Clinicopathological and molecular characterization of gastroesophageal junction (GEJ) adenocarcinoma before age of 40 years

Gastroesophageal junction (GEJ) adenocarcinoma are uncommon before age of 40 years. While certain clinical, pathological and molecular features of GEJ adenocarcinoma in older patients have been extensively studied, these characteristics in the younger population remain to be determined. In the recent literature, a high sensitivity and specificity for the detection of dysplasia and esophageal adenocarcinoma was demonstrated by using multicolor fluorescence in situ hybridization (FISH) DNA probe set specific for the locus specific regions 9p21 (p16), 20q13.2 and Y chromosome. We evaluated 663 patients with GEJ adenocarcinoma and further divided them into 2 age-groups of or= 50 years, rispectively. FISH with selected DNA probe for Y chromosome, locus 9p21 (p16), and locus 20q13.2 was investigated with formalin fixed and parassin embedded tissue from surgical resections of 17 younger and 11 older patients. Signals were counted in > 100 cells with each given histopathological category. The chromosomal aberrations were then compared in the 2 age-groups with the focus on uninvolved squamous and columnar epithelium, intestinal metaplasia (Barrett's mucosa), glandular dysplasia, and adenocarcinoma. Comparisons were performed by the X2 test, Fisher's exact test, Student's t-test and Mann-Whitney U-test as appropriate. Survival was estimated by the Kaplan-Meier method with univariate analysis by the log-rank. Significance was taken at the 5% level. There was no difference in the surgical technique applied in both age groups and most patients underwent Ivor Lewis esophagectomy. Among clinical variables there was a higher incidence of smocking history in older patient group. We identified a progressive loss of Y chromosome from benign squamos epithelium to Barrett's mucosa and glandular dysplasia, and, ultimately, to a near complete loss in adenocarcinoma in both age groups. The young group revealed significantly more losses of 9p21 in both benign and neoplastic cells when compared to the older patients group. In addition, we demonstrated an increase in the percentage of cells showing gain of locus 20q13.2 with progression from benign epithelium through dysplasia to adenocarcinoma with almost the same trend in both the young and the older patients. When compared with the older age-group, younger patients with GEJ adenocarcinoma possess similar known demographics, environmental factors, clinical, and pathologic characteristics. The most commonly detected genetic aberrations of progressive Y chromosomal loss, 9p21 locus loss, and 20q13 gains were similar in the younger and older patients. However the rate of loss of 9p21 is significantly higher in young patients, in both the benign and the neoplastic cells. The loss of 9p21, and possibly, the subsequent inactivation of p16 gene may be one of the molecular mechanisms responsible for the accelerated neoplastic process in young patients.

Molecular analysis of special type breast carcinomas

The project was developed into three parts: the analysis of p63 isoform in breast tumours; the study of intra-tumour eterogeneicity in metaplastic breast carcinoma; the analysis of oncocytic breast carcinoma. p63 is a sequence-specific DNA-binding factor, homologue of the tumour suppressor and transcription factor p53. The human p63 gene is composed of 15 exons and transcription can occur from two distinct promoters: the transactivating isoforms (TAp63) are generated by a promoter upstream of exon 1, while the alternative promoter located in intron 3 leads to the expression of N-terminal truncated isoforms (ΔNp63). It has been demonstrated that anti-p63 antibodies decorate the majority of squamous cell carcinomas of different organs; moreover tumours with myoepithelial differentiation of the breast show nuclear p63 expression. Two new isoforms have been described with the same sequence as TAp63 and ΔNp63 but lacking exon 4: d4TAp63 and ΔNp73L, respectively. Purpose of the study was to investigate the molecular expression of N-terminal p63 isoforms in benign and malignant breast tissues. In the present study 40 specimens from normal breast, benign lesions, DIN/DCIS, and invasive carcinomas were analyzed by immunohistochemistry and RT-PCR (Reverse Transcriptase-PCR) in order to disclose the patterns of p63 expression. We have observed that the full-length isoforms can be detected in non neoplastic and neoplastic lesions, while the short isoforms are only present in the neoplastic cells of invasive carcinomas. Metaplastic carcinomas of the breast are a heterogeneous group of neoplasms which exhibit varied patterns of metaplasia and differentiation. The existence of such non-modal populations harbouring distinct genetic aberrations may explain the phenotypic diversity observed within a given tumour. Intra-tumour morphological heterogeneity is not uncommon in breast cancer and it can often be appreciated in metaplastic breast carcinomas. Aim of this study was to determine the existence of intra-tumour genetic heterogeneity in metaplastic breast cancers and whether areas with distinct morphological features in a given tumour might be underpinned by distinct patterns of genetic aberrations. 47 cases of metaplastic breast carcinomas were retrieved. Out of the 47 cases, 9 had areas that were of sufficient dimensions to be independently microdissected. Our results indicate that at least some breast cancers are composed of multiple non-modal populations of clonally related cells and provide direct evidence that at least some types of metaplastic breast cancers are composed of multiple non-modal clones harbouring distinct genetic aberrations. Oncocytic tumours represent a distinctive set of lesions with typical granular cytoplasmatic eosinophilia of the neoplastic cells. Only rare example of breast oncocytic carcinomas have been reported in literature and the incidence is probably underestimated. In this study we have analysed 33 cases of oncocytic invasive breast carcinoma of the breast, selected according to morphological and immunohistochemical criteria. These tumours were morphologically classified and studied by immunohistochemistry and aCGH. We have concluded that oncocytic breast carcinoma is a morphologic entity with distinctive ultrastructural and histological features; immunohistochemically is characterized by a luminal profile, it has a frequency of 19.8%, has not distinctive clinical features and, at molecular level, shows a specific constellation of genetic aberration.

Targeting epigenetic mechanisms in gastric cancer

Gastric cancer (GC) is a hard challenge for medical oncology, with globally over one million of new diagnoses each year and low survival rates. Gastric carcinogenesis is guided by the interaction of several risk factors, exerting through sequential histopathologic steps, including chronic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia and cancer. GC is classified on the basis of anatomical, histological or molecular classification, reflecting the wide cancer heterogeneity, also highlighted by the inefficacy of the actual treatment schedules. Epigenetic mechanisms alterations affecting DNA methylation, histone methylation and acetylation, are a recognized hallmark of cancer and stand at the basis of gastric carcinogenesis and tumor development. The pharmacological targeting of these altered mechanisms is an attractive option for new cancer treatments. Aim of this study was to test the therapeutic potential of the compound CM-272 for GC, a selective and strong dual inhibitor of DNMT1 and EHMT2, which reached important results in pre-clinical models of other gastrointestinal malignancies. Moreover, in a GC patients case series, the expression of the target of the compound was tested, to prove the rationale for inhibition of DNMT1, EHMT2 and their functional adaptor were over-expressed in the majority of GC patients tissues. Through in-vitro testing of CM-272 alone and in combination with the most used chemotherapeutic treatments for GC in a panel of GC cell lines, this study demonstrated that the compound has a strong ability in inhibiting GC cells growth. Even though not directly inducing apoptosis, CM-272 was able to induce a senescent phenotype in GC cells, and to epigenetically reprogram the transcription of genes involved in phosphorylation cascades and mitochondria metabolism, thus affecting the growth and energetic machinery of cancer cells. In conclusion, the pharmacological targeting of epigenetic mechanisms demonstrated good potential pre-clinical models of GC, and further investigations to test in-vivo efficacy are needed.

Riscontri istologici in individui transgender AFAB in terapia con testosterone

CONTESTO: Il rischio oncologico dell’esposizione al testosterone (T) di organi genitali in transgender AFAB non è noto. SCOPO: valutazione istologica di utero, cervice, salpingi e ovaia asportati in corso di intervento chirurgico di affermazione di genere (GAS) in AFAB che assumevano testosterone. MATERIALI E METODI: valutazione dei dati istologici condotta retrospettivamente tramite la consultazione di 187 cartelle cliniche di soggetti transgender AFAB sottoposti a GAS presso la Ginecologia dell’IRCCS Sant’Orsola, Bologna. RISULTATI: 187 transgender AFAB sono stati sottoposti a isteroannessiectomia bilaterale. Nessun paziente sottoposto a ovariectomia, chemioterapia o radioterapia prima della chirurgia. La mediana della durata di assunzione di T era di 36 mesi (12 mesi-14 anni). 96/187 (51.4%) uteri presentavano endometrio ipoattivo/atrofico, mentre 1 caso di iperplasia senza atipie cellulari è stato identificato (0.5%), 8/187 (4.3%) endometrio polipoide e 4/187 (2.2%) secretivo. Il più comune riscontro istologico cervicale è stata la cervicite cronica (n=174, 93%) associata a metaplasia (n=131,76%). Le salpingi sono risultate indenni in 90/187 (48.1%) casi e con infiammazione cronica in 91/187 (48,7%) casi. La maggior parte delle ovaie analizzate mostravano follicoli in diversi stati di maturazione (n=117, 62.5%). In 20 analisi istologiche sono stati identificati corpi lutei/corpi lutei emorragici (10.7%). CONCLUSIONI: Nessuna lesione premaligna o maligna è stata riscontrata in questi 187 soggetti che assumevano testosterone fino a un massimo di 168 mesi prima della chirurgia. La presenza di follicoli in vari stadi di sviluppo e di corpi lutei suggerisce la possibilità di cicli ovulatori in corso di terapia con testosterone. I risultati di questo studio confermano la sicurezza dell'uso prolungato di T sugli organi genitali di transgender AFAB. Seppur ancora limitate, le evidenze suggeriscono sempre più la mancanza di necessità assoluta di rimuovere utero e ovaia nei soggetti trasgender in terapia con T con il solo fine di prevenire patologie oncologiche.