Substantial advances have been made recently in the pathobiology of pituitary tumors. Similar to many other endocrine tumors, over the last few years we have recognized the role of germline and somatic mutations in a number of syndromic or non-syndromic conditions with pituitary tumor predisposition. These include the identification of novel germline variants in patients with familial or simplex pituitary tumors and establishment of novel somatic variants identified through next generation sequencing. Advanced techniques have allowed the exploration of epigenetic mechanisms mediated through DNA methylation, histone modifications and non-coding RNAs, such as microRNA, long noncoding RNAs and circular RNAs. These mechanisms can influence tumor formation, growth and invasion. While genetic and epigenetic mechanisms often disrupt similar pathways, such as cell cycle regulation, in pituitary tumors there is little overlap between genes altered by germline, somatic and epigenetic mechanisms. The interplay between these complex mechanisms driving tumorigenesis are best studied in the emerging multi-omics studies. Here, we summarize insights from the recent developments in the regulation of pituitary tumorigenesis.
Summary A male patient with a germline mutation in MEN1 presented at the age of 18 with classical features of gigantism. Previously, he had undergone resection of an insulin-secreting pancreatic neuroendocrine tumour (pNET) at the age of 10 years and had subtotal parathyroidectomy due to primary hyperparathyroidism at the age of 15 years. He was found to have significantly elevated serum IGF-1, GH, GHRH and calcitonin levels. Pituitary MRI showed an overall bulky gland with a 3 mm hypoechoic area. Abdominal MRI showed a 27 mm mass in the head of the pancreas and a 6 mm lesion in the tail. Lanreotide-Autogel 120 mg/month reduced GHRH by 45% and IGF-1 by 20%. Following pancreaticoduodenectomy, four NETs were identified with positive GHRH and calcitonin staining and Ki-67 index of 2% in the largest lesion. The pancreas tail lesion was not removed. Post-operatively, GHRH and calcitonin levels were undetectable, IGF-1 levels normalised and GH suppressed normally on glucose challenge. Post-operative fasting glucose and HbA1c levels have remained normal at the last check-up. While adolescent-onset cases of GHRH-secreting pNETs have been described, to the best of our knowledge, this is the first reported case of ectopic GHRH in a paediatric setting leading to gigantism in a patient with MEN1. Our case highlights the importance of distinguishing between pituitary and ectopic causes of gigantism, especially in the setting of MEN1, where paediatric somatotroph adenomas causing gigantism are extremely rare. Learning points It is important to diagnose gigantism and its underlying cause (pituitary vs ectopic) early in order to prevent further growth and avoid unnecessary pituitary surgery. The most common primary tumour sites in ectopic acromegaly include the lung (53%) and the pancreas (34%) (1): 76% of patients with a pNET secreting GHRH showed a MEN1 mutation (1). Plasma GHRH testing is readily available in international laboratories and can be a useful diagnostic tool in distinguishing between pituitary acromegaly mediated by GH and ectopic acromegaly mediated by GHRH. Positive GHRH immunostaining in the NET tissue confirms the diagnosis. Distinguishing between pituitary (somatotroph) hyperplasia secondary to ectopic GHRH and pituitary adenoma is difficult and requires specialist neuroradiology input and consideration, especially in the MEN1 setting. It is important to note that the vast majority of GHRH-secreting tumours (lung, pancreas, phaeochromocytoma) are expected to be visible on cross-sectional imaging (median diameter 55 mm) (1). Therefore, we suggest that a chest X-ray and an abdominal ultrasound checking the adrenal glands and the pancreas should be included in the routine work-up of newly diagnosed acromegaly patients.
Long-term survivors (LS) of metastatic colorectal cancer (mCRC) who experience multiple recurrences with resectable oligometastatic disease provide an opportunity to explore co-evolution of the tumor and immune microenvironment. We profiled 16 LS of mCRC with a median follow-up of 9.3 years and median of 3 biopsies/resections per patient (range 2-7). We performed multi-omic profiling of 56 primary and 176 metastatic samples from formalin-fixed paraffin-embedded tissue using low pass whole genome sequencing, 3’ RNA sequencing and DNA methylation arrays. A machine learning cell classifier was used to quantify immune cell and fibroblast infiltration from hematoxylin and eosin staining. Copy number profiling showed that the fraction of genome altered remained relatively stable across time and tissue type but that already-altered segments underwent progressive fragmentation. Inter-timepoint divergence of copy number alterations was significantly higher than intra-timepoint divergence, and intra-timepoint divergence was lower for liver and lung metastases than for primary tumors. Chemotherapy treatment did not significantly affect either divergence type. Differential expression and gene set enrichment analysis (GSEA) revealed common pathways dysregulated in metastases compared to primaries, including reductions in E2F (important in G1/S checkpoint) and G2M checkpoint, suggestive of the onset of senescence in metastases. Tumors underwent progressive hypomethylation over time and analysis of genes with concordant changes in promoter methylation and expression revealed dysregulation in pathways related to endocytosis, cell adhesion and migration. This suggests an important role for phenotypic plasticity in driving the metastatic phenotype. There were transient increases in the proportion of macrophages, lymphocytes and neutrophils in tumors that had undergone neoadjuvant chemotherapy in the 6 months prior to resection and slight increases in M1 macrophage activity (by GSEA) in tumors that were previously therapy naïve. There were concordant transient increases in pathways associated with immune response (MYC V1 and MTORC1), as well as xenobiotic metabolism. The latter is a known mechanism of drug resistance to both the platinum- and fluoropyridine-based therapies used in CRC. There were also more sustained increases post-chemotherapy in inflammatory and immune pathways associated with the adaptive immune response and tissue injury and repair. These findings were corroborated by concordant changes in promoter methylation. These data suggest that there is a threshold level of aneuploidy required to facilitate CRC metastasis but the migratory phenotype and adaptation to the metastatic niche are driven by plasticity. Chemotherapy induces differing short-term and long-term anti-tumor immune responses in the local microenvironment. We see evidence that mCRCs are able to mount plastic pro-survival mechanisms in response to chemotherapy. Citation Format: Alison May Berner, Calum Gabbutt, Salpie Nowinski, Jacob Househam, Nick Trahearn, George D. Cresswell, Vinaya Srirangam Nadhamuni, Christopher Kimberley, Matteo Fassan, Ann-Marie Baker, Andrea Sottoriva, Christina Thirlwell, John Bridgewater, Trevor Graham. Multiple roles for plasticity in metastasis and therapy resistance in long-term survivors of metastatic colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A045.
Background In Inflammatory Bowel Disease (IBD), clonal evolution and field cancerisation precedes the development of colitis-associated colorectal cancer (CA-CRC), however the extent and spread of pre-cancerous clones in the IBD colon remains incompletely determined and consequently clinical practice is poorly informed of how best to detect these clones by endoscopy and accurately predict future cancer risk. This study aims to quantify the number and size of mutant clones arising across the length of the colitic bowel, reveal the mechanism of how they arise and spread, and through this gain a detailed molecular understanding of the evolutionary dynamics of progression to CA-CRC. Methods Three IBD patients undergoing a total panproctocolectomy for multifocal dysplasia or CA-CRC were recruited prospectively. Fresh-frozen biopsies were taken at regularly spaced intervals (~2cm) across the entire colon (rectum to caecum, comprising 118, 108 and 25 biopsies respectively). Epithelial tissue was isolated from each biopsy using laser capture microdissection and DNA was extracted. Low pass whole genome sequencing (lpWGS) was performed to generate genome-wide copy number alteration (CNA) profiles. Results Analysis from the first 45 samples from colon 1 show; 1) Multiple CNA events occur in macroscopically ‘normal’ parts of the colon. 2) Recurrent CNAs were shared between biopsies, revealing clonal expansions in multiple areas of the colon, both proximal and distal to the cancer, and comprising in normal, inflammed, dysplastic and cancer-adjacent tissue. 3) Clonal expansions ranged from 4-18cm in size, and were separated by distances of 2-20cm. 4) Certain CNA events occur more commonly across the colon, both independently and from within different clonal patches, such as a gain on chromosome 7 and 20, and losses on chromosomes 5, 8 and 17. 5) Whole genome doubling events within clonal clades. Conclusion These data show that across the IBD bowel, CNAs occur and expand in ostensibly ‘normal’ cells, demonstrating evidence of field cancerisation. Moreover, similar CNAs are seen occurring independently throughout the whole colon, suggesting patterns of convergent evolution. Further work is needed to more precisely quantify the clonal and sub-clonal distribution across the IBD colon, in addition to deriving measures of intra-colon, intra-lesion and intra-clade genomic diversity to complement the above measures of evolvability. This data, along with the genomic-phenotypic mapping (from pending RNA analysis) and analysis of the stromal microenvironment will help demonstrate the mechanisms of CA-CRC progression and therefore help guide clinical practice through endoscopic sampling, to best predict future cancer risk.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.