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PubMed2026

Comprehensive genomic profiling and tumor mutational burden in parathyroid carcinoma: a nationwide real-world study from Japan.

PURPOSE: Parathyroid carcinoma (PC) is an extremely rare endocrine malignancy with limited treatment options for unresectable or recurrent cases. With the increasing use of comprehensive genomic profiling (CGP), treatment based on genomic findings is becoming more common. However, the frequency and clinical significance of elevated tumor mutational burden (TMB) in PC remain unclear because previous studies have been limited by small sample sizes. METHODS: We retrospectively analyzed genomic and clinical data of patients with PC registered in the Center for Cancer Genomics and Advanced Therapeutics database in Japan between June 2019 and March 2025. TMB values were obtained as reported by each CGP assay. TMB-H was defined as TMB ≥ 10 mut/Mb for descriptive analyses. We also assessed genomic alterations, microsatellite instability (MSI) status, and clinicogenomic characteristics. RESULTS: Twenty-five patients with PC were included. The median assay-reported TMB was 4.0 mut/Mb (range, 0-35). Seven tumors (28.0%) had assay-reported TMB values of ≥ 10 mut/Mb, including three (12.0%) with TMB ≥ 20 mut/Mb. The most frequently altered genes were CDC73 (40%), TP53 (32%), and MEN1 (24%). No co-alterations were observed between CDC73 and MEN1 or between CDC73 and TP53. One tumor was MSI-high and was included in the TMB-H group. POLE alterations were detected in three cases, including two tumors in the TMB-H group. CONCLUSION: This nationwide, real-world study demonstrated that a subset of PCs showed elevated assay-reported TMB values and genomic features potentially related to abnormalities in DNA replication or repair pathways. These findings support the clinical relevance of comprehensive genomic profiling in identifying the molecular heterogeneity and potential therapeutic opportunities for this rare malignancy.

Humans↗
PubMed2000

Primary node negative breast cancer in BRCA1 mutation carriers has a poor outcome.

BACKGROUND: The association between BRCA1 germ-line mutations and breast cancer prognosis is controversial. A historical cohort study was designed to determine the prognosis for women with axillary lymph node negative hereditary breast cancer. PATIENTS AND METHODS: We tested pathology blocks from 118 Ashkenazi Jewish women with axillary lymph node negative breast cancer for the presence of the two common BRCA1 founder mutations, 185delAG and 5382insC. Patients were followed up for a median of 76 months. Somatic TP53 mutations were screened for by immunohistochemistry, and direct sequencing was performed in the BRCA1-positive tumours. RESULTS: Sixteen breast cancer blocks (13.6%) carried a BRCA1 mutation. Young age of onset, high nuclear grade, negative estrogen receptor status and over-expression of p53 were highly associated with BRCA1-positive status (P-values all <0.01). BRCA1 mutation carriers had a higher mortality than non-carriers (five-year overall survival, 50% and 89.6%, respectively, P = 0.0001). Young age of onset, estrogen receptor negative status, nuclear grade 3, and over-expression of p53 also predicted a poor outcome. Cox multivariate analyses showed that only germ-line BRCA1 mutation status was an independent prognostic factor for overall survival (P = 0.01). Among nuclear grade 3 tumours, the BRCA1 mutation carrier status was a significant prognostic factor of death (risk ratio 5.8, 95% confidence interval: 1.5-22, P = 0.009). Sequencing of BRCA1-related breast cancers revealed one TP53 missense mutation not previously reported in breast cancer. CONCLUSIONS: Using a historical cohort approach, we have identified BRCA1 mutation status as an independent prognostic factor for node negative breast cancer among the Ashkenazi Jewish women. Those managing women carrying a BRCA1 mutation may need take these findings into consideration. Additionally, our preliminary results, taken together with the work of others suggest a different carcinogenic pathway in BRCA1-related breast cancer, compared to non-hereditary cases.

Adult↗
PubMed2002

Cells obtained from colorectal microadenomas mirror early premalignant growth patterns in vitro.

LT97, a permanent cell line consisting of epithelial cells with an early premalignant genotype was established from small colorectal polyps. LT97 cells have lost both alleles of the APC tumour suppressor gene. In addition, they carry a mutated Ki-ras oncogene, while TP53 is normal. LT97 growth characteristics are thus representative of early adenomas. They had to be passaged as multicellular aggregates indicating a dependency of survival on cell-cell contact and in accordance with their premalignant genotype were not capable of growth in soft agar. LT97 cells did express both the EGF-receptor and small amounts of TGF(alpha) establishing an autocrine growth or survival pathway. However, in spite of autocrine TGF(alpha) production, growth was strongly dependent on exogenous growth factors--mainly EGF, insulin and HGF. Inhibition of the EGF-receptor kinase induced apoptosis at an IC(50) concentration of 4 micromolar indicating that TGF(alpha) activated survival pathways in the early adenoma cell.

Adenoma↗
PubMed1999

Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma.

To understand the molecular pathways involved in the pathogenesis of squamous cell lung carcinoma, we obtained DNA from 94 microdissected foci from 12 archival surgically resected tumors including histologically normal epithelium (n=13), preneoplastic lesions (n=54), carcinoma is situ (CIS) (n=15) and invasive tumors (n=12). We determined loss of heterozygosity (LOH) at 10 chromosomal regions (3p12, 3p14.2, 3p14.1-21.3, 3p21, 3p22-24, 3p25, 5q22, 9p21, 13q14 RB, and 17p13 TP53) frequently deleted in lung cancer, using 31 polymorphic microsatellite markers, including 24 that spanned the entire 3p arm. Our major findings are as follows: (1) Thirty one percent of histologically normal epithelium and 42% of mildly abnormal (hyperplasia/metaplasia) specimens had clones of cells with allelic loss at one or more regions; (2) There was a progressive increase of the overall LOH frequency within clones with increasing severity of histopathological changes; (3) The earliest and most frequent regions of allelic loss occurred at 3p21, 3p22-24, 3p25 and 9p21; (4) The size of the 3p deletions increased with progressive histologic changes; (5) TP53 allelic loss was present in many histologically advanced lesions (dysplasia and CIS); (6) Analyses of 58 normal and non-invasive foci having any molecular abnormality, indicated that 30 probably arose as independent clonal events, while 28 were potentially of the same clonal origin as the corresponding tumor; (7) Nevertheless, when the allelic losses in the 30 clonally independent lesions and their clonally unrelated tumors were compared the same parental allele was lost in 113 of 125 (90%) of comparisons. The mechanism by which this phenomenon (known as allele specific mutations) occurs is unknown; (8) Four patterns of allelic loss in clones were found. Histologically normal or mildly abnormal foci had a negative pattern (no allelic loss) or early pattern of loss while all foci of CIS and invasive tumor had an advanced pattern. However dysplasias demonstrated the entire spectrum of allelic loss patterns, and were the only histologic category having the intermediate pattern. Our findings indicate that multiple, sequentially occurring allele specific molecular changes commence in widely dispersed, apparently clonally independent foci, early in the multistage pathogenesis of squamous cell carcinomas of the lung.

Aged↗
PubMed2000

p53 regulates myogenesis by triggering the differentiation activity of pRb.

The p53 oncosuppressor protein regulates cell cycle checkpoints and apoptosis, but increasing evidence also indicates its involvement in differentiation and development. We had previously demonstrated that in the presence of differentiation-promoting stimuli, p53-defective myoblasts exit from the cell cycle but do not differentiate into myocytes and myotubes. To identify the pathways through which p53 contributes to skeletal muscle differentiation, we have analyzed the expression of a series of genes regulated during myogenesis in parental and dominant-negative p53 (dnp53)-expressing C2C12 myoblasts. We found that in dnp53-expressing C2C12 cells, as well as in p53(-/-) primary myoblasts, pRb is hypophosphorylated and proliferation stops. However, these cells do not upregulate pRb and have reduced MyoD activity. The transduction of exogenous TP53 or Rb genes in p53-defective myoblasts rescues MyoD activity and differentiation potential. Additionally, in vivo studies on the Rb promoter demonstrate that p53 regulates the Rb gene expression at transcriptional level through a p53-binding site. Therefore, here we show that p53 regulates myoblast differentiation by means of pRb without affecting its cell cycle-related functions.

Animals↗
PubMed2001

[What do we know about ATM protein expression in breast tissue?].

The great majority of breast cancer cases are not associated with a mutated gene of high penetrance such as BRCA1, BRCA2 and TP53. Genes of low penetrance, frequently mutated in the general population, might play an important role in breast cancer development. The ATM gene, which encodes the ATM protein, mutated in the disorder ataxia telangiectasia (AT) could be such a susceptibility gene. Indeed, 1% of the general population is estimated to be AT heterozygote and females have an increased risk of developing breast cancer. The ATM protein is involved in the signalling pathway of DNA double-strand breaks. Studies on its expression in normal breast tissues have shown that ATM is expressed in the epithelial cells of breast ducts, but not in the myoepithelial cells. In sclerosing adenosis, a benign lesion of the breast, the ATM protein is expressed in both cell types whereas its expression is absent or reduced in tumour epithelial cells in about 30-50% of invasive carcinomas. Moreover, the study of the p53 status in some of these tumours has revealed that the ATM/p53 signalling pathway is frequently altered either by a very low ATM expression or by the presence of a mutated p53. It remains to be determined whether alterations in the expression of other proteins also involved in this DNA damage signalling cascade are specifically associated with breast cancer development and/or a radiosensitive phenotype seen in some breast cancer patients after radiotherapy.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2024

Comparative genomic landscape of lower-grade glioma and glioblastoma.

Biomarkers for classifying and grading gliomas have been extensively explored, whereas populations in public databases were mostly Western/European. Based on public databases cannot accurately represent Chinese population. To identify molecular characteristics associated with clinical outcomes of lower-grade glioma (LGG) and glioblastoma (GBM) in the Chinese population, we performed whole-exome sequencing (WES) in 16 LGG and 35 GBM tumor tissues. TP53 (36/51), TERT (31/51), ATRX (16/51), EFGLAM (14/51), and IDH1 (13/51) were the most common genes harboring mutations. IDH1 mutation (c.G395A; p.R132H) was significantly enriched in LGG, whereas PCDHGA10 mutation (c.A265G; p.I89V) in GBM. IDH1-wildtype and PCDHGA10 mutation were significantly related to poor prognosis. IDH1 is an important biomarker in gliomas, whereas PCDHGA10 mutation has not been reported to correlate with gliomas. Different copy number variations (CNVs) and oncogenic signaling pathways were identified between LGG and GBM. Differential genomic landscapes between LGG and GBM were revealed in the Chinese population, and PCDHGA10, for the first time, was identified as the prognostic factor of gliomas. Our results might provide a basis for molecular classification and identification of diagnostic biomarkers and even potential therapeutic targets for gliomas.

Humans↗
PubMed2026

Characterization of the genomic and transcriptomic landscape of invasive non-mucinous lung adenocarcinoma based on IASLC grading.

BACKGROUND: The IASLC grading system has prognostic utility and potential therapeutic implications in invasive non-mucinous lung adenocarcinoma (LUAD), but the molecular basis underlying the grading spectrum remains unclear. METHODS: We performed whole-genome sequencing in 138 Chinese patients with invasive non-mucinous LUAD and RNA sequencing of 96 matched tumor-normal tissue pairs to systematically characterize the molecular features across grades, including coding driver events, mutational signatures, non-coding regulatory disruptions, and transcriptional programs. RESULTS: Compared with Grade 1-2 tumors, Grade 3 LUADs exhibited heightened invasive potential, manifested by more advanced stage, more frequent spread through air spaces, and independently worse survival. Grade 3 tumors had elevated tumor mutational burden and were enriched for alterations in genome maintenance and cell-cycle genes, including TP53, as well as genes implicated in DNA damage response, including ZFHX4. APOBEC-associated mutagenesis was selectively enriched in Grade 3 tumors independent of smoking status, consistent with an instability-associated phenotype. Recurrent non-coding regulatory disruptions affected lung lineage-defining genes, particularly surfactant-associated genes, and were correlated with reduced expression. Transcriptomic profiling revealed epithelial dedifferentiation, loss of pulmonary homeostatic programs, and activation of proliferative and stress-related pathways. Notably, MUC16 emerged as a convergent event linking genomic and transcriptional dysregulation, with coding mutations associated with higher expression and increased expression in Grade 3 tumors correlating with the proportion of high-grade histologic patterns. CONCLUSIONS: These findings provide a molecular framework for the IASLC grading spectrum and identify Grade 3 LUAD as a distinct instability-associated and dedifferentiated biological state.

IASLC grading↗
PubMed2026

The ASH HematOmics Program supports integrative analysis of genomic and clinical data in hematologic diseases.

The increasing availability of genomic and transcriptomic sequencing has uncovered diverse genomic alterations and distinct gene expression profiles driving hematologic diseases, yet a data integration and sharing platform dedicated to hematology remains lacking. We developed the American Society of Hematology (ASH) HematOmics Program (ASHOP; ashop.hematology.org), a resource for exploring somatic alterations and gene fusions, transcriptomic results, and clinical data from 5960 patients spanning B-cell precursor and T-cell acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndromes, and chronic lymphocytic leukemia. Users can explore genomic alteration landscapes and comutation patterns via lollipop and matrix plots and analyze significantly altered genes in user-defined subcohorts. Transcriptomes can be explored through interactive uniform manifold approximation and projections, clustering, differential expression, and pathway enrichment. Genomic, transcriptomic features, and clinical outcomes can be correlated in a user-driven manner or combined to precisely define study cohorts. We illustrate the following 4 use cases of ASHOP: (1) stratification of DUX4-rearranged B-cell leukemias into Early/Multipotent and Committed subgroups with distinct outcomes, (2) characterization of HOXA/HOXB expression patterns in acute myeloid leukemias, (3) correlating mutational burden with mismatch repair deficiency and mutational signatures, and (4) investigation of TP53 alteration landscape. ASHOP is an open-access resource to inform genomic and transcriptomic data interpretation for hematologic malignancies and will expand to support additional diseases and data modalities from the ASH community.

Humans↗
PubMed2002

Different pattern of allelic loss in Epstein-Barr virus-positive gastric cancer with emphasis on the p53 tumor suppressor pathway.

Both Helicobacter pylori (HP) and Epstein-Barr virus (EBV) have been implicated in carcinogenesis of the stomach. Fifty-seven gastric carcinomas were tested for microsatellite instability and allelic loss at several tumor suppressor loci using 21 polymorphic microsatellite markers. Furthermore, immunohistochemistry for p53 and DPC4/SMAD4 was performed. Results were analyzed according to HP and EBV status of the tumors, as assessed by immunohistochemistry and RNA in situ hybridization, respectively. Fractional allelic loss was lower in EBV-positive carcinomas (n = 15) when compared to EBV-negative carcinomas (P < 0.001). EBV positivity was inversely associated with allelic loss at specific markers on chromosomal arms 5q (APC), 17p (TP53), and 18q (DPC4/SMAD4). Allelic loss at the TP53 locus was not encountered in EBV-positive carcinomas, but occurred in 51% of EBV-negative carcinomas (P < 0.005). Moreover, none of the EBV-positive carcinomas showed unequivocal p53 immunopositivity in contrast to 39% of the EBV-negative carcinomas (P < 0.01). EBV-status was not related to microsatellite instability. There was no correlation between HP-status and any of the molecular alterations tested. In conclusion, EBV-positive gastric carcinomas follow a distinct pathogenesis at the molecular level, in which p53 is not, or differently inactivated.

Adolescent↗
PubMed2005

Biology and management of histologic transformation of indolent lymphoma.

The evolution of indolent lymphomas to aggressive histologies, known as histologic transformation (HT), is a frequent occurrence for all subtypes of low grade B cell lymphoproliferative disorders. The risk of developing HT is approximately 3% per year for patients with indolent lymphoma. Clinically these present with a rapid change in the behavior of the disease, with evidence of a highly proliferative malignancy with a propensity to involve extranodal sites. The prognosis of patients following transformation is generally poor, with median survival of about 12 months. Recent studies suggest that the development of HT is very complex with the acquisition of multiple cytogenetic abnormalities in the low-grade lymphoma cells prior to HT. To date, there are no biologic or genetic parameters predictive of the development of HT. A myriad of genetic lesions have been identified in HT, and provide insight into its pathogenesis. These include genes regulating proliferation (C-MYC and C-MYC-regulated genes); control of the cell cycle (CDKN2a and CDKN2B); and programmed cell death (TP53, C-MYC, and BCL2). Gene expression profiling has been applied to the study of HT and has increased our understanding of the transformation process. There has been limited progress in the treatment of patients with HT. Conventional chemotherapy is generally of limited benefit, although a subset of patients are long-term survivors following high-dose therapy and autologous stem cell transplantation. The use of radioimmunotherapy and new agents targeting specific lesions or aberrant pathways may impact on the management of these aggressive diseases.

Cell Cycle↗
PubMed1998

Intercellular communication is involved in the bystander regulation of gene expression in human cells exposed to very low fluences of alpha particles.

We demonstrate by western analysis that the expression levels of TP53 (formerly known as p53), CDKN1A (formerly known as p21Waf1), CDC2 (formerly known as p34cdc2), CCNB1 (cyclin B1) and RAD51 are significantly modulated in confluent, density-inhibited human diploid cell populations exposed to doses where only a small fraction of the nuclei are actually traversed by an alpha-particle track. The extent of modulation of TP53 and CDKN1A is significantly reduced in the presence of the gap junction inhibitor lindane and in irradiated low-density cell populations. In situ immunofluorescence studies show that at doses where about 2% of the nuclei would be traversed by an alpha particle, induction of CDKN1A occurs in more cells than predicted. Furthermore, the induced cells are present in isolated aggregates of neighboring cells. Therefore, our studies at the gene expression level indicate that similar signaling pathways are induced in bystander cells that are not traversed by an alpha particle as in traversed cells, and that biological effects in cell populations are not restricted to the response of individual cells to the DNA damage they receive.

Alpha Particles↗
PubMed2006

Molecular and cytogenetic subgroups of oropharyngeal squamous cell carcinoma.

PURPOSE: The aim of this study was to acquire further insights into the pathogenetic pathways of head and neck squamous cell carcinomas (HNSCC) that may be useful for identifying new biomarkers instrumental in developing more specific treatment approaches. EXPERIMENTAL DESIGN: Cell cycle regulators and epidermal growth factor receptor (EGFR) and BRAF genes were analyzed in a series of 90 oropharyngeal SCCs of a cohort of surgically treated patients from a single institution, and the results were matched with the presence of high-risk human papillomavirus (HR-HPV) DNA and the TP53 status. RESULTS: At least four distinct groups of tumors were identified sharing a common histology but displaying different molecular/cytogenetic patterns: (a) 19% were HPV-positive SCCs whose lack of alterations of the investigated genes could explain their particular natural history, which requires less aggressive treatment; (b) 37% were HPV-negative SCCs carrying TP53 mutations, which may be more effectively treated by drugs acting through p53-independent apoptosis; (c) 34% were HPV-negative SCCs carrying wild-type TP53 and loss of 9p21 (p16INK4a and p15INK4b) and/or cyclin D1 overexpression that justify treatment with DNA-damaging drugs followed by cell cycle inhibitors; and (d) 10% were HPV-negative lacking tumor suppressor genes and cell cycle alterations. The second, third, and fourth groups also showed an increased copy number of EGFR and chromosome 7 (43%) that might justify the additional or alternative use of EGFR inhibitors. CONCLUSIONS: Our findings suggest that assessing HPV, TP53, 9p21, and EGFR status may be crucial to finding more tailored and beneficial treatments for oropharyngeal SCCs.

Biomarkers, Tumor↗
PubMed1996

Prognostic significance of p53 expression, chromosome 17 copy number, and DNA ploidy in non-metastasized colorectal carcinomas (stages IB and II).

BACKGROUND AND METHODS: Paraffin-embedded tumor tissue from 101 non-metastasized colorectal adenocarcinomas (tumor stages IB and II--that is, pT2 and 3, pN0, M0) was investigated for p53 expression by immunohistology (IH) (moab DO1), chromosome 17 (#17) copy number by interphase cytogenetics using non-radioactive in situ hybridization (NISH) with a centromer-specific DNA probe (D17Z1), and DNA ploidy by flow cytometry (FCM). The aims of the study were 1) to test whether numerical #17 aberrations are involved in functional TP53 loss in locally confined colorectal carcinomas; 2) to search for correlations between aberrant p53 expression and #17 aberrations with DNA ploidy and histopathology; and 3) to test the prognostic significance of these factors. RESULTS: Sixty cases (59.4%) showed nuclear p53 expression IH (low-grade p53 accumulation (< 50%), n = 16 (15.8%); high-grade (> or = 50%), n = 44 (43.6%)). Nish showed #17 aneusomy in 46% of the carcinomas (34% deletions, 12% gains). In FCM analysis, 43% of the carcinomas were DNA non-diploid. p53 overexpression correlated statistically significantly with FCM non-diploidy (p = 0.013). Furthermore, #17 aneusomy also correlated with FCM non-diploidy (p = 0.001). However, there was no association between #17 status and p53 expression (IH). CONCLUSIONS: Our data suggest a role for the TP53 gene in the aneuploidization process. Numerical deletions of #17, however, were not associated with p53 immunoreactivity in the analyzed tumors. With regard to prognosis, the most important independent variable in stage IB/II colorectal carcinomas was tumor stage, followed by high-grade p53 expression of tumor cells; #17 aneusomy was an independent risk factor for tumor relapse/progression but not for survival. As alterations of the investigated variables were not found in all carcinomas under study, different pathogenetic pathways seem to exist in colorectal carcinogenesis.

Adenocarcinoma↗
PubMed2002

BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair.

Inheritance of a mutation in the gene BRCA1 confers on women a 50-85% lifetime risk of developing breast cancer. Mutations in the TP53 tumor-suppressor gene are found in 70-80% of BRCA1-mutated breast cancer but only 30% of those with wildtype BRCA1 (ref. 3). The p53 protein regulates nucleotide excision repair (NER) through transcriptional regulation of genes involved in the recognition of adducts in genomic DNA. Loss of p53 function results in deficient global genomic repair (GGR), a subset of NER that targets and removes lesions from the whole genome. Here we show that BRCA1 specifically enhances the GGR pathway, independent of p53, and can induce p53-independent expression of the NER genes XPC, DDB2, and GADD45. Defects in the NER pathway in BRCA1-associated breast cancers may be causal in tumor development, suggesting a multistep model of carcinogenesis.

BRCA1 Protein↗
PubMed2006

Proteomics of acute myeloid leukaemia: Cytogenetic risk groups differ specifically in their proteome, interactome and post-translational protein modifications.

Acute myeloid leukaemia (AML) is characterized by specific cytogenetic aberrations that are strong determinants of prognostic outcome and therapeutic response. Because the pathological outcome of AML patients with cytogenetic abnormalities differs considerably, we hypothesized that their proteome may also differ specifically in their expression pattern, protein interaction pathways and post-translational modifications (PTM). We performed this study using 42 AML patients diagnosed for various cytogenetic abnormalities based on two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MS) and MSMS tandem MS. We could identify significant differences in the proteome and PTM of peptides, later confirmed by other methods, between cytogenetic groups. The interactome analysis based on computational bioinformatics reveals major regulating networks: MAPK8 and MYC for complex aberrant karyotype, TP53 for t(8;21), TP53-MYC-PRKAC for 11q23 and JUN and MYC for Inv(16). Further, we analysed 42 MS spectra representative of hnRNPH1, calreticulin and hnRNPA2/B1 in a peak explorer, which reveals a cytogenetic-specific PTM of beta-O-linked N-acetyl glucosamine (O-GlcNAc) of hnRNPH1 in AML patients with 11q23 translocation, an acetylation of calreticulin in t(8;21) translocation and methylation of hnRNPA2/B1 in patients with translocations of t(8;21) and inv(16). This report may lead to a new thinking about AML pathogenesis, as differences at PTM level could be used to distinguish different subtypes of AML.

Cell Shape↗
PubMed2005

Basal cell nevus syndrome.

PURPOSE OF REVIEW: Basal cell nevus syndrome (BCNS), is a hereditary condition transmitted as an autosomal dominant trait exhibiting high penetrance and variable expressivity. Inherited or spontaneous mutations in the human homologue of the Drosophila patched gene underlie the disorder and in addition to tumor predisposition, are associated with a range of 'patterning' defects. Recent advances, with glimpses of possible therapies are emerging, but because of the wide-ranging nature of phenotypic expression and overlap with other syndromes, there is difficulty. Finally, because of the importance of PTCH and paralogous genes in many species other than humans, reports appear in a correspondingly wide range of journals, which makes 'keeping abreast' difficult. RECENT FINDINGS: Progress has been achieved in understanding the role of Gli-1, 2, & 3 in development of 'sporadic' BCCs and BCNS. Expression of PTCH1 is now known to be regulated by alternative promoters and a single functional Gli-binding site. Expression of FOXE1 as a new transcriptional target of Gli2 has been demonstrated in human epidermis and BCCs. Finally, the discovery of Shh pathway inhibitors such as cyclopamine, a naturally occurring alkaloid and ornithine decarboxylase inhibition suggest possible interventional therapies. SUMMARY: In BCNS, phenotype does not correlate with position of mutations within Patched, suggesting genetic makeup and environment modulate effects of premature protein truncation induced by PTCH mutation. These developmental abnormalities occur as a result of haplo-insufficiency in heterozygotes for the mutated gene, whereas neoplastic complications arise from a classical two-hit tumor suppressor gene model. Attention is therefore turning toward TP53 and PTCH associations.

Animals↗
PubMed2026

Tumor genomic landscape of older patients with metastatic breast cancer&#x2606;.

BACKGROUND: Metastatic breast cancer (MBC) in older patients has distinct clinical and histologic characteristics. Elucidating the genomic basis of MBC helps identify potential therapeutic targets to improve outcomes for older patients with MBC. PATIENTS AND METHODS: Using a prospective database and targeted DNA sequencing (OncoPanel), we examined MBC's genomic landscape in older patients (age &#x2265;70 years at MBC diagnosis) and compared findings with those in younger (aged <50 years) and middle-aged (aged 50-69 years) patients. After classifying single nucleotide variants (SNVs) and copy number variations (CNVs) as oncogenic (via OncoKB), the frequencies of SNVs and CNVs, tumor mutational burden (TMB), and oncogenic signaling pathways were compared by age group using Fisher's exact tests. We estimated the association between continuous age at MBC diagnosis and mutations via multivariate logistic regression analysis, adjusting for race, stage at initial diagnosis, subtype, histology, and sample tested (primary versus metastatic). RESULTS: Our study included 2379 patients [853 (35%) younger, 1311 (55%) middle-aged, and 215 (9%) older] who underwent OncoPanel testing between 2013 and 2020. The most frequent tumor alterations in older patients were SNVs in PIK3CA (44%), TP53 (33%), CDH1 (22%) and amplifications in CCND1 (18%). After adjustment, older age was associated with higher frequency of SNVs in CDH1 [odds ratio (OR) = 1.43, 95% confidence interval (CI) 1.21-1.68, q < 0.001], MAP3K1 [OR = 1.30, 95% CI 1.10-1.54, q = 0.008], and PIK3CA [OR = 1.21, 95% CI 1.11-1.31, q < 0.001] and fewer SNVs in TP53 [OR = 0.84, 95% CI 0.77-0.91, q < 0.001]. Patients in the older group were more likely to have tumors with &#x2265;10 mutations/megabase than the youngest patients (26% versus 17%, P = 0.003). CONCLUSIONS: In this large cohort of patients with MBC, the tumor genomic landscape differed between older and younger patients even after accounting for tumor subtype. Older patients were more likely to have high-TMB and PIK3CA-mutated tumors, highlighting the importance of genomic testing for treatment applications in this population.

NGS↗