the diagnosis of asymptomatic sporadic nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) has increased significantly due to the widespread use of high-resolution imaging tests, which is why ...the most appropriate management at the time of diagnosis is the subject of debate, as is how to follow-up patients.
the objective of this study was to analyze the frequency of imaging and endoscopic studies performed during long-term follow-up.
a retrospective review was performed of a database collected between January 2008 and December 2020 of patients with an incidental diagnosis of small NF-PNETs; follow-up was closed in March 2023. The imaging tests performed at the time of diagnosis and long-term follow-up were recorded. Growing less than 1 mm per year has not been considered as a worrisome feature. Follow-up was performed through imaging tests, considering endoscopic cytology for lesions with a faster grow rate.
fifty-eight patients were included; the median age was 69 years. The initial mean size of the lesions studied was 12.79 mm (5-27). Follow-up was carried out only with computed tomography (CT) or magnetic resonance imaging (MRI). The initial size did not influence the behavior of the lesion in a statistically significant manner. Twenty-eight tumors (45 %) increased in size, with a growth equal to or less than 4 mm in 24 cases. The mean follow-up time was 82.41 months (12-164). No patient developed metastasis or died from PNET progression.
the follow-up of neuroendocrine tumors of small size can be performed safely with only imaging tests.
The clinical impact on fertility in carriers of
and
mutations remains unclear. The aim of this study was to assess ovarian reserve as measured by anti-mullerian hormone levels in
or
mutation ...carriers, as well as to investigate the impact of anti-mullerian hormone levels on reproductive outcomes.
The study involved a cohort of women who tested positive for
and
screening or were tested for a BRCA1 or BRCA2 family mutation. Blood samples were collected for anti-mullerian hormone analysis and the reproductive outcomes were analyzed after a mean follow-up of 9 years. Participants were classified into
mutation-positive versus
mutation-negative. Controls were healthy relatives who tested negative for the family mutation. All patients were contacted by telephone to collect data on reproductive outcomes. Linear regression was used to predict anti-mullerian hormone levels by
status adjusted for a polynomial form of age.
Results of anti-mullerian hormone analysis and reproductive outcomes were available for 135 women (
mutation-negative, n=66;
mutation-positive, n=32;
mutation-positive, n=37). Anti-mullerian hormone curves according to BRCA status and adjusted by age showed that
mutation-positive patients have lower levels of anti-mullerian hormone as compared with
-negative and BRCA1 mutation-positive. Among the women who tried to conceive, infertility was observed in 18.7% of
mutation-negative women, in 22.2% of
mutation-positive women, and in 30.8% of
mutation-positive women (p=0.499). In the multivariable analysis, there were no factors independently associated with infertility.
mutation-positive carriers showed more diminished anti-mullerian hormone levels than
mutation-positive and
mutation-negative women. However, these differences do not appear to have a negative impact on reproductive outcome. This is important to consider at the time of reproductive counseling in women with
or
mutations.
Colorectal cancer(CRC)is a very heterogeneous disease that is caused by the interaction of genetic and environmental factors.CRC develops through a gradual accumulation of genetic and epigenetic ...changes,leading to the transformation of normal colonic mucosa into invasive cancer.CRC is one of the most prevalent and incident cancers worldwide,as well as one of the most deadly.Approximately 1235108 people are diagnosed annually with CRC,and 609051 die from CRC annually.The World Health Organization estimates an increase of77%in the number of newly diagnosed cases of CRCand an increase of 80%in deaths from CRC by 2030.The incidence of CRC can benefit from different strategies depending on its stage:health promotion through health education campaigns(when the disease is not yet present),the implementation of screening programs(for detection of the disease in its early stages),and the development of nearly personalized treatments according to both patient characteristics(age,sex)and the cancer itself(gene expression).Although there are different strategies for screening and although the number of such strategies is increasing due to the potential of emerging technologies in molecular marker application,not all strategies meet the criteria required for screening tests in population programs;the three most accepted tests are the fecal occult blood test(FOBT),colonoscopy and sigmoidoscopy.FOBT is the most used method for CRC screening worldwide and is also the primary choice in most population-based screening programs in Europe.Due to its non-invasive nature and low cost,it is one of the most accepted techniques by population.CRC is a very heterogeneous disease,and with a few exceptions(APC,p53,KRAS),most of the genes involved in CRC are observed in a small percentage of cases.The design of genetic and epigenetic marker panels that are able to provide maximum coverage in the diagnosis of colorectal neoplasia seems a reasonable strategy.In recent years,the use of DNA,RNA and protein markers in different biological samples has been explored as strategies for CRC diagnosis.Although there is not yet sufficient evidence to recommend the analysis of biomarkers such as DNA,RNA or proteins in the blood or stool,it is likely that given the quick progression of technology tools in molecular biology,increasingly sensitive and less expensive,these tools will gradually be employed in clinical practice and will likely be developed in mass.
Background Mutations in the
gene explain abnormally long telomeres and multiple tumors including cardiac angiosarcomas (CAS). However, the link between long telomeres and tumorigenesis is poorly ...understood. Methods and Results Here, we have studied the somatic landscape of 3 different angiosarcoma patients with mutations in the
gene to further investigate this tumorigenesis process. In addition, the genetic landscape of 7 CAS patients without mutations in the
gene has been studied. Patients with CAS and nonfunctional
did not repress ATR (ataxia telangiectasia RAD3-related)-dependent DNA damage signaling and showed a constitutive increase of cell cycle arrest and somatic activating mutations in the VEGF (vascular endothelial growth factor)/angiogenesis pathway (
gene). The same observation was made in
mutation carriers with tumors different from CAS and also in CAS patients without mutations in the
gene but with mutations in other genes involved in DNA damage signaling. Conclusions Inhibition of POT1 function and damage-response malfunction activated DNA damage signaling and increased cell cycle arrest as well as interfered with apoptosis, which would permit acquisition of somatic mutations in the VEGF/angiogenesis pathway that drives tumor formation. Therapies based on the inhibition of damage signaling in asymptomatic carriers may diminish defects on cell cycle arrest and thus prevent the apoptosis deregulation that leads to the acquisition of driver mutations.
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, ...specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
Carcinoid crisis: The challenge is still there Guerrero-Pérez, Fernando; Peiró, Inmaculada; Vercher-Conejero, José L. ...
Endocrinología, diabetes y nutrición.,
06/2024, Letnik:
71, Številka:
6
Journal Article
The variants c.306+5G>A and c.1865T>A (p.Leu622His) of the DNA repair gene MLH1 occur frequently in Spanish Lynch syndrome families. To understand their ancestral history and clinical effect, we ...performed functional assays and a penetrance analysis and studied their genetic and geographic origins. Detailed family histories were taken from 29 carrier families. Functional analysis included in silico and in vitro assays at the RNA and protein levels. Penetrance was calculated using a modified segregation analysis adjusted for ascertainment. Founder effects were evaluated by haplotype analysis. The identified MLH1 c.306+5G>A and c.1865T>A (p.Leu622His) variants are absent in control populations and segregate with the disease. Tumors from carriers of both variants show microsatellite instability and loss of expression of the MLH1 protein. The c.306+5G>A variant is a pathogenic mutation affecting mRNA processing. The c.1865T>A (p.Leu622His) variant causes defects in MLH1 expression and stability. For both mutations, the estimated penetrance is moderate (age-cumulative colorectal cancer risk by age 70 of 20.1% and 14.1% for c.306+5G>A and of 6.8% and 7.3% for c.1865T>A in men and women carriers, respectively) in the lower range of variability estimated for other pathogenic Spanish MLH1 mutations. A common haplotype was associated with each of the identified mutations, confirming their founder origin. The ages of c.306+5G>A and c.1865T>A mutations were estimated to be 53 to 122 and 12 to 22 generations, respectively. Our results confirm the pathogenicity, moderate penetrance, and founder origin of the MLH1 c.306+5G>A and c.1865T>A mutations. These findings have important implications for genetic counseling and molecular diagnosis of Lynch syndrome.
Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, ...were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10
, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
It has been demonstrated that monoallelic
PALB2
(Partner and Localizer of BRCA2) gene mutations predispose to familial breast cancer. Some of the families reported with germline
PALB2
mutations ...presented male breast cancer as a characteristic clinical feature. Therefore, we wanted to investigate the contribution of germline
PALB2
mutations in a set of 131 Spanish
BRCA1/BRCA2
-negative breast/ovarian cancer families with at least one male breast cancer case. The analysis included direct sequencing of all coding exons and intron/exon boundaries as well as a Multiplex Ligation-dependent Probe Amplification-based analysis of genomic rearrangements. For the first time we have identified a genomic rearrangement of
PALB2
gene involving a large deletion from exon 7 to 11 in a breast cancer family. We have also identified several
PALB2
variants, but no other obvious deleterious
PALB2
mutation has been found. Thus, our study does not support an enrichment of
PALB2
germline mutations in the subset of breast cancer families with male breast cancer cases. The identification of intronic and exonic variants indicates the necessity of assessing the implications of variants that do not lead to PALB2 truncation in the pathoghenicity of the
PALB2
gene.
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