Jeferson Rodríguez Machado G, Lima von Ammon J, Oliveira Tosta Telles AC
… +5 more, Cassemiro JF, Esberard de Lima Beltrão F, Rolim da Paz A, de Castro Lopes G, Estrela Ramos H
Cancer Genet
· 2026 Jun · PMID 42085892
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Thyroid carcinoma in children and adolescents displays distinct molecular features compared with adult disease, with gene fusions playing a prominent oncogenic role. This retrospective multicenter study, representing the...Thyroid carcinoma in children and adolescents displays distinct molecular features compared with adult disease, with gene fusions playing a prominent oncogenic role. This retrospective multicenter study, representing the largest pediatric thyroid cancer molecular cohort reported from Latin America to date, aimed to characterize the spectrum of molecular alterations in pediatric, adolescent, and young adult patients with differentiated thyroid carcinoma from Northeast Brazil. Seventy-nine tumor samples from patients aged 21 years or younger were analyzed using targeted next-generation sequencing for hotspot point mutations and gene fusions. BRAF mutations were identified in five cases and excluded from fusion analysis. Among the samples, pathogenic point mutations were detected in 26.6% (21/79), while gene fusions were identified in 13.5% (10/74) of cases. RET rearrangements were observed in 8.6% (03/35) of evaluable tumors, including CCDC6:RET, NCOA4::RET, and TRIM24::RET fusions. Gene fusions overall were significantly more frequent in younger patients, whereas no association was found with tumor size or risk of recurrence. A high proportion of inconclusive results was observed, likely reflecting technical limitations related to the use of formalin-fixed, paraffin-embedded tissue. In conclusion, RET fusions were relatively uncommon in this Brazilian cohort but were enriched in younger patients, underscoring age-related differences in the molecular landscape of pediatric thyroid carcinoma and highlighting the need for larger, standardized multicenter studies.
Maffei R, Paolini A, Conte B
… +24 more, Bonamici L, Giorgi S, Martinelli S, Giacobbi F, Corradini G, Pilato F, Debbia G, Atene CG, Morselli M, Potenza L, Giusti D, Colaci E, Bettelli F, Bresciani P, Cuoghi A, Gilioli A, Messerotti A, Pioli V, Maccaferri M, Leonardi G, Forghieri F, Luppi M, Marasca R, Tagliafico E
Cancer Genet
· 2026 Jun · PMID 42044618
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B-cell prolymphocytic leukemia (B-PLL) is a rare B-cell neoplasm that presents splenomegaly, lymphocytosis, minimal or absent lymphoadenopathy, at least 55% of prolymphocytes in peripheral blood and a variable clinical c...B-cell prolymphocytic leukemia (B-PLL) is a rare B-cell neoplasm that presents splenomegaly, lymphocytosis, minimal or absent lymphoadenopathy, at least 55% of prolymphocytes in peripheral blood and a variable clinical course. Complex/composite karyotype and recurrent structural variants (SVs), including TP53 aberrations (mutations/deletion) and MYC abnormalities (translocation or gain) are genetic features typically seen in B-PLL. We applied the genome-wide technology of optical genome mapping (OGM) in 3 cases with B-PLL, finding multiple genomic aberrations, including SVs, copy number variations (CNVs) and aneuploidies. MYC aberrations were not observed in our cases, whereas all B-PLL showed concomitant deletion 17p and TP53 mutations. TP53-disrupted B-PLL cells showed additional genomic alterations that affect genes implicated in extrinsic and intrinsic apoptotic pathways i.e., TNFRSF10, FAS, MDM2, BCL2, and BCL2L11 and genes involved in cell-cycle regulation i.e., IKBKB, CDK2, CDK4, and RB1, suggesting that a convergent multifactorial pathogenetic mechanism may be involved in B-PLL. Applying the OGM technology on cytogenetically complex rare hematological neoplasia may be useful to improve the genetic definition and differential diagnosis of B PLL/SBLPN and related splenic B cell neoplasms.
Cancer Genet
· 2026 Jun · PMID 42033847
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Carney complex (CNC) is an autosomal dominant multiple neoplasm syndrome, characterized by the presence of endocrine and non-endocrine tumors; it includes myxomas, lentigines and primary pigmented nodular adrenocortical...Carney complex (CNC) is an autosomal dominant multiple neoplasm syndrome, characterized by the presence of endocrine and non-endocrine tumors; it includes myxomas, lentigines and primary pigmented nodular adrenocortical disease, among other signs/symptoms. In CNC type 1, inactivating mutations of the PRKAR1A gene were identified as the main cause of the disease, although since 2015 variants in other genes, including PRKACA and PRKACB, have also been linked to this pathology. PKA is an enzyme involved in the G protein-coupled intracellular pathways and serves as a mediator of c-AMP actions that promote cell metabolism, proliferation and apoptosis. The penetrance of CNC due to pathogenic variants in the PRKAR1A gene is close to 100%. We present the case of a 33-year-old female patient with cutaneous and mucosal lentiginosis, blue nevus, malignant melanocytic psammomatous schwannoma, cutaneous myxoma and a novel variant in the PRKAR1A gene.
Cancer Genet
· 2026 Jun · PMID 42033846
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This study investigated the molecular mechanism by which FAM134B regulates endoplasmic reticulum stress (ERS) and autophagy to promote thyroid carcinoma (THCA) development. FAM134B expression in clinical THCA samples was...This study investigated the molecular mechanism by which FAM134B regulates endoplasmic reticulum stress (ERS) and autophagy to promote thyroid carcinoma (THCA) development. FAM134B expression in clinical THCA samples was examined. FAM134B expression was knocked down in TPC-1 cells, while FAM134B was overexpressed in KTC-1 cells. Cell proliferation and apoptosis were determined. Cleaved caspase-3 (C-Casp-3), caspase-12, and unfolded protein response markers were detected. LC3B fluorescence expression and Calnexin-LAMP1 co-localization were assessed. FAM134B was highly expressed in THCA, and its overexpression was significantly associated with higher T staging. Knocking down FAM134B reduced THCA cell proliferation and encouraged apoptosis, while its overexpression resulted in contrary effects. FAM134B knockdown activated ERS (upregulating p-PERK/PERK, p-IRE1α/IRE1α, and CHOP) and enhanced autophagy (increasing LC3-II/I expression levels, decreasing p62 expression levels, and enhancing Calnexin-LAMP1 colocalization). Inhibition of ERS partially reversed the suppression of malignant biological behavior in THCA cells caused by FAM134B knockdown. FAM134B acts as an oncogene in THCA. Silencing FAM134B inhibits THCA cell proliferation and promotes apoptosis by inducing ERS and autophagy.
Patel H, Li Y, Chen XY
… +5 more, Chen X, Wu Z, Patel S, Chen ZS, Tang H
Cancer Genet
· 2026 Jun · PMID 41950861
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Colorectal cancer (CRC) remains a leading cause of cancer mortality globally. Vincristine is a well-characterized substrate of ABCB1 and ABCC1 and thus serves as a mechanistic probe to model transporter-driven multidrug...Colorectal cancer (CRC) remains a leading cause of cancer mortality globally. Vincristine is a well-characterized substrate of ABCB1 and ABCC1 and thus serves as a mechanistic probe to model transporter-driven multidrug resistance in a CRC cellular background. We established two novel vincristine-resistant human colon cancer sublines (S1/V1 and S1/V4) to investigate resistance pathways, focusing on the overexpression of ATP-binding cassette (ABC) transporters. These resistant variants, S1/V1 and S1/V4, were produced by continuous vincristine exposure of parental S1 cells. MTT cytotoxicity assays demonstrated that S1/V1 cells possess approximately 39-fold and S1/V4 cells approximately 35-fold higher resistance to vincristine than S1 cells, with S1/V1 also showing cross-resistance to other ABCB1 substrates, and S1/V4 exhibiting cross-resistance to other ABCC1 substrates. RT-qPCR and Western blot analyses revealed marked upregulation of ABCB1 in S1/V1 and ABCC1 in S1/V4 at both the mRNA and protein levels. Immunofluorescence analysis showed that these transporters were localized at the cell membrane, indicating active drug efflux. Inhibiting their efflux activity fully restored vincristine sensitivity in both sublines. In summary, we establish in vitro CRC models for vincristine resistance and identify ABCB1 and ABCC1 overexpression as principal mediators of this phenotype. These cell lines provide useful models for developing strategies to overcome drug resistance in CRC. Because ABCB1 and ABCC1 are dynamically regulated during tumor evolution and therapeutic pressure, these models capture a heritable transporter-driven component of multidrug resistance.
Magri A, Savoia G, Rutenberg NJ
… +5 more, Avior G, Zarruk A, da Silva Wurzba SD, Payne RJ, Forest VI
Cancer Genet
· 2026 Jun · PMID 41950860
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BACKGROUND: The thyrotropin receptor (TSHR) mutation can be present in autonomously functioning thyroid nodules (AFTNs). Our objective was to evaluate whether patients with a TSHR mutation developed AFTNs and to assess t...BACKGROUND: The thyrotropin receptor (TSHR) mutation can be present in autonomously functioning thyroid nodules (AFTNs). Our objective was to evaluate whether patients with a TSHR mutation developed AFTNs and to assess the impact of this mutation on thyroid malignancy. METHODS: We conducted a multicenter retrospective study of 1211 patients from Montreal, Canada, and from Tel Aviv, Israel, who underwent molecular testing (ThyroseqV3®) from January 2018 to December 2022 following an indeterminate cytology result (Bethesda III-IV). All TSHR-positive patients (n = 56) and 90 randomly selected mutation-negative patients were included. TSH levels were measured at least twice over 1-3 years following molecular testing. RESULTS: The case group was predominantly female (94.8%) with a mean age of 51.2 years. The mean TSH levels in the control and case groups were 2.29 (CI=95% 1.93-2.66) and 1.55 (CI=95% 1.23-1.86) at first follow-up, and 2.17 (CI=95% 1.80-2.54) and 1.33 (CI=95% 1.01-1.66) at second follow-up. Higher allele frequency correlated with lower TSH levels (P = 0.005, P = 0.002). All isolated TSHR mutations were associated with benignity regardless of allele frequency, while co-occurring genetic alterations were associated with malignant outcomes. CONCLUSIONS: TSHR mutations are generally benign and correlate with lower TSH levels. Co-mutations may influence thyroid function and malignancy risk.
Harb N, Romey M, Grass A
… +35 more, von Kügelgen F, Hattesohl A, Schäfer JA, Frey L, Mack E, Rinke A, Brendel C, Gremke N, Gschnell M, Görg M, Faoro C, Riera-Knorrenschild J, Gehring S, Litmeyer AS, Maurer E, Adeberg S, Frickel N, Keber U, Nimsky C, Ruchholtz S, Bartsch DK, Burchert A, Rohde G, Stuck BA, Groeben C, Gress TM, Wilhelm C, Hoffmann J, Rodepeter F, Wagner U, Neubauer A, Jesinghaus M, Wündisch T, Denkert C, Teply-Szymanski J
Cancer Genet
· 2026 Jun · PMID 41950859
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BACKGROUND AND PURPOSE: Personalized medicine is guided by an expanding array of molecular targets. This study investigates whether larger next-generation sequencing (NGS) gene panels (> 1 Mb) yield more clinically relev...BACKGROUND AND PURPOSE: Personalized medicine is guided by an expanding array of molecular targets. This study investigates whether larger next-generation sequencing (NGS) gene panels (> 1 Mb) yield more clinically relevant therapy options in molecular tumor boards (MTB) compared to smaller panels. PATIENTS AND METHODS: We analyzed 281 consecutive patients using a 430-gene DNA panel (1.3 Mb) combined with a RNA-fusion panel and compared the findings to a 185-gene DNA panel (618 kb). RESULTS: Molecular alterations were detected in 97.2 % of tumors with either oncogenic variants and/or gene fusions. Among these, 170 (60.5 %) received a molecular-stratified therapy recommendation from the local MTB. Only 8.8 % depended on the expanded 430-gene DNA panel, and additionally identified actionable variants in five additional genes. High TMB alone enabled 4.1 % of MTB recommendations. CONCLUSION: Our findings indicate that sufficient genomic coverage in DNA panels is essential for reliable TMB calculation, defining a minimal standard for genomic cancer care.
Li J, Wang XJ, Zhang LD
… +8 more, Yu Y, Xiao Y, Xu CD, Ye L, Wang XQ, Ma XY, Li CY, Lu WL
Cancer Genet
· 2026 Jun · PMID 41936330
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PURPOSE: Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary disease involving multiple endocrine glands. However, early diagnosis and precise treatment remain challenging. This study aimed to explore the pat...PURPOSE: Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary disease involving multiple endocrine glands. However, early diagnosis and precise treatment remain challenging. This study aimed to explore the pathogenicity and function of a novel MEN1 gene mutation (c.583G>T, p.E195*) found in a 4-year-old boy presenting with recurrent hypoglycemic episodes. METHODS: Functional assays were conducted, including the construction of a plasmid containing the MEN1 mutation, co-transfection and luciferase reporter gene assays to assess the impact of the MEN1 mutation on JunD-mediated transcription levels. Empty plasmid vector, wild-type (WT), and mutant MEN1 plasmids were transfected, and the proliferation of tumor cells was assessed using the CCK-8 assay. Statistical analysis was performed using one-way ANOVA with Tukey's post hoc test. RESULTS: The patient was diagnosed with MEN1 and insulinoma via clinical, imaging, pathological, and genetic findings. Hypoglycemia resolved after robotic resection. Genetic testing detected a heterozygous mutation (c.583G>T, p.E195*) in the MEN1 gene. This variation is a de novo mutation. Functional experiments in vitro demonstrated that the MEN1 mutation caused a loss of inhibition on transcriptional activity mediated by the transcription factor JunD. This loss promoted tumor cell proliferation, which led to hypoglycemia caused by the insulinoma. CONCLUSIONS: The novel mutation (c.583G>T, p.E195*) in the MEN1 gene was the causative genetic lesion in this MEN1 patient with insulinoma, and its pathogenicity might partially result from the loss of inhibition of JunD-mediated transcriptional activation caused by the MEN1 mutation.
Wang X, Shi X, Liao S
… +4 more, Su T, Gu Y, Zhang H, Li Z
Cancer Genet
· 2026 Jun · PMID 41905085
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Cancer is a complex disease driven by progressive genetic abnormalities, with initiation, progression, and therapy response governed by multilayered genetic mechanisms. This review synthesizes key advances in cancer gene...Cancer is a complex disease driven by progressive genetic abnormalities, with initiation, progression, and therapy response governed by multilayered genetic mechanisms. This review synthesizes key advances in cancer genetics, highlighting driver mutations, epigenetic reprogramming, non-coding RNAs, chromosomal instability, and viral integration in tumorigenesis and drug resistance. Unlike traditional reviews that primarily catalog genetic alterations, this review presents a dynamic interaction framework that integrates the bidirectional crosstalk between genetic abnormalities and the tumor microenvironment, metabolic reprogramming, and microbiota. We emphasize the context-dependent functionality of genetic events within specific tissue niches rather than treating them as static drivers. Moreover, we provide a mechanistic synthesis linking multidimensional genetic mechanisms to therapeutic resistance, offering a systems-level perspective that bridges molecular genetics and tumor ecology. By shifting the paradigm from isolated genetic events to their dynamic interplay within the tumor ecosystem, this review aims to inspire new research directions that address the context-dependent nature of genetic effects and ultimately inform precision oncology strategies.
Morris G, Vlachostergios PJ, Rai MP
… +6 more, Scherr D, Molina A, Elemento O, Mosquera JM, Cheng L, Faltas BM
Cancer Genet
· 2026 Jun · PMID 41880698
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BACKGROUND: Sarcomatoid carcinoma of the bladder is a rare and aggressive biphasic malignant neoplasm, representing approximately 0.1-0.3% of all bladder cancers. It is characterized by the coexistence of malignant epith...BACKGROUND: Sarcomatoid carcinoma of the bladder is a rare and aggressive biphasic malignant neoplasm, representing approximately 0.1-0.3% of all bladder cancers. It is characterized by the coexistence of malignant epithelial and mesenchymal components. Its poor prognosis and limited systemic treatment options underscore the need for improved molecular characterization. CASE PRESENTATION: A 75-year-old male with chronic cystitis and squamous metaplasia of the bladder presented with acute urinary obstruction caused by a large bladder mass. Histopathological evaluation revealed a biphasic tumor with rhabdomyosarcomatous and adenocarcinomatous components. Following radical cystoprostatectomy (pT2a pN0 cM0), whole-exome sequencing (WES) using the EXaCT-1 pipeline identified amplification of the 19q13 locus, including copy-number gains in AKT2 and ERCC2. Nine months postoperatively, the patient developed metastatic recurrence. CONCLUSIONS: This case contributes to the molecular characterization of bladder sarcomatoid carcinoma through WES. The 19q13 amplification with AKT2 and ERCC2 copy-number gains represents a hypothesis-generating finding that warrants further investigation in larger cohorts.
Peng W, Yang ZR, Wang Z
… +2 more, Zhao YL, Tan SS
Cancer Genet
· 2026 Jun · PMID 41875719
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BACKGROUND: Colorectal cancer (CRC) remains one of the most common and lethal malignancies worldwide, with metastatic disease accounting for the majority of CRC-related mortality. Immunotherapy with programmed death (PD)...BACKGROUND: Colorectal cancer (CRC) remains one of the most common and lethal malignancies worldwide, with metastatic disease accounting for the majority of CRC-related mortality. Immunotherapy with programmed death (PD)-1/PD-ligand 1 (PD-1/PD-L1) inhibitors has shown remarkable success in treating metastatic colorectal cancers (CRC) with deficient mismatch repair (dMMR) but is less effective in cancers with proficient mismatch repair (pMMR). Recent studies suggest that enhanced autophagy may negatively regulate the effects of PD-1/PD-L1 inhibitors in pMMR tumors. This study aims to investigate the role of autophagy in reducing the effectiveness of PD-1/PD-L1 inhibitors and explore whether combining autophagy inhibitors can improve treatment outcomes in pMMR CRC. METHODS: We utilized CRISPR/Cas9 to delete the mismatch repair gene Mlh1 in CT26 colorectal cancer cells, generating CT26-dMMR cells. The parental CT26-pMMR cells and CT26-dMMR cells were treated with the autophagy inhibitor 3-Methyladenine (3-MA) and Tumor Necrosis Factor-alpha (TnfA) to assess cell viability. Flow cytometry was used to analyze the effects of 3-MA and TnfA on the cell cycle, apoptosis, and immune cell populations. Protein levels related to cell cycle regulation, apoptosis, and autophagy were measured by immunoblotting. Additionally, in vivo experiments were conducted using a cell line-derived xenograft (CDX) model to evaluate the anti-cancer effects of combining 3-MA with the PD-1/PD-L1 inhibitor BMS-1. RESULTS: CT26-pMMR cells were less sensitive to TnfA compared to CT26-dMMR cells. Combination treatment with 3-MA and TnfA significantly suppressed the cell cycle regulator Cyclin D1 and activated apoptotic signaling via elevated Casp3/Cleaved Casp3 and Casp9/Cleaved Casp9 levels. In vivo, co-treatment with 3-MA and BMS-1 inhibited tumor growth more effectively than either treatment alone. Notably, regulatory T cells (Tregs) were reduced, and CD8+ T cells increased, indicating an enhanced immune response. CONCLUSIONS: Our findings demonstrate that inhibiting autophagy improves the immunotherapeutic efficacy of PD-1/PD-L1 inhibitors in pMMR colorectal cancer. This study offers a new strategy to overcome resistance to PD-1/PD-L1 inhibitors in pMMR metastatic CRC by combining autophagy inhibition with immunotherapy.
Soper ER, Casasanta NA, Dubois B
… +3 more, Belbin GM, Kenny EE, Abul-Husn NS
Cancer Genet
· 2026 Jun · PMID 41855952
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Limited data are available on genomic risk factors for breast cancer in diverse populations. We evaluated breast cancer risk conferred by high and moderate penetrance genes, polygenic risk scores (PRS), and family histor...Limited data are available on genomic risk factors for breast cancer in diverse populations. We evaluated breast cancer risk conferred by high and moderate penetrance genes, polygenic risk scores (PRS), and family history (FH) in an ancestrally diverse biobank. We identified expected pathogenic variants (EPVs) in 14 genes among 30,223 sequenced individuals, including 15,919 unrelated women. Using electronic health records (EHRs), we evaluated associations of EPVs and PRS with breast cancer, stratified by FH and relative to individuals without EPVs and without FH. EPVs in high penetrance genes were associated with increased risk of breast cancer both without FH (OR 6.8, p = 1.4 × 10) or with FH (OR 11.8, p = 4.1 × 10). EPVs in moderate penetrance genes were associated with increased risk only among individuals with FH (OR 7.0, p = 4.7 × 10 with FH; OR 1.2, p = 0.6 without FH). High PRS (≥ 90 percentile) was associated with increased risk (OR 1.8, p = 3.3 × 10) and low PRS (≤ 10 percentile) with reduced risk (OR 0.6, p = 1.6 × 10) of breast cancer. FH further modified risk across PRS strata. EHR review of 252 women with EPVs in moderate penetrance genes revealed that 75 (29.8%) met criteria for clinical genetic testing, and only 27 (36.0%) had undergone testing. High and moderate penetrance genes and PRS confer varying degrees of breast cancer risk, with FH modifying these associations. There is a need to better identify women with moderate penetrance gene variants.
Shao B, Yin H, Zhang S
… +4 more, He S, Lu H, Fang Y, Zhou C
Cancer Genet
· 2026 Jun · PMID 41844453
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BACKGROUND: Hepatoblastoma (HB) is the most common primary liver malignancy in children. Oxidative DNA damage is primarily repaired through the base excision repair (BER) pathway, and genetic polymorphisms in BER-related...BACKGROUND: Hepatoblastoma (HB) is the most common primary liver malignancy in children. Oxidative DNA damage is primarily repaired through the base excision repair (BER) pathway, and genetic polymorphisms in BER-related genes may influence individual susceptibility to HB. However, the contribution of BER gene variants to HB risk remains unclear. METHODS: A multicenter case-control study including 193 HB patients and 773 cancer-free controls were conducted. Twenty potentially functional single nucleotide polymorphisms (SNPs) in key BER pathway genes were genotyped using TaqMan assays. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models controlling for age and sex. The Benjamini-Hochberg false discovery rate (FDR) procedure was applied to account for multiple testing in the primary analysis. Expression quantitative trait loci (eQTL) analyses were performed using publicly available GTEx data to explore potential regulatory effects. RESULTS: In unadjusted analyses, several BER SNPs showed nominal associations with HB susceptibility under specific genetic models, including PARP1 rs2666428, APEX1 rs1760944, LIG3 rs4796030, XRCC1 rs25487, and XRCC1 rs915927. However, after Benjamini-Hochberg false discovery rate (FDR) correction across the 20 examined SNPs in the primary (dominant-model) analysis, none of the associations remained statistically significant at an FDR threshold of 0.05. The smallest FDR-adjusted q values were 0.053 (PARP1 rs2666428, APEX1 rs1760944, and XRCC1 rs25487), indicating borderline but non-significant signals. Stratified analyses suggested potential subgroup-specific effects, but these findings were based on limited sample sizes and should be interpreted cautiously. eQTL analyses indicated that selected variants were associated with altered gene expression in normal tissues, providing preliminary functional support. CONCLUSION: This study provides exploratory evidence suggesting that genetic variation in BER pathway genes may contribute to HB susceptibility in Chinese children. Given the multiple testing burden and modest effect sizes, these findings should be considered hypothesis-generating and require validation in independent cohorts and functional studies.
Laitman Y, Zalmanoviz S, Netzer I
… +2 more, Bernstein-Molho R, Friedman E
Cancer Genet
· 2026 Jun · PMID 41819754
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PURPOSE: Multigene panel testing (MGPT) enables simultaneous detection of germline pathogenic/likely pathogenic variants (P/LP SV) in cancer susceptibility genes (CSG). The utility of MGPT in Israel, where most individua...PURPOSE: Multigene panel testing (MGPT) enables simultaneous detection of germline pathogenic/likely pathogenic variants (P/LP SV) in cancer susceptibility genes (CSG). The utility of MGPT in Israel, where most individuals eligible for oncogenetic testing undergo first-pass genotyping for predominant PSVs in the BRCA1, BRCA2, MSH2, and MSH6 genes, has not been reported. METHODS: Individuals who underwent MGPT after oncogenetic counseling between October 2013 and December 2024 were eligible for participation in this ethically approved study. NGS genotyping of 29-160 genes was performed using commercial or in-house platforms. Clinical data were obtained from records. RESULTS: Among 2990 individuals, 139 pathogenic sequence variants were detected in 39 genes in 234 individuals (7.8%). Recurring PSVs in BRCA1, BRCA2, CHEK2, ATM, MSH2, and MSH6 were noted. CHEK2 (c.592+3A>T), PMS2 (c.943C>T), and CDKN2A (c.176T>G) were identified as potentially recurring founder variants. CONCLUSIONS: The yield of MGPT in Israel, after exclusion of predominant founder PSVs, was modest. The identification of recurring PSVs warrants further investigation and potential inclusion in updated first-pass genotyping schemes.
Gomez F, Shea L, Sharavanan SA
… +16 more, Russler-Germain D, Mosior M, Krysiak K, Matlock M, Skidmore ZL, Lee YS, Duncavage EJ, O'Laughlin M, Fronick C, Fulton RS, Bartlett NL, Cashen AF, Griffith M, Fehniger TA, Griffith OL, Wartman LD
Cancer Genet
· 2026 Jun · PMID 41791303
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The occurrence of both non-Hodgkin lymphoma (NHL) and classic Hodgkin lymphoma (cHL) in an individual patient (hereafter referred to as composite lymphoma) is a relatively rare and poorly characterized phenomenon. We hyp...The occurrence of both non-Hodgkin lymphoma (NHL) and classic Hodgkin lymphoma (cHL) in an individual patient (hereafter referred to as composite lymphoma) is a relatively rare and poorly characterized phenomenon. We hypothesized that analysis of the shared and divergent mutations harbored by composite lymphomas might shed light on genetic drivers of composite lymphomagenesis. We performed exome sequencing of two cases of composite NHL and cHL, and validated somatic variants using the AmpliSeq platform. Additionally, we utilized B-cell receptor sequencing of the immunoglobulin heavy chain (IGH) gene region as a tool to provide an orthogonal comparison of the composite lymphomas. Interestingly, both cases contained stop gain mutations in TNFRSF14 that were shared between the cHL and NHL samples. Other genes with shared somatic variants of potential biologic significance included TP53, SRSF6, PLCG2, BCL10, and PCLO. Furthermore, sequencing of the B-cell receptor immunoglobulin heavy chain (IGH) gene region revealed clones with common V(D)J gene usage in the NHL and cHL cases. Our data suggest a common precursor in these two cases of composite lymphoma. The shared somatic variants we identified may represent early events in lymphomagenesis and potential therapeutic targets.
Cancer Genet
· 2026 Jun · PMID 41780368
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Bone metastasis affects approximately 40% of patients with non-small cell lung cancer (NSCLC), significantly impacting patient survival and prognosis. However, the molecular mechanisms linking driver gene mutations to bo...Bone metastasis affects approximately 40% of patients with non-small cell lung cancer (NSCLC), significantly impacting patient survival and prognosis. However, the molecular mechanisms linking driver gene mutations to bone metastasis remain poorly understood. This study retrospectively analyzed 362 East Asian population patients with NSCLC to investigate the association and to construct a prediction model based on machine learning. EGFR mutations were the most common genetic alterations (57.7%) and were significantly associated with an increased risk of bone metastasis, with odds ratios of 2.395 for synchronous metastasis and 2.228 for metastasis within one year of diagnosis. Among EGFR subtypes, 19-Del and L858R showed the strongest association with bone metastases. In contrast, other common driver mutations, such as KRAS and ALK, were not significantly associated with bone metastasis. Additionally, advanced T stage (T3-T4), advanced N stage (N2-N3), and adenocarcinoma histology were also significant risk factors for bone metastasis. A logistic regression model, constructed using predictors selected by LASSO regression, showed optimal and stable performance, with validation set AUCs of 0.704 for synchronous bone metastasis and 0.708 for metastasis within one year. SHAP analysis revealed that T stage and EGFR mutation status contributed most to the model's predictions. These findings suggest EGFR mutation is a key molecular driver of early bone metastasis in NSCLC. Integrating molecular markers with clinical features into an interpretable prediction model can improve personalized risk assessment for bone metastasis and facilitate timely intervention.
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with approximately 25-30 % of cases exhibiting a familial component driven by germline mutations in DNA mismatch repair genes (Lynch...Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with approximately 25-30 % of cases exhibiting a familial component driven by germline mutations in DNA mismatch repair genes (Lynch syndrome) or the APC gene (familial adenomatous polyposis). Despite advances in screening and early detection, significant challenges persist in identifying at-risk individuals, optimizing surveillance strategies and addressing disparities in access to genetic testing and preventive care. This narrative review synthesizes current evidence on the genetic underpinnings, modifiable risk factors and personalized screening approaches for familial CRC. We highlight the critical interplay between hereditary predisposition and environmental exposures including diet, obesity, smoking and gut microbiome alterations, which cumulatively influence disease penetrance and clinical outcomes. Emerging predictive models integrating family history, polygenic risk scores and proteomic biomarkers offer unprecedented opportunities for risk stratification, enabling tailored screening initiation and intervals that balance clinical efficacy with cost-effectiveness. Novel non-invasive biomarkers, such as circulating tumor DNA and stool RNA tests, demonstrate promising sensitivity and specificity, potentially enhancing patient adherence while complementing gold-standard colonoscopy. Furthermore, artificial intelligence-assisted endoscopy and comprehensive genetic panels are reshaping precision oncology by improving adenoma detection rates and guiding targeted therapies. Addressing social determinants of health and implementing structured genetic counseling remain essential to achieving equitable CRC prevention. By transitioning from age-based to individualized, risk-adapted screening paradigms, healthcare systems can significantly reduce CRC incidence and mortality, particularly among genetically predisposed populations.
Tatton-Brown-Rahman syndrome (TBRS) is a rare overgrowth disorder caused by germline alterations in DNMT3A, a gene essential for DNA methylation and epigenetic regulation. Affected individuals typically present with tall...Tatton-Brown-Rahman syndrome (TBRS) is a rare overgrowth disorder caused by germline alterations in DNMT3A, a gene essential for DNA methylation and epigenetic regulation. Affected individuals typically present with tall stature, intellectual disability, and neurodevelopmental disorders, and they also demonstrate an increased susceptibility to neoplastic disease. Reported tumors include hematologic malignancies, with acute myeloid leukemia being the most notable, as well as solid tumors such as neuroblastoma, medulloblastoma, benign glioma, and pituitary adenoma. Despite this expanding tumor spectrum, pineal gland tumors have not previously been described in association with TBRS. Here, we present the first known case of a presumed pineal gland tumor in a patient with TBRS. Although the lesion lacks histopathologic confirmation and a sporadic occurrence cannot be excluded, this observation raises the possibility that germline DNMT3A alterations may predispose to a broader range of tumors than previously recognized. This report underscores the need for continued documentation of unusual tumor presentations in TBRS to further elucidate the biology of DNMT3A-related tumorigenesis.
Breast cancer (BC) metastasis is a serious concern in BC treatment. Early diagnosis and prompt intervention are extremely important for patients. Alterations in epigenetic modifications of circulating free DNA (cfDNA) ha...Breast cancer (BC) metastasis is a serious concern in BC treatment. Early diagnosis and prompt intervention are extremely important for patients. Alterations in epigenetic modifications of circulating free DNA (cfDNA) have been reported during BC occurrence, but not before or after metastasis. Therefore, this study aimed to establish a highly metastatic 4T1 BC mouse model closely resembling stage IV human BC to explore changes in cfDNA methylation modifications before and after metastasis. The timing of BC metastasis was defined based on the first visible fluorescence detection in axillary lymph nodes using in small-animal imaging. The results showed that the methylation levels of CDH1 and Gjb1 in serum cfDNA changed significantly in BC before and after metastasis, displaying trends analogous to those observed in tumor tissue DNA. The methylation levels of cfDNA can be used as candidate biomarkers for the early diagnosis and monitoring of BC metastasis.
Multiple myeloma (MM) is characterized by marked genomic instability and progressive clonal evolution, particularly in the relapsed/refractory setting. Here, we report a case of aggressive relapsed/refractory MM in which...Multiple myeloma (MM) is characterized by marked genomic instability and progressive clonal evolution, particularly in the relapsed/refractory setting. Here, we report a case of aggressive relapsed/refractory MM in which next-generation sequencing (NGS) revealed spatio-temporal clonal heterogeneity after anti-MM treatment. Serial molecular profiling demonstrated dynamic shifts in clonal architecture during successive lines of therapy, highlighting the selective pressure exerted by treatment and the emergence of resistant clones. This case underscores the limitations of traditional cytogenetic approaches, such as conventional karyotyping or fluorescence in situ hybridization, in detecting small subclones and supports the integration of NGS into clinical practice to better characterize molecular heterogeneity and potentially guide therapeutic strategies in high-risk MM.