scholarly journals Young-Onset Carcinogenesis – The Potential Impact of Perinatal and Early Life Metabolic Influences on the Epigenome

2021 ◽  
Vol 11 ◽  
Author(s):  
Savio George Barreto ◽  
Stephen J. Pandol
Keyword(s):  
Familial Cancer ◽  
Perinatal Period ◽  
Experimental Models ◽  
Significant Rise ◽  
Solid Organ ◽  
Young Onset ◽  
Neoplastic Process ◽  
Underlying Causes ◽  
Genetic Level ◽  
Familial Cancer Syndromes

The last decade has witnessed a significant rise in cancers in young adults. This spectrum of solid organ cancers occurring in individuals under the age of 40 years (some reports extending the age-group to <50 years) in whom aetiology of cancer cannot be traced back to pre-existing familial cancer syndromes, is referred to as termed young-, or early- onset cancers. The underlying causes for young-onset carcinogenesis have remained speculative. We recently proposed a hypothesis to explain the causation of this entity. We propose that the risk for young-onset cancer begins in the perinatal period as a result of the exposure of the foetus to stressors, including maternal malnutrition, smoking or alcohol, with the consequent epigenomic events triggered to help the foetus cope/adapt. Exposure to the same stressors, early in the life of that individual, facilitates a re-activation of these ‘responses designed to be protective’ but ultimately resulting in a loss of regulation at a metabolic and/or genetic level culminating in the evolution of the neoplastic process. In this manuscript, we will provide a rationale for this hypothesis and present evidence to further support it by clarifying the pathways involved, including elucidating a role for Acetyl-CoA and its effect on the epigenome. We present strategies and experimental models that can be used to test the hypothesis. We believe that a concerted effort by experts in different, but complementary fields, such as epidemiology, genetics, and epigenetics united towards the common goal of deciphering the underlying cause for young-onset cancers is the urgent need. Such efforts might serve to prove, or disprove, the presented hypothesis. However, the more important aim is to develop strategies to reverse the disturbing trend of the rise in young-onset cancers.

Glioblastoma Multiforme with Hypodipsic Hypernatremia in a Seven-Month-Old Golden Retriever

2016 ◽  
Vol 52 (5) ◽  
pp. 319-324 ◽  
Author(s):  
Stephanie Engel ◽  
Karen Marie Hilling ◽  
Travis Kuder Meuten ◽  
Chad Brendan Frank ◽  
Angela J. Marolf
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glioblastoma Multiforme ◽  
Glial Cell ◽  
Congenital Malformations ◽  
Cell Tumor ◽  
Golden Retriever ◽  
Neoplastic Process ◽  
Underlying Causes ◽  
The Central Nervous System

ABSTRACT Primary hypodipsic hypernatremia is a rarely reported disease in dogs. Reported underlying causes associated with this disease in dogs include congenital malformations, encephalitis, intracranial neoplasia, and pressure atrophy of the hypothalamus secondary to hydrocephalus. The dog in this report had an infiltrative neoplastic disorder, likely causing damage to the hypothalamic osmoreceptors responsible for the thirst generation. The neoplastic process was identified histopathologically as glioblastoma multiforme, an unusual tumor to occur in a dog this young. A tumor of the central nervous system causing physical destruction of the osmoreceptors has rarely been reported in dogs and none of the previously reported cases involved a glial cell tumor.

Familial Cancer Syndromes

2008 ◽  
pp. 449-466
Author(s):  
Michelle P. Elieff ◽  
Antonio Lopez-Beltran ◽  
Rodolfo Montironi ◽  
Liang Cheng
Keyword(s):  
Familial Cancer ◽  
Familial Cancer Syndromes ◽  
Cancer Syndromes

Familial cancer syndromes and genetic counselling

2016 ◽  
pp. 276-290
Author(s):  
Henry T. Lynch ◽  
Carrie L. Snyder ◽  
Jane F. Lynch
Keyword(s):  
Colorectal Cancer ◽  
Molecular Genetics ◽  
Genetic Counselling ◽  
Hereditary Cancer ◽  
Genetic Model ◽  
Familial Cancer ◽  
Hereditary Cancer Syndromes ◽  
Clinical Genetic ◽  
Familial Cancer Syndromes ◽  
Cancer Syndromes

Thanks to the veritably logarithmic advances in the molecular genetics of many emerging hereditary cancer syndromes, genetic counselling has become of paramount importance. It is a key element of the emerging concepts for patient education and management, which have become the clinical bedrock for diagnosis and management of hereditary cancer. Genetic counsellors have become proficient in the understanding of the complexities of molecular genetics in relation to hereditary cancer syndromes, demonstrating their ability both to supplement and replace the customary physician’s role in this overall process. We have used colorectal cancer, in particular Lynch syndrome, as a clinical genetic model based on the authors’ experience with diagnosis, DNA testing, and counselling of thousands of families for over four decades. Undoubtedly, the surface of the proverbial iceberg has barely been grazed in regard to the developments for the genetic counseling discipline.

Genetics

2019 ◽  
pp. 341-348
Keyword(s):  
Birth Defects ◽  
Trisomy 21 ◽  
Chromosomal Abnormalities ◽  
Familial Cancer ◽  
Single Gene ◽  
Medical Specialty ◽  
Clinical Genetics ◽  
Single Gene Disorders ◽  
Familial Cancer Syndromes ◽  
Cancer Syndromes

Clinical genetics is the medical specialty that deals with diagnosis and counselling of patients affected (or potentially affected) with disease that may have a genetic basis. These conditions include chromosomal abnormalities (e.g. Down’s syndrome/trisomy 21), single gene disorders (e.g. cystic fibrosis), familial cancer syndromes (e.g. hereditary non-polyposis colorectal cancer), and birth defects with a genetic component (e.g. cleft palate). The service is largely consultant led, supported by genetic counsellors in tertiary referral centres. Different inheritance patterns are described, autosomal dominant, autosomal recessive, X-linked, and mitochondrial, as well as the range of different genetic tests currently in clinical use (karyotype, microarray, gene panel, exome sequencing, and genome studies). The importance of empathetic communication, a detailed family history, and a multidisciplinary approach are emphasized.

Familial cancer syndromes

The Lancet ◽  
1994 ◽  
Vol 343 (8899) ◽  
pp. 709-713 ◽  
Author(s):  
C Eng ◽  
B Ponder ◽  
V Murday ◽  
D Easton ◽  
M Stratton ◽  
...  
Keyword(s):  
Familial Cancer ◽  
Familial Cancer Syndromes ◽  
Cancer Syndromes

Utility of Discordant Mismatch Repair-Deficiency (MMR)/Microsatellite Instability (MSI) Testing in Screening Uterine Leiomyosarcoma Patient for Lynch/Other Familial Cancer Syndromes

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S149-S150
Author(s):  
K S Reddy
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Familial Cancer ◽  
False Negative ◽  
Uterine Leiomyosarcoma ◽  
Average Risk ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency ◽  
Familial Cancer Syndromes ◽  
The Impact

Abstract Casestudy Lynch Syndrome (LS) is primarily linked to colorectal and endometrial cancers. Occasional sarcomas, including leiomyosarcoma, have been recognized within the spectrum of LS demonstrating mismatch repair-deficiency (MMR)/microsatellite instability (MSI) in this context. Results A 67-year-old female of bilineal Ashkenazi Jewish descent was recently diagnosed with uterine leiomyosarcoma in addition to metastatic papillary thyroid carcinoma at age 58. She met NCCN criteria for LS and BRCA1/2 (brother with renal cancer at age 64, father with colon cancer at age 60, paternal half-sister with rectal cancer at age 50 and maternal aunt with breast cancer). Studies have shown that immunohistochemistry (IHC) for MMR proteins and PCR-based MSI have comparable sensitivity and specificity with high concordance, but neither test alone is sufficient to capture all defective MMR tumors. Screening strategies vary depending on the level of clinical suspicion for LS. When high, a normal result by one method warrants testing via a second method or concurrent IHC plus PCR testing to minimize the impact of rare false normal results. Rarely, this strategy can yield discordant results, as in our case wherein MSI by PCR was stable (MSS) but IHC for MLH-1 and PMS-2 showed heterogeneous (patchy/focal) nuclear loss of protein expression. The latter is not always due to artefact but can correspond to MMR status differences within the tumor, requiring recognition to prevent false-positive/false-negative evaluations. Heterogenous MLH1 and/or PMS2 expression, may be suggestive of variable MLH1 methylation/second hit mutations, variable epitope expression or expression related to variable differentiation. Conclusion The clinical significance of this pattern was unclear in our patient whose initial genetic screen (including MLH1, PMS2, MSH2, MSH6, EPCAM) was negative. However, as studies have indicated that patients with indeterminate IHC findings can have MLH1 hypermethylation or germline mutations, she had justification to undergo extended genetic screening. A heterozygous pathogenic variant in BLM 2207_2212delinsTAGATTC (p.Tyr736Leufs*5) associated with autosomal recessive Bloom Syndrome (BS) was identified. Carriers of BS do not show symptoms of the disease, but they are at a greater than average risk of developing cancers.

Oestrous cycle-related LH responsiveness to naloxone: effect of high oestrogen levels on the activity of opioid receptors

1986 ◽  
Vol 108 (1) ◽  
pp. 89-94 ◽  
Author(s):  
F. Petraglia ◽  
V. Locatelli ◽  
F. Facchinetti ◽  
M. Bergamaschi ◽  
A. R. Genazzani ◽  
...  
Keyword(s):  
Time Of Day ◽  
Experimental Models ◽  
Significant Rise ◽  
Oestrous Cycle ◽  
Endogenous Opioid ◽  
Functional Changes ◽  
Opioid Mechanisms ◽  
Endogenous Opioid Systems ◽  
Lh Releasing Hormone ◽  
Lh Secretion

ABSTRACT Endogenous opioid peptides have a tonic inhibitory control on LH secretion, participating in the functional changes of the hypothalamic-pituitary-ovarian axis. To evaluate the activity of the endogenous opioid systems during the oestrous cycle, we measured plasma LH levels after naloxone administration (5 mg/kg, s.c.) at 09.00 and 16.00 h on all days of the cycle (two further measurements were taken at 14.00 and 18.00 h on the day of pro-oestrus) and after one dose or one week's treatment with oestradiol benzoate (OB; 0·2 μg/rat). Concentrations of LH were measured in the same experimental models after injection of LH-releasing hormone (LHRH; 1 μg/kg, i.p.) or saline. Naloxone induced a significant rise in LH levels on the day of oestrus, dioestrus day-1 and dioestrus day-2; this response was blunted on the morning of pro-oestrus and absent in the afternoon and after acute and chronic OB treatment. Conversely LHRH was most effective in increasing LH levels on the day of pro-oestrus and in OB-treated rats. These results indicate that opioid mechanisms, independently of the time of day and the pituitary responsiveness, exhibit a reduced activity when preovulatory changes occur, probably as a result of increased oestrogen levels. J. Endocr. (1986) 108, 89–94

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