIVE: The PErsonalized TReatment for Endometrial Carcinoma (PETREC) trial clarifies the value of molecular classification in the determination of adjuvant therapies of high-intermediate risk and early-stage high-risk endometrial carcinoma. STUDY HYPOTHESIS: Compared with vaginal brachytherapy, the utilization of whole pelvic radiotherapy may result in improved outcomes for either MMRd or NSMP high-intermediate risk carcinomas. Early-stage high-risk p53abn and nonendometrioid carcinomas are postulated to gain benefits from chemoradiotherapy, as opposed to chemotherapy alone. POLE ultramutated carcinomas harboring high-intermediate or high-risk clinicopathologic features are speculated to have favorable prognosis without any adjuvant therapy. TRIAL DESIGN: This prospective, multicenter, phase 3 trial compares the efficacy of vaginal brachytherapy vs whole pelvic radiotherapy in high-intermediate risk MMRd and NSMP molecular subgroups, and chemotherapy vs chemoradiotherapy in early-stage high-risk p53abn subtype and nonendometrioid carcinomas. Eligible women who consent to participation in the trial are randomly allocated (1:1) to treatment arms. MAJOR INCLUSION/EXCLUSION CRITERIA: Women with stages I-II molecular integrated high-intermediate risk or high-risk endometrial carcinoma will be included. PRIMARY ENDPOINT: The primary endpoint is the 5 year cumulative incidence of disease recurrence. SAMPLE SIZE: A total sample size of 294 patients (49 subjects in each treatment arm of the three subgroups intended for randomization) was estimated to be sufficient. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Patient recruitment will be completed in 2025, and follow-up will be completed in 2030. TRIAL REGISTRATION: NCT05655260.
Assuntos
Carcinoma , Neoplasias do Endométrio , Humanos , Feminino , Finlândia , Estudos Retrospectivos , Medicina de Precisão , Estudos Prospectivos , Estadiamento de Neoplasias , Recidiva Local de Neoplasia/patologia , Neoplasias do Endométrio/patologia , Carcinoma/patologiaRESUMO
Uterine leiomyomas (ULs) are benign smooth muscle tumors that are common in premenopausal women. Somatic alterations in MED12, HMGA2, FH, genes encoding subunits of the SRCAP complex, and genes involved in Cullin 3-RING E3 ligase neddylation are mutually exclusive UL drivers. Established predisposition genes explain only partially the estimated heritability of leiomyomas. Here, we examined loss-of-function variants across 18,899 genes in a cohort of 233,614 White European women, revealing variants in four genes encoding SRCAP complex subunits (YEATS4, ZNHIT1, DMAP1, and ACTL6A) with a significant association to ULs, and YEATS4 and ZNHIT1 strikingly rank first and second, respectively. Positive mutation status was also associated with younger age at diagnosis and hysterectomy. Moderate-penetrance UL risk was largely attributed to rare non-synonymous mutations affecting the SRCAP complex. To examine this disease phenotype more closely, we set out to identify inherited mutations affecting the SRCAP complex in our in-house sample collection of Finnish individuals with ULs (n = 860). We detected one individual with an ACTL6A splice-site mutation, two individuals with a YEATS4 missense mutation, and four individuals with DMAP1 mutations: one splice-site, one nonsense, and two missense variants. These individuals had large and/or multiple ULs, were often diagnosed at an early age, and many had family history of ULs. When a somatic second hit was found, ACTL6A and DMAP1 were silenced in tumors by somatic mutation and YEATS4 by promoter hypermethylation. Decreased H2A.Z staining was observed in the tumors, providing further evidence for the pathogenic nature of the germline mutations. Our results establish inactivation of genes encoding SRCAP complex subunits as a central contributor to moderate-penetrance UL predisposition.
Assuntos
Leiomioma , Neoplasias Uterinas , Humanos , Feminino , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Mutação em Linhagem Germinativa , Penetrância , Análise Mutacional de DNA , Leiomioma/genética , Leiomioma/patologia , Mutação , Complexo Mediador/genética , Actinas/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Adenosina Trifosfatases/genéticaRESUMO
Many efforts are underway to develop novel therapies against the aggressive high-grade serous ovarian cancers (HGSOCs), while our understanding of treatment options for low-grade (LGSOC) or mucinous (MUCOC) of ovarian malignancies is not developing as well. We describe here a functional precision oncology (fPO) strategy in epithelial ovarian cancers (EOC), which involves high-throughput drug testing of patient-derived ovarian cancer cells (PDCs) with a library of 526 oncology drugs, combined with genomic and transcriptomic profiling. HGSOC, LGSOC and MUCOC PDCs had statistically different overall drug response profiles, with LGSOCs responding better to targeted inhibitors than HGSOCs. We identified several subtype-specific drug responses, such as LGSOC PDCs showing high sensitivity to MDM2, ERBB2/EGFR inhibitors, MUCOC PDCs to MEK inhibitors, whereas HGSOCs showed strongest effects with CHK1 inhibitors and SMAC mimetics. We also explored several drug combinations and found that the dual inhibition of MEK and SHP2 was synergistic in MAPK-driven EOCs. We describe a clinical case study, where real-time fPO analysis of samples from a patient with metastatic, chemorefractory LGSOC with a CLU-NRG1 fusion guided clinical therapy selection. fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.
Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Humanos , Feminino , Medicina de Precisão , Neoplasias Ovarianas/genética , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso/genética , Quinases de Proteína Quinase Ativadas por MitógenoRESUMO
Uterine leiomyomas, or fibroids, are very common smooth muscle tumors that arise from the myometrium. They can be divided into distinct molecular subtypes. We have previously shown that 3'RNA-sequencing is highly effective in classifying archival formalin-fixed paraffin-embedded (FFPE) leiomyomas according to the underlying mutation. In this study, we performed 3'RNA-sequencing with 111 FFPE leiomyomas previously classified as negative for driver alterations in mediator complex subunit 12 (MED12), high mobility group AT-hook 2 (HMGA2), and fumarate hydratase (FH) by Sanger sequencing and immunohistochemistry. This revealed 43 tumors that displayed expression features typically seen in HMGA2-positive tumors, including overexpression of PLAG1. We explored 12 such leiomyomas by whole-genome sequencing to identify their underlying genomic drivers and to evaluate the feasibility of detecting chromosomal driver alterations from FFPE material. Four tumors with significant HMGA2 overexpression at the protein-level served as controls. We identified chromosomal rearrangements targeting either HMGA2, HMGA1, or PLAG1 in all 16 tumors, demonstrating that it is possible to detect chromosomal driver alterations in archival leiomyoma specimens as old as 18 years. Furthermore, two tumors displayed biallelic loss of DEPDC5 and one tumor harbored a COL4A5-COL4A6 deletion. These observations suggest that instead of only HMGA2-positive leiomyomas, a distinct leiomyoma subtype is characterized by rearrangements targeting either HMGA2, HMGA1, or PLAG1. The results indicate that the frequency of HMGA2-positive leiomyomas may be higher than estimated in previous studies where immunohistochemistry has been used. This study also demonstrates the feasibility of detecting chromosomal driver alterations from archival FFPE material.
Assuntos
Leiomioma , Neoplasias Uterinas , Feminino , Humanos , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Proteína HMGA1a/genética , Leiomioma/genética , Leiomioma/patologia , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Fumarato Hidratase/genética , Aberrações Cromossômicas , Mutação , Fatores de Transcrição/genética , RNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismoRESUMO
Precision medicine carries great potential for management of all tumor types. The aim of this retrospective study was to investigate if the two most common genetically distinct uterine fibroid subclasses, driven by aberrations in MED12 and HMGA2 genes, respectively, influence response to treatment with the progesterone receptor modulator ulipristal acetate. Changes in diameter and mutation status were derived for 101 uterine fibroids surgically removed after ulipristal acetate treatment. A significant difference in treatment response between the two major subclasses was detected. MED12 mutant fibroids had 4.4 times higher odds of shrinking in response to ulipristal acetate treatment as compared to HMGA2 driven fibroids (95% confidence interval 1.37-13.9; P = 0.013), and in a multivariate analysis molecular subclassification was an independent predictive factor. Compatible with this finding, gene expression and DNA methylation analyses revealed subclass specific differences in progesterone receptor signaling. The work provides a proof-of-principle that uterine fibroid treatment response is influenced by molecular subclass and that the genetic subclasses should be taken into account when evaluating current and future uterine fibroid therapies.
Assuntos
Leiomioma , Neoplasias Uterinas , Feminino , Humanos , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Leiomioma/tratamento farmacológico , Leiomioma/genética , Leiomioma/patologia , Fatores de TranscriçãoRESUMO
Endometrial carcinoma (EC) is one of the most common gynecological cancers in the world. In this work we apply Cox proportional hazards (CPH) and optimal survival tree (OST) algorithms to the retrospective prognostic modeling of disease-specific survival in 842 EC patients. We demonstrate that linear CPH models are preferred for the EC risk assessment based on clinical features alone, while interpretable, non-linear OST models are favored when patient profiles can be supplemented with additional biomarker data. We show how visually interpretable tree models can help generate and explore novel research hypotheses by studying the OST decision path structure, in which L1 cell adhesion molecule expression and estrogen receptor status are correctly indicated as important risk factors in the p53 abnormal EC subgroup. To aid further clinical adoption of advanced machine learning techniques, we stress the importance of quantifying model discrimination and calibration performance in the development of explainable clinical prediction models.
Assuntos
Neoplasias do Endométrio , Molécula L1 de Adesão de Célula Nervosa , Feminino , Humanos , Prognóstico , Estudos Retrospectivos , Biomarcadores Tumorais , Neoplasias do Endométrio/patologiaRESUMO
BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13â071 EOC cases and 17â306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Ovarianas , Feminino , Humanos , Carcinoma Epitelial do Ovário/genética , Alelos , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologiaRESUMO
Uterine leiomyomas, or fibroids, are the most common tumors in women of reproductive age. Uterine leiomyomas can be classified into at least three main molecular subtypes according to mutations affecting MED12, HMGA2, or FH. FH-deficient leiomyomas are characterized by activation of the NRF2 pathway, including upregulation of the NRF2 target gene AKR1B10. Here, we have identified a novel leiomyoma subtype showing AKR1B10 expression but no alterations in FH or other known driver genes. Whole-exome and whole-genome sequencing revealed biallelic mutations in key genes involved in neddylation of the Cullin 3-RING E3 ligase, including UBE2M, NEDD8, CUL3, and NAE1. 3'RNA sequencing confirmed a distinct molecular subtype with activation of the NRF2 pathway. Most tumors displayed cellular histopathology, perivascular hypercellularity, and characteristics typically seen in FH-deficient leiomyomas. These results suggest a novel leiomyoma subtype that is characterized by distinct morphological features, genetic alterations disrupting neddylation of the Cullin 3-RING E3 ligase, and oncogenic NRF2 activation. They also present defective neddylation as a novel mechanism leading to aberrant NRF2 signaling. Molecular characterization of uterine leiomyomas provides novel opportunities for targeted treatment options.
RESUMO
The Cancer Genome Atlas research network performed a genome-wide analysis of endometrial carcinomas in 2013 and classified tumours into four distinct subgroups: polymerase-ϵ ultramutated, microsatellite unstable hypermutated, copy-number low and copy-number high. These molecular alterations are mostly mutually exclusive as only about 3% of tumours exhibit more than one molecular signature. Apart from the polymerase-ϵ ultramutated subgroup, molecular classification can be reproduced by using surrogate markers. This has facilitated the implementation of molecular diagnostics into routine patient care. Molecular subgroups are associated with different prognoses; thus, improved risk assessment is their most obvious clinical application. However, based on their unique molecular architectures, molecular subgroups should not be regarded simply as risk groups but rather as distinct diseases. This has prompted us and others to examine the role of molecular subgroups in modifying the prognostic effect of traditional risk factors, including clinical factors, uterine factors and tissue biomarkers, and in predicting the response to adjuvant therapies. In the following review, we summarise the current knowledge of molecularly classified endometrial carcinoma and present, based on our own experience, a proposal for implementing molecular classification into daily practice in pathology laboratories.
RESUMO
Identification of ovarian cancer patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22% of the high-grade ovarian cancer tumors at diagnosis express CIP2A oncoprotein at low levels. Furthermore, regardless of their significantly lower likelihood of disease relapse after standard chemotherapy, a portion of relapsed tumors retain their CIP2A-deficient phenotype. Through a screen for therapeutics that would preferentially kill CIP2A-deficient ovarian cancer cells, we identified reactive oxygen species inducer APR-246, tested previously in ovarian cancer clinical trials. Consistent with CIP2A-deficient ovarian cancer subtype in humans, CIP2A is dispensable for development of MISIIR-Tag-driven mouse ovarian cancer tumors. Nevertheless, CIP2A-null ovarian cancer tumor cells from MISIIR-Tag mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the ovarian cancer cells to APR-246 by inhibition of NF-κB activity. Accordingly, combination of APR-246 and NF-κB inhibitor compounds strongly synergized in killing of CIP2A-positive ovarian cancer cells. Collectively, the results warrant consideration of clinical testing of APR-246 for CIP2A-deficient ovarian cancer tumor subtype patients. Results also reveal CIP2A as a candidate APR-246 combination therapy target for ovarian cancer.
Assuntos
NF-kappa B , Neoplasias Ovarianas , Animais , Autoantígenos/genética , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , QuinuclidinasRESUMO
Uterine leiomyoma (UL) is a common benign neoplasm which can sometimes be difficult to differentiate from the uterine inflammatory myofibroblastic tumor (IMT) based on morphology alone. IMT is a myofibroblastic/fibroblastic neoplasm which has typically been considered to be rare in the uterus. Its clinical behavior is usually indolent although aggressive variants exist. The majority of IMTs harbor genomic rearrangement of anaplastic lymphoma kinase ( ALK ), while ALK fusion has not been thus far detected in ULs. We analyzed 2263 ULs of which 9 (0.4%) had tyrosine-kinase activation. Seven of the samples were ALK immunopositive: 6 had an ALK fusion gene and 1 overexpressed an ALK transcript skipping exons 2 to 3, Moreover, 1 sample had a RET , and 1 a PDGFRB fusion gene. While no recurrent somatic mutations were found, 1 patient had an ALK germline mutation. Seven tumors showed leiomyoma-like morphology, 1 tumor had slightly loose, and 1 fibrous growth pattern. Six tumors had mild to moderate lymphocyte infiltration, while no immune cell infiltration was detected in 3 cases. None of the tumors showed aggressive behavior. Except for strong ALK positivity (7/9 tumors) the protein expression profile of the tumors was identical to ULs and distinct from other mesenchymal uterine tumors. In gene expression level, these tumors and the known UL subclasses did not separate perfectly. However, vitamin C metabolism and epithelial-mesenchymal transition pathways were uniquely enriched in these lesions. The overall similarity of the analyzed tumors to UL raises the question whether an UL diagnosis would be more proper for a subset of uterine IMTs.
Assuntos
Granuloma de Células Plasmáticas , Leiomioma , Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Neoplasias Uterinas , Feminino , Fusão Gênica , Granuloma de Células Plasmáticas/genética , Humanos , Leiomioma/genética , Proteínas Tirosina Quinases/genética , Neoplasias Uterinas/patologiaRESUMO
Uterine leiomyomas, or fibroids, are very common smooth muscle tumors. Their potential to metastasize or transform into leiomyosarcomas is extremely low. Here, we report a patient who underwent hysterectomy due to a large leiomyoma and who was diagnosed with pulmonary tumors seven and nine years later. Histopathological re-evaluation confirmed the cellular leiomyoma diagnosis for the uterine tumor, whereas the pulmonary tumors met the diagnostic criteria of a leiomyosarcoma. Whole-exome sequencing revealed very similar mutational profiles in all three tumors, including a somatic homozygous deletion in a rare, but well-established leiomyoma driver gene FH. Tumor evolution analysis confirmed the clonal origin of all three tumors. In addition to mutations shared by all three tumors, pulmonary tumors harbored additional alterations affecting e.g. the cancer-associated genes NRG1 and MYOCD. The second pulmonary leiomyosarcoma harbored additional changes, including a mutation in FGFR1. In global gene expression profiling, the uterine tumor showed similar expression patterns as other FH-deficient leiomyomas. Taken together, this comprehensive molecular data supports the occasional metastatic capability and malignant transformation of uterine leiomyomas. Further studies are required to confirm whether FH-deficient tumors and/or tumors with cellular histopathology have higher malignant potential than other uterine leiomyomas.
Assuntos
Leiomioma , Leiomiossarcoma , Neoplasias Pulmonares , Neoplasias Uterinas , Feminino , Fumarato Hidratase/genética , Fumarato Hidratase/metabolismo , Homozigoto , Humanos , Leiomioma/genética , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Neoplasias Pulmonares/genética , Deleção de Sequência , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologiaRESUMO
BACKGROUND: Clear cell and endometrioid ovarian carcinomas (OCC and OEC, respectively) have a presumed origin in endometriosis and share molecular alterations with each other and with their endometrial counterparts. The Cancer Genome Atlas (TCGA)-based molecular classification stratifies endometrial carcinomas into four categories: POLE mutated (POLEmut), mismatch repair deficient (MMRd), p53 abnormal (p53abn) and no specific molecular profile (NSMP) with divergent prognoses. The subsequent studies are indicative that this TCGA classification has some value in OEC, but the knowledge related to OCC is limited. METHODS: Endometrial carcinoma molecular classification was evaluated and compared in a large series of OCCs (n = 115) and OECs (n = 158). POLE mutation analysis and tissue microarray-based immunohistochemistry for mismatch repair and p53 proteins were performed. RESULTS: The distribution to the molecular groups was as follows: POLEmut 0.9%/3.2%, MMRd 3.5%/6.3%, p53abn 20%/30%, and NSMP 76%/60% in OCCs/OECs, respectively. The proportion of NSMP tumors was the largest in both histological types and significantly higher in OCC than OEC (p = 0.009). The molecular classification correlated significantly with DSS in both OCCs and OECs (p < 0.001 and p = 0.009, respectively), and with DFS in OCCs (p = 0.001). POLEmut and MMRd OCCs carried excellent prognosis, whereas MMRd OECs presented with poorer outcome. The p53abn group was associated with the poorest prognosis in both tumor types, particularly emphasized in OCCs. CONCLUSIONS: TCGA molecular classification associated with patient outcome in both histotypes, and the difference in prognosis between the molecular groups was even more marked in OCC. The large amount of NSMP tumors highlights the need for further studies.