Abstract
Uterine leiomyomas (ULMs) are highly common benign tumors that affect the health of millions of women by causing a variety of symptoms. Furthermore, ULMs are the most common indication for ...hysterectomy, generating considerable economic costs for the health care system. Recurrent and mutually exclusive genetic aberrations leading to unique gene expression profiles have been identified in ULMs. Thus these tumors can be divided into distinct subclasses according to their molecular genetic background.
The majority of ULMs (80-90%) have specific mutations in MED12 or aberrations in HMGA2. Somatic biallelic inactivation of FH can also, albeit rarely, drive ULM tumorigenesis and has previously been detected in 1.3% of sporadic ULM samples (2/153; Lehtonen et al, 2004).
FH encodes the fumarase enzyme that catalyzes the hydration of fumarate to L-malate in the tricarboxylic acid cycle. Biallelic inactivation of FH leads to accumulation of fumarate and aberrant succination of proteins. Heterozygous germline FH mutations predispose to a rare autosomal dominant tumor predisposition syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC). This highly penetrant syndrome is characterized by uterine and cutaneous leiomyomas and in some cases renal cell cancer.
In this study, we re-evaluated the frequency of somatic biallelic inactivation of FH in ULMs in the largest sample set thus far. The study material consisted of 1167 fresh frozen ULM and their respective normal myometrium tissue samples from 375 hysterectomy patients. All samples were analyzed with high-throughput SNP array (Infinium Human Core-24+ Kit, Illumina Inc., San Diego, CA). All tumors detected with somatic deletions or loss of heterozygosity (LOH) in the FH locus were included in S-(2-succinyl) cysteine (2SC) immunohistochemistry (IHC) to indirectly detect biallelic FH inactivation. Also samples without FH double deletions were selected for Sanger sequencing of FH coding regions to detect inactivating mutations.
Somatic FH deletions or LOH were detected in 30 tumors, of which 10 were identified FH deficient by 2SC IHC. In these samples, another deletion (a double deletion) in three ULMs and a somatic nucleotide change in six ULMs was found to be the second hit causing biallelic inactivation of FH. In one sample no second hit was detected with these methods. From the six somatic nucleotide changes, four were different FH missense mutations predicted to be damaging (SIFT, PolyPhen-2, Provean) and two were synonymous substitutions in the last nucleotide of different exons. Studies to determine the impact of these synonymous changes on splicing are underway.
To conclude, in our sample set we detected 0.9% (10/1167) of the ULMs to harbour somatic biallelic inactivation of FH. MED12 exon 1 or 2 mutations and HMGA2 rearrangements were not detected in these tumors. Thus the previously published results were validated in this study with the largest sample set so far.
Citation Format: Jaana Tolvanen, Netta Mäkinen, Hanna-Riikka Heinonen, Simona Bramante, Miika Mehine, Nanna Sarvilinna, Jari Sjöberg, Oskari Heikinheimo, Annukka Pasanen, Ralf Bützow, Lauri A. Aaltonen. Somatic biallelic inactivation of fumarate hydratase (FH) in uterine leiomyomas abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1457. doi:10.1158/1538-7445.AM2017-1457
Abstract
Uterine leiomyomas (ULs) are benign, estrogen- and progesterone-dependent smooth muscle tumors of the uterus. They are among the most common human neoplasms with an estimated prevalence of ...20-40% in women of reproductive age, but also percentages as high as 77% have been reported. Although benign, ULs form a major burden to women's health. Approximately 25% of women with ULs have clinically relevant lesions, which cause morbidity and thus require treatment. As a consequence, ULs are the leading cause of hysterectomy worldwide. Despite the high prevalence and socio-economic impact of ULs, the molecular mechanisms underlying the growth and development of these lesions remain largely unknown. Familial, epidemiological, and cytogenetic studies indicate that genetic factors play a central role in the development of these lesions. Our recent findings, derived from the use of high-throughput technologies, have pointed to at least three distinct molecular UL subclasses, each candidate subclass displaying a characteristic genetic driver aberration as well as global gene expression profile: MED12 (mediator complex subunit 12) mutation-positive, HMGA2 (high mobility group AT-hook 2)-overexpressing, and FH (fumarate hydratase)-deficient ULs. Although the majority of ULs show estrogen and progesterone receptor (ER and PR) positivity on protein level, a subgroup of these tumors are ER- or PR-negative with an estimated frequency of up to 10%. The aim of this study is to assess the potential correlation between steroid receptor expression and different molecular UL subclasses. The study material consists of 1100 ULs collected from hysterectomy patients during surgery in Helsinki University Central Hospital and Central Finland Central Hospital, Finland. All ULs are systematically screened for MED12 mutations by Sanger sequencing. Because overexpression of HMGA2 typically arises through a chromosomal translocation, HMGA2-overexpressing ULs as well as FH-deficient tumors are tentatively identified using a high-density customizable Infinium® HumanCore-24+ BeadChip with 4000 additional custom markers that cover known genes, candidate regions, and single-nucleotide variations related to UL genesis. Also ULs without any known genetic driver aberrations are included in the study. ER and PR protein expression are analyzed by immunohistochemistry. Currently, molecular classification of the tumors plays no role in choosing treatment, but ULs are treated as a single entity. Different molecular subclasses may, however, use different molecular pathways, have different clinical outcome, or response to treatment. Identification of ER- and PR-negative ULs and their potential association with the genetic driver aberrations may provide important new information on the molecular mechanisms underlying UL genesis. Increased knowledge is also essential for developing new targeted treatments and improving management of the condition.
Citation Format: Netta Mäkinen, Annukka Pasanen, Hanna-Riikka Heinonen, Kati Kämpjärvi, Simona Bramante, Miika Mehine, Jyrki Jalkanen, Oskari Heikinheimo, Jari Sjöberg, Ralf Bützow, Lauri Aaltonen. Estrogen and progesterone receptor expression in different molecular uterine leiomyoma subclasses. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 120.
Preoperative or intraoperative risk assessment models are used to stratify patients with endometrial carcinoma to lymphadenectomy. Our aim was to determine whether preoperative analysis of L1 cell ...adhesion molecule (L1CAM) can improve risk assessment.
Immunohistochemical L1CAM staining was performed on endometrial biopsies of 241 patients and paired hysterectomy samples of 75 patients. Risk assessment models based on preoperative histologic type and grade, myometrial invasion, and/or tumor diameter and alternative models incorporating preoperative L1CAM were compared with regard to their capability of predicting lymph nodal or distant metastasis. Soluble L1 levels were measured by enzyme-linked immunosorbent assay in serum samples of 40 patients with endometrial carcinoma.
The concordance rate between L1CAM staining results of preoperative and hysterectomy samples was moderate (κ = 0.586,
< 0.0001). Preoperative L1CAM expression was associated with nonendometrioid histology, lymph node involvement, advanced stage, and positive peritoneal cytology. Receiver operating characteristic curve analyses showed that L1CAM did not significantly improve risk stratification algorithms based on traditional risk factors. Intraoperative tumor diameter was an effective surrogate for myometrial invasion. There was no statistical difference between L1 serum levels of patients with an L1CAM-positive or L1CAM-negative endometrial carcinoma (
= 0.786).
L1 cell adhesion molecule expression in endometrial biopsy correlates with high-risk features of endometrial carcinoma but does not significantly improve risk stratification algorithms based on traditional factors. Soluble L1 detected in the serum of patients with endometrial carcinoma does not correlate with tumoral L1CAM expression.
Esophageal small cell carcinoma La Torre, Marco; Ferrari, Linda; Cosenza, Giulia ...
The American surgeon
76, Številka:
5
Journal Article
Recenzirano
According to Medgyesy et al.,2 the median age of patients affected is 58 years (range comprised between 31 and 79 years), and the majority of patients had a history of smoking and/or alcohol ...consumption. ...the rarity of extrapulmonary SCC, and particularly of esophageal SCC, led to the physician's only preliminary and not standardized experiences ex- trapolated from few reports in literature.
Problem statementUterine leiomyomas (ULM) are benign smooth muscle tumors, occurring in up to 70% of women by the age of 50 years. Myomectomy is a surgical treatment option where the uterus and ...thereby reproductive potential are preserved. The most important known genetic changes in ULM are mutations in mediator complex subunit 12 (MED12), changes leading to high mobility group AT-hook (HMGA2) overexpression, and heterozygous germline mutations in fumarate hydratase (FH), resulting in hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. The earlier studies on molecular background of ULM are mostly based on hysterectomy samples from middle aged women. Therefore, we wanted to know whether the pathogenesis of ULM is similar in younger women.MethodsThe research material comprises of women up to 45 years old, who have undergone myomectomy at Helsinki University Central Hospital. We have collected formalin fixed paraffin embedded samples from patients operated during 2009u20142014. MED12 mutation frequency was determined by direct sequencing of exons 1 and 2, and HMGA2 expression levels were assessed by immunohistochemistry. Biallelic FH inactivation was detected with 2SC staining. Patientsu00b4 medical records were reviewed. ResultsWe analyzed 234 patients with 361 leiomyomas. The median age of patients at operation was 34 years. 6.4% of the patients had had a prior myomectomy. The majority of patients (58%) were operated for a single leiomyoma. The frequency of MED12 mutation was 71%, as reported in tumors obtained through hysterectomy. 9% of leiomyomas showed HMGA2 overexpression, 3% were FH deficient, and 17% were wildtype for all of the studied alterations. Interestingly, in solitary leiomyomas, the MED12 frequency was only 49%, and 27% of the solitary tumors were wildtype. Leiomyomas with MED12 mutation were smaller in size compared to tumors with HMGA2 overexpression, and more often subserosal compared to tumors with other drivers. ConclusionThis study is a comprehensive sample series of young ULM patients. Our findings emphasize the meaning of solitary leiomyomas in clinical practice. Molecular changes behind the notable proportion of wildtype leiomyomas need more research. The authors declare that they have no conflict of interest.
Endometriosis is an estrogen dependent disease, which causes chronic inflammation and may lead to pelvic pain and infertility. Women with endometriosis have a 1.5 to 2-fold risk for ovarian ...epithelial cancer. The risk is increased especially for the endometrioid and clear cell histological types of ovarian carcinoma. Endometriosis and its atypical form are often found in the proximity of these cancers, and molecular changes similar to those in cancer have been detected in nearby endometriosis. The risk of cancer is associated with ovarian endometriosis, i.e. endometriomas and is increased by prolonged disease and/or older age at diagnosis and infertility. The progression of endometriosis to cancer is usually slow, possibly enabling diagnosis at an early stage of the disease.
PDF
