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High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer
... This phenomenon is called germline mutation or malignant variation. It is either inherited from one parent or occurs during gametogenesis, and consequently, a mutated gene is present in every cell of the body (12,13). However, not everyone who inherits such a mutation will develop melanoma because this also depends on gene penetrance, expressed as a proportion of mutation carriers who develop a disease. ...
... Among several isoforms of the MITF gene, only MITF-M is specific for melanocytes (70). Wnt, TGF-beta and 12 RTK are only some of the signaling pathways related to the expression of this gene (71). ...
Melanoma is a highly aggressive cancer originating from melanocytes. Its etiopathogenesis is strongly related to genetic, epigenetic, and environmental factors. Melanomas encountered in clinical practice are predominantly sporadic, whereas hereditary melanomas account for approximately 10% of the cases. Hereditary melanomas mainly develop due to mutations in the CDKN2A gene, which encodes two tumor suppressor proteins involved in the cell cycle regulation. CDKN2A, along with CDK4, TERT, and POT1 genes, is a high-risk gene for melanoma. Among the genes that carry a moderate risk are MC1R and MITF, whose protein products are involved in melanin synthesis. The environment also contributes to the development of melanoma. Patients at risk of melanoma should be offered genetic counseling to discuss genetic testing options and the importance of skin UV protection, avoidance of sun exposure, and regular preventive dermatological examinations. Although cancer screening cannot prevent the development of the disease, it allows for early diagnosis when the survival rate is the highest.
... This phenomenon is called germline mutation or malignant variation. It is either inherited from one parent or occurs during gametogenesis, and consequently, a mutated gene is present in every cell of the body (12,13). However, not everyone who inherits such a mutation will develop melanoma because this also depends on gene penetrance, expressed as a proportion of mutation carriers who develop a disease. ...
... Among several isoforms of the MITF gene, only MITF-M is specific for melanocytes (70). Wnt, TGF-beta and 12 RTK are only some of the signaling pathways related to the expression of this gene (71). ...
Melanoma is a highly aggressive cancer originating from melanocytes. Its etiopathogenesis is strongly related to genetic, epigenetic, and environmental factors. Melanomas encountered in clinical practice are predominantly sporadic, whereas hereditary melanomas account for approximately 10% of the cases. Hereditary melanomas mainly develop due to mutations in the CDKN2A gene, which encodes two tumor suppressor proteins involved in the cell cycle regulation. CDKN2A, along with CDK4, TERT, and POT1 genes, is a high-risk gene for melanoma. Among the genes that carry a moderate risk are MC1R and MITF, whose protein products are involved in melanin synthesis. The environment also contributes to the development of melanoma. Patients at risk of melanoma should be offered genetic counseling to discuss genetic testing options and the importance of skin UV protection, avoidance of sun exposure, and regular preventive dermatological examinations. Although cancer screening cannot prevent the development of the disease, it allows for early diagnosis when the survival rate is the highest.
... Here, we determined the TP53 variation in 1% of the cases. This rate reaches 6% in cases with very early BC onset (Evans et al. 2022), and 50% of the TP53 + cases in our study were diagnosed with BC before the age of 40, with one as early as 25 years old. Unlike BRCA1/BRCA2-positive cases, patients with germline TP53 PVs present higher HER2 amplifications than non-TP53 cases (Escudeiro et al. 2021;Rath et al. 2013), and almost 60% of the patients with BC with TP53 PVs were HER2-positive in our cohort. ...
Advances in high-throughput sequencing have increased the detection of TP53 variations, many of which occur at low allelic fractions. Such variants may arise due to clonal hematopoiesis (CHIP) or constitutional mosaicism, complicating their clinical classification and management. Since guidelines recommend Li-Fraumeni syndrome (LFS)-like management for individuals carrying TP53 variations, accurately determining the origin of low variant allelic fraction (VAF) variants is essential for risk assessment and clinical decision-making. This study evaluates TP53 VAF in patients with suspected hereditary cancer predisposition, tested via multigene panels and emphasizes the importance of conducting a detailed investigation before making clinical decisions in patients with low-VAF. In retrospectively analyzed 1,520 cases, we identified 17 actionable TP53 variations in 16 cases (1%). All cases were female (mean cancer onset age of 45.9 years) and classified as attenuated LFS. Eleven of the variants had an allelic fraction of ≤ 20%. Patients over 60 years showed significantly lower VAF than those under 40 (p = 0.03). The TP53 variant was detected in only one ancillary sample, and her tumor sample was monoallelic, confirming the germline origin. For an accurate classification and successful management of cases with TP53 variations, defining the origin of variants, especially for low VAF, is imperative.
... Here, we determined the TP53 variation in 1% of the cases, which aligns with the literature. This rate goes up to 6% in cases with very early onset of breast cancer [12], and half of the TP53+ cases in this study were diagnosed with BC before the age of 40, one is as early as 25 years old. ...
PTEN hamartoma tumor syndrome (PHTS) has a broad clinical spectrum including various benign and malignant tumors at varying age of diagnosis. Many patients remain unrecognized, unaware of their increased cancer risk. We aimed to describe the cancer spectrum, age of onset and histopathological cancer characteristics to assess whether specific cancer characteristics could improve PHTS recognition. Genetic testing results and pathology reports were collected for patients tested for germline PTEN variants between 1997 and 2020 from the diagnostic laboratory and the Dutch nationwide pathology databank (Palga). The cancer spectrum and age of onset were assessed in patients with (PTENpos) and without (PTENneg) a germline PTEN variant. Histopathological cancer characteristics were assessed in a nested cohort. 341 PTENpos patients (56% females) and 2882 PTENneg patients (66% females) were included. PTENpos patients presented mostly with female breast (BC, 30%), endometrial (EC, 6%), thyroid (TC, 4%) or colorectal cancer (4%). PTENpos were significantly younger at cancer onset (43 vs. 47 years) and had more often (46% vs. 18%) a second BC than PTENneg. PTEN detection rates were highest for BC <40 years (9%), TC <20 years (15%) and EC <50 years (28%), and dropped to 6%, 4%, and 15% by age 60. Histopathological characteristics were similar between groups. No histopathological cancer characteristics were distinctive for PHTS. However, PTENpos were significantly younger at cancer onset. Therefore early‐onset BC, EC, or TC warrants consideration of PHTS diagnostics either through a pre‐screen for other PHTS features or direct germline testing.
Background:
Breast cancer in young women is more likely to have higher risk features and be associated with germline BRCA1/BRCA2 mutations. We present the clinicopathologic features of breast cancers in a prospective cohort of young women, and associations between surrogate molecular subtype and BRCA1/BRCA2 mutation status.
Methods:
Histopathological features, biomarker status, tumour stage and BRCA status were collected. Invasive tumours were categorised as luminal A-like (ER + and/or PR + , HER2-, grade 1/2), luminal B-like (ER + and/or PR + , HER2 + , or ER + and/or PR + , HER2-, and grade 3), HER2-enriched (ER/PR-, HER2 + ) or triple-negative.
Results:
In all, 57.3% (654/1143) of invasive tumours were high grade. In total, 32.9% were luminal A-like, 42.4% luminal B-like, 8.3% HER2-enriched, and 16.4% triple-negative. Among different age groups, there were no differences in molecular phenotype, stage, grade or histopathology. 11% (131) of tumours were from BRCA mutation carriers; 64.1% BRCA1 (63.1% triple-negative), and 35.9% BRCA2 (55.3% luminal B-like).
Discussion:
The opportunity to provide comparisons across young age groups, BRCA mutation status, surrogate molecular phenotype, and the identification of more aggressive hormone receptor-positive phenotypes in this population provides direction for future work to further understand and improve disparate outcomes for young women with luminal B-like cancers, particularly BRCA2-associated cancers, with potential implications for tailored prevention and treatment.
Background
The most common cancer diagnosed in germline TP53 pathogenic variant (PV) carriers is premenopausal breast cancer. An increased rate of breast tumour HER2 positivity has been reported in this group. Screening for breast/other cancers is recommended in PV carriers.
Objectives
1. To assess the frequency of germline TP53 PVs reported diagnostically in women with breast cancer at <30 years of age.
2. To evaluate the impact of personal/family history and HER2 status on the likelihood of germline TP53 pathogenic/likely pathogenic variant (PV/LPV) identification.
Methods
Genetic test results from patients undergoing diagnostic germline TP53 tests between 2012 and 2017 in the four London Regional Clinical Genetics Services were reviewed. Clinical/pathology data and family history were extracted from genetics files for women diagnosed with breast cancer at <30 years.
Results
The overall germline TP53 PV/LPV variant detection rate was 9/270=3.3% in all women diagnosed with breast cancer at <30 years and 2/171=1.2% in those with no second/subsequent cancer diagnosis or family history of TP53 -spectrum cancers. Breast cancers were significantly more likely to be HER2-positive in TP53 PV/LPV carriers than in non-carriers (p=0.00006).
Conclusions
Germline TP53 PVs/LPVs are uncommon among women diagnosed with breast cancer aged <30 years without other relevant personal or family cancer history but have an important clinical impact when identified.
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