Tricia A. Numan

Clinicopathologic and Molecular Analysis of Malignant Neoplasms With Yolk Sac Tumor Differentiation in Women 40 Years of Age and Older

Gynecologic yolk sac tumors (YSTs) are more commonly encountered in children and young women as pure or mixed germ cell tumors and are rarely observed in older women. YSTs in older women are sometimes accompanied by a Müllerian-type carcinoma component, indicating a likely somatic rather than germ-cell origin. Studies of YSTs of germ cell and somatic types in this age group are limited. Analysis of additional pure and mixed tumors with YST differentiation could elucidate differences between these tumor subtypes and the relationship between components in mixed tumors. Clinicopathologic features of 32 malignant neoplasms with YST differentiation in women aged 40+ were analyzed. There were 11 pure YSTs, 7 mixed germ cell tumors, and 14 YSTs with a malignant non-germ cell tumor component (somatically derived yolk sac tumor [SDYST]). Targeted next-generation sequencing (NGS) was performed in 4/11 pure YSTs, 0/7 mixed germ cell tumors, and 4/14 SDYSTs. For the pure YSTs, alterations in DICER1 (1/4), PIK3R1 and PTPRT (1/4), PMS1 (1/4), and TP53 (2/4) were identified. One other pure YST had alterations in PTEN, ARID1A, ARID1B, FGFR2, and CTNNB1 (alterations common in endometrioid carcinoma). SDYSTs demonstrated shared alterations between both components including TP53, KRAS, FBXW7, and KMT2C, suggesting a common origin. The findings in the pure YSTs in older women suggest that for some, the origin could be germ cell as they harbor similar alterations as those described in pure YSTs in young women, whereas in other “pure” YSTs, the molecular profile aligns with previously described SDYSTs, which suggests a SDYST with an unsampled Müllerian carcinoma component rather than a germ cell origin. In SDYSTs, shared alterations are consistent with prior studies and suggest a somatic rather than germ-cell origin.

The addition of metformin to progestin therapy in the fertility-sparing treatment of women with atypical hyperplasia/endometrial intraepithelial neoplasia or endometrial cancer: Little impact on response and low live-birth rates

Our objectives were 1) to compare the efficacy of progestin therapy combined with metformin (Prog-Met) to Prog alone as primary fertility sparing treatment in women with atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) or early-stage endometrioid carcinoma (EC), and 2) to analyze the proportion of women achieving live birth following treatment. A retrospective cohort study of all reproductive-aged women with AH/IN or EC treated with Prog ± Met from 1999-2018 was conducted. Complete response (CR) was assessed and Kaplan-Meier analysis used to calculate time to CR. Comparison of potential response predictors was performed with multivariable Cox regression models. Ninety-two women met criteria; 59% (n = 54) were treated for AH/EIN and 41% (n = 38) for EC. Their median age, body mass index, and follow up time was 35 years, 37.7 kg/m Our study does not support the use of Prog-Met therapy for treatment of AH/EIN or EC. Additionally, fewer than 20% of women achieved a live-birth pregnancy during the study period, with most requiring ART.

Spatial Transcriptomic Analysis of Ovarian Cancer Precursors Reveals Reactivation of IGFBP2 during Pathogenesis

Abstract Elucidating the earliest pathogenic steps in cancer development is fundamental to improving its early detection and prevention. Ovarian high-grade serous carcinoma (HGSC), a highly aggressive cancer, mostly originates from the fallopian tube epithelium through a precursor stage, serous tubal intraepithelial carcinoma (STIC). In this study, we performed spatial transcriptomic analysis to compare STICs, carcinoma, and their matched normal fallopian tube epithelium. Several differentially expressed genes in STICs and carcinomas were involved in cancer metabolism and detected in a larger independent transcriptomic dataset of ovarian HGSCs. Among these, insulin-like growth factor binding protein-2 (IGFBP2) was found to undergo DNA hypomethylation and to be increased at the protein level in STICs. Pyrosequencing revealed an association of IGFBP2 expression with the methylation state of its proximal enhancer, and 5-azacytidine treatment increased IGFBP2 expression. In postmenopausal fallopian tubes, where most STICs are detected, IGFBP2 immunoreactivity was detected in all 38 proliferatively active STICs but was undetectable in morphologically normal tubal epithelia, including those with TP53 mutations. In premenopausal fallopian tubes, IGFBP2 expression was limited to the secretory epithelium at the proliferative phase, and estradiol treatment increased IGFBP2 expression levels. IGFBP2 knockdown suppressed the growth of IGFBP2-expressing tubal epithelial cells via inactivation of the AKT pathway. Taken together, demethylation of the proximal enhancer of IGFBP2 drives tumor development by maintaining the increased IGFBP2 required for proliferation in an otherwise estrogen-deprived, proliferation-quiescent, and postmenopausal tubal microenvironment. Significance: Molecular studies of the earliest precursor lesions of ovarian cancer reveal a role of IGFBP2 in propelling tumor initiation, providing new insights into ovarian cancer development.

Aneuploidy Landscape in Precursors of Ovarian Cancer

Abstract Purpose: Serous tubal intraepithelial carcinoma (STIC) is now recognized as the main precursor of ovarian high-grade serous carcinoma (HGSC). Other potential tubal lesions include p53 signatures and tubal intraepithelial lesions. We aimed to investigate the extent and pattern of aneuploidy in these epithelial lesions and HGSC to define the features that characterize stages of tumor initiation and progression. Experimental Design: We applied RealSeqS to compare genome-wide aneuploidy patterns among the precursors, HGSC (cases, n = 85), and histologically unremarkable fallopian tube epithelium (HU-FTE; control, n = 65). On the basis of a discovery set (n = 67), we developed an aneuploidy-based algorithm, REAL-FAST (Repetitive Element AneupLoidy Sequencing Fallopian Tube Aneuploidy in STIC), to correlate the molecular data with pathology diagnoses. We validated the result in an independent validation set (n = 83) to determine its performance. We correlated the molecularly defined precursor subgroups with proliferative activity and histology. Results: We found that nearly all p53 signatures lost the entire Chr17, offering a “two-hit” mechanism involving both TP53 and BRCA1 in BRCA1 germline mutation carriers. Proliferatively active STICs harbor gains of 19q12 (CCNE1), 19q13.2, 8q24 (MYC), or 8q arm, whereas proliferatively dormant STICs show 22q loss. REAL-FAST classified HU-FTE and STICs into 5 clusters and identified a STIC subgroup harboring unique aneuploidy that is associated with increased proliferation and discohesive growth. On the basis of a validation set, REAL-FAST showed 95.8% sensitivity and 97.1% specificity in detecting STIC/HGSC. Conclusions: Morphologically similar STICs are molecularly distinct. The REAL-FAST assay identifies a potentially “aggressive” STIC subgroup harboring unique DNA aneuploidy that is associated with increased cellular proliferation and discohesive growth. REAL-FAST offers a highly reproducible adjunct technique to assist the diagnosis of STIC lesions.

Integrated Spatial Analysis Reveals the Molecular Landscape of Ovarian Precancerous Lesions

Abstract Studying precancerous lesions is essential for improving early detection and prevention, particularly in aggressive cancers such as ovarian carcinoma. In this study, we conducted integrated and spatial analyses of transcriptomes, aneuploidy, and clinicopathologic features in 166 ovarian precancerous lesions. Four precancerous transcriptomic subtypes were identified: proliferative, immunoreactive, dormant, and mixed. These subtypes varied in their frequency of germline BRCA1/2 mutations, aneuploidy, CCNE1/MYC amplification, proliferative activity, immunoregulatory gene expression, and histologic features. Notably, the immunoreactive subtype upregulated immunoregulatory genes, exhibited chronic inflammation, and was enriched in cases with germline BRCA1/2 mutations and deletions of chromosomes 17 (harboring TP53 and BRCA1) and 13 (harboring BRCA2), leading to a double “two-hit” involving TP53 and BRCA1/2. Tumor invasion was associated with the activation of interferon response pathways, epithelial–mesenchymal transition, and extracellular matrix remodeling. In summary, these results elucidate the earliest molecular landscape of ovarian precancerous lesions, serving as the foundation for future risk stratification to identify aggressive precancerous lesions. Significance: Integrated spatial multiomics analysis of ovarian precancerous lesions reveals molecular subtypes and mechanisms underlying tumor initiation, offering a foundation for future risk stratification and prevention. See related commentary by Soong et al. p. 1537