Ju‐Yoon Yoon

Molecular and immunohistochemical characterization of ERBB2 activating mutations in low‐grade serous ovarian carcinoma

AimsLow‐grade serous carcinoma (LGSC) of the ovary presents unique therapeutic challenges due to its resistance to platinum‐based chemotherapies and a tendency to present at an advanced stage. Approximately 50% of LGSC possess activating mutations in KRAS, NRAS, and BRAF, a finding associated with better overall survival. However, many tumours lack obvious driver alterations against which to direct targeted treatment strategies, necessitating further investigation into molecular drivers of LGSC and their impact on clinical outcomes.Methods and ResultsWe conducted a retrospective analysis of 84 LGSC patients who underwent tumour‐only targeted next‐generation sequencing at our institution. Molecular data were correlated with clinical outcomes, HER2 immunohistochemistry, and supplemented with additional tumour sequencing data from the AACR GENIE cohort v15.1 (n = 295). Approximately 5% of LGSC cases across the combined cohort harboured activating alterations in ERBB2 (n = 17/369), which encodes the HER2 receptor tyrosine kinase. These alterations were mutually exclusive of other MAP kinase pathway mutations and included exon 20 insertions (n = 6), extracellular domain/transmembrane domain missense alterations (n = 4), and exon 16 skipping mutations (n = 7). ERBB2 exon 16 emerged as a mutational hotspot in LGSC when compared to other tumour types. Immunohistochemistry revealed variable HER2 expression patterns that were independent of ERBB2 mutational status. In our institutional cohort, patients with RAS/RAF mutant tumours (n = 38) showed better overall survival compared to RAS/RAF wildtype tumours (n = 35). No tumours in our internal cohort (n = 84) harboured ERBB2 amplifications.ConclusionAs the landscape of HER2‐directed therapies continues to evolve, these findings suggest that ERBB2 alterations and HER2 expression may represent a potential therapeutic target in LGSC.

Pitfalls in MLH1 promoter methylation assessment, including POLEmut/MLH1meth endometrial adenocarcinoma

MLH1 promoter methylation status may serve as an important diagnostic, prognostic, and predictive biomarker in management of mismatch repair (MMR)-deficient cancers. A new commercial assay for detection of MLH1 promoter hyper-methylation (EntroGen), which interrogates regions C and D, was assessed for its performance characteristics. False positive results were obtained in 5/21 non-lesional cases, with signals limited to region C. Three were explained by overloaded reactions. Two unexplained cases were both muscle samples (2/6 muscle samples, one each of skeletal and smooth). The assay was 100 % concordant (52/52) for lesional samples with expected MLH1 promoter methylation status. These included two exceptional cases-one Lynch-associated, and one POLE-mutated endometrial carcinoma; thus expanding the spectrum of extreme cases, and demonstrate neither germline or somatic NGS results completely rule out MLH1 promoter methylation, and vice versa. The POLE

Genomic catastrophe, the peritoneal cavity and ovarian cancer prevention

AbstractThe current theory of carcinogenesis for the deadliest of ‘ovarian’ cancers—high‐grade serous carcinoma (HGSC)—holds that the malignancy develops first in the fallopian tube and spreads to the ovaries, peritoneum, and/or regional lymph nodes. This is based primarily on the observation of early forms of serous neoplasia (serous tubal intraepithelial lesions [STILs], and serous tubal intraepithelial carcinomas [STICS]) in the fimbria of women undergoing risk reduction surgery. However, these lesions are uncommon in the general population, confer a low risk (5%) of HGSC following their removal in at‐risk women with germ‐line BRCA1/2 mutations, and require 4 or more years to recur as intraperitoneal HGSC. These features suggest that isolated STILs and STICs behave as precursors, with uncertain cancer risk rather than carcinomas. Their evolution to HGSC within, or after, escape from the tube could proceed stepwise with multiple biologic events; however, it is unclear whether tubal or ovarian HGSCs encountered in the setting of advanced disease evolved in the same fashion. The latter scenario could also be explained by a ‘catastrophic’ model in which STICs suddenly develop with invasive and metastatic potential, overwhelming or obscuring the site of origin. Moreover, a similar model might explain the sudden emergence of HGSC in the peritoneal cavity following escape of precursor cells years before. Long‐term follow‐up data from opportunistic or prophylactic salpingectomy should shed light on where malignant transformation occurs, as well as the timeline from precursor to metastatic HGSC. © 2022 The Pathological Society of Great Britain and Ireland.