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1.
J Pathol ; 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34767264

RESUMO

Alterations in chromatin remodelling genes are increasingly recognised as drivers of undifferentiated malignancies. In atypical teratoid/rhabdoid tumours (ATRT) and extracranial rhabdoid tumours (ECRT), inactivation of SMARCB1 underlies >95% of cases. In the remainder, the culprit is another SWI-SNF family member, SMARCA4. By contrast, in small cell carcinoma of the ovary hypercalcemic type (SCCOHT), SMARCA4 deficiency is by far the most common driver mechanism, while SMARCB1 alterations are rarely seen. It is unclear why alterations are so heavily weighted towards one or another subunit based on site alone, but both have become essential markers for the diagnosis and management of these undifferentiated lesions. Core SMARCA4-deficient undifferentiated malignancies share an aggressive clinical course and show an overlapping morphologic phenotype. In their study, Andrianteranagna and colleagues used DNA methylation and gene expression profiling to compare two subsets of SMARCA4-deficient malignancies diagnosed as SCCOHT and ECRT. Their work gives further insight into the subtle molecular spectrum of SMARCA4-deficient tumours, and their distinction from ATRT and ECRT with SMARCB1 inactivation. The characterisation of these molecular features is likely to play an important role in the future as we try to establish a clinically meaningful framework for the diagnosis and management of these lesions. This article is protected by copyright. All rights reserved.

5.
Mod Pathol ; 34(12): 2096-2097, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34642426
7.
Nat Commun ; 12(1): 5404, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518526

RESUMO

Inactivating mutations in SMARCA4 and concurrent epigenetic silencing of SMARCA2 characterize subsets of ovarian and lung cancers. Concomitant loss of these key subunits of SWI/SNF chromatin remodeling complexes in both cancers is associated with chemotherapy resistance and poor prognosis. Here, we discover that SMARCA4/2 loss inhibits chemotherapy-induced apoptosis through disrupting intracellular organelle calcium ion (Ca2+) release in these cancers. By restricting chromatin accessibility to ITPR3, encoding Ca2+ channel IP3R3, SMARCA4/2 deficiency causes reduced IP3R3 expression leading to impaired Ca2+ transfer from the endoplasmic reticulum to mitochondria required for apoptosis induction. Reactivation of SMARCA2 by a histone deacetylase inhibitor rescues IP3R3 expression and enhances cisplatin response in SMARCA4/2-deficient cancer cells both in vitro and in vivo. Our findings elucidate the contribution of SMARCA4/2 to Ca2+-dependent apoptosis induction, which may be exploited to enhance chemotherapy response in SMARCA4/2-deficient cancers.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , DNA Helicases/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Mitocôndrias/metabolismo , Mutação , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , DNA Helicases/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Transporte de Íons/genética , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
Cell Death Dis ; 12(9): 838, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489406

RESUMO

Hereditary non-polyposis colorectal cancer, now known as Lynch syndrome (LS) is one of the most common cancer predisposition syndromes and is caused by germline pathogenic variants (GPVs) in DNA mismatch repair (MMR) genes. A common founder GPV in PMS2 in the Canadian Inuit population, NM_000535.5: c.2002A>G, leads to a benign missense (p.I668V) but also acts as a de novo splice site that creates a 5 bp deletion resulting in a truncated protein (p.I668*). Individuals homozygous for this GPV are predisposed to atypical constitutional MMR deficiency with a delayed onset of first primary malignancy. We have generated mice with an equivalent germline mutation (Pms2c.1993A>G) and demonstrate that it results in a splicing defect similar to those observed in humans. Homozygous mutant mice are viable like the Pms2 null mice. However, unlike the Pms2 null mice, these mutant mice are fertile, like humans homozygous for this variant. Furthermore, these mice exhibit a significant increase in microsatellite instability and intestinal adenomas on an Apc mutant background. Rectification of the splicing defect in human and murine fibroblasts using antisense morpholinos suggests that this novel mouse model can be valuable in evaluating the efficacy aimed at targeting the splicing defect in PMS2 that is highly prevalent among the Canadian Inuits.

9.
NPJ Precis Oncol ; 5(1): 83, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535742

RESUMO

Circulating tumor DNA (ctDNA) sequencing studies could provide novel insights into the molecular pathology of cancer in sub-Saharan Africa. In 15 patient plasma samples collected at the time of diagnosis as part of the Ghana Breast Health Study and unselected for tumor grade and subtype, ctDNA was detected in a majority of patients based on whole- genome sequencing at high (30×) and low (0.1×) depths. Breast cancer driver copy number alterations were observed in the majority of patients.

10.
J Med Genet ; 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556502

RESUMO

BACKGROUND: Traditional medical genetics models are unable to meet the growing demand for germline genetic testing (GT) in patients with exocrine pancreatic cancer (PC). This study investigates the impact of an ambulatory oncology clinic-based GT model. METHODS: From 2012 to 2021, patients with PC were prospectively enrolled and considered for GT. Two chronological cohorts were compared: (1) the preuniversal genetic testing (pre-UGT) cohort, which received GT based on clinical criteria or family history; and (2) the post-UGT cohort, where an 86-gene panel was offered to all patients with PC. RESULTS: Of 847 eligible patients, 735 (86.8%) were enrolled (pre-UGT, n=579; post-UGT, n=156). A higher proportion of the post-UGT cohort received prospective GT (97.4% vs 58.5%, p<0.001). The rate of pathogenic germline alterations (PGA) across both cohorts was 9.9%, with 8.0% of PGAs in PC susceptibility genes. The post-UGT cohort had a higher prevalence of overall PGAs (17.2% vs 6.6%, p<0.001) and PGAs in PC susceptibility genes (11.9% vs 6.3%, p<0.001). The median turnaround time from enrolment to GT report was shorter in the post-UGT cohort (13 days vs 42 days, p<0.001). Probands with a PGA disclosed their GT results to 84% of their first-degree relatives (FDRs). However, only 31% of informed FDRs underwent GT, and the number of new cases per index case was 0.52. CONCLUSION: A point-of-care GT model is feasible and expedites access to GT for patients with PC. Strategies to increase the uptake of cascade testing are needed to maximise the clinical impact of an oncology clinic-based GT model.

11.
J Natl Compr Canc Netw ; 19(8): 883-887, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34416708

RESUMO

Pancreatic ductal adenocarcinomas (PDACs) with DNA mismatch repair deficiency (MMRd) respond preferentially to immune checkpoint inhibitors (ICIs). However, a subset of MMRd PDACs does not respond to these agents. This report describes a patient with PDAC who experienced rapid disease progression suggestive of hyperprogressive disease. The case involved a 63-year-old man carrying a pathogenic germline PMS2 mutation who developed metastatic PDAC. His tumor showed isolated loss of PMS2 expression by immunohistochemistry (IHC). He was treated with pembrolizumab, but his disease rapidly progressed. Whole-genome and transcriptome sequencing of a liver metastasis biopsy, acquired at disease progression, showed a retained wild-type PMS2 allele and hallmarks of microsatellite stability, including low tumor mutational burden and low MSIsensor score. PCR-based microsatellite instability (MSI) testing of the treatment-naïve tumor showed microsatellite stability. The ICI-treated tumor had a lower density of CD8+ T-cell infiltration than the treatment-naïve tumor, which is contrary to the expected evolution with ICI responsiveness. Through this case and a review of the literature, we highlight the low penetrance of PMS2 germline mutations in PDAC and discuss pitfalls in ascertaining MMRd and MSI based on IHC testing alone. An orthogonal confirmatory assay is warranted in the presence of uncommon immunophenotypes, such as isolated PMS2 loss, to optimize selection of patients with PDAC for immunotherapy.

12.
Int J Gynecol Pathol ; 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380971

RESUMO

A variety of unusual tumors are associated with both germline and somatic DICER1 pathogenic variants (PVs), including, in the female genital tract, embryonal rhabdomyosarcoma at various sites and ovarian Sertoli-Leydig cell tumor. There have been occasional reported cases of ovarian germ cell tumors [mainly yolk sac tumor (YST)] harboring DICER1 PVs but, as far as we are aware, none of these has been proven to have a germline provenance. We report an unusual enteric variant of ovarian YST in a 28-yr-old woman associated with a germline PV c.901C>T (p.Gln301Ter) in exon 7 of DICER1, accompanied by a somatic (YST-only) hotspot mutation: c.5437G>A, p.E1813K. To our knowledge, this is the first report of an ovarian germ cell tumor associated with a germline DICER1 PV. We review other reported cases of ovarian germ cell tumor with DICER1 PVs and discuss the differential diagnosis of this unusual variant of YST which was originally diagnosed as a mucinous adenocarcinoma.

13.
NPJ Breast Cancer ; 7(1): 109, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433815

RESUMO

It was hypothesized that variants in underexplored homologous recombination repair (HR) genes could explain unsolved multiple-case breast cancer (BC) families. We investigated HR deficiency (HRD)-associated mutational signatures and second hits in tumor DNA from familial BC cases. No candidates genes were associated with HRD in 38 probands previously tested negative with gene panels. We conclude it is unlikely that unknown HRD-associated genes explain a large fraction of unsolved familial BC.

14.
Cancer Epidemiol Biomarkers Prev ; 30(11): 2038-2043, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34426412

RESUMO

BACKGROUND: Weight gain and other anthropometric measures on the risk of ovarian cancer for women with BRCA mutations are not known. We conducted a prospective analysis of weight change since age 18, height, body mass index (BMI) at age 18, and current BMI and the risk of developing ovarian cancer among BRCA1 and BRCA2 mutation carriers. METHODS: In this prospective cohort study, height, weight, and weight at age 18 were collected at study enrollment. Weight was updated biennially. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for ovarian cancer. RESULTS: This study followed 4,340 women prospectively. There were 121 incident cases of ovarian cancer. Weight gain of more than 20 kg since age 18 was associated with a 2-fold increased risk of ovarian cancer, compared with women who maintained a stable weight (HR, 2.00; 95% CI, 1.13-3.54; P = 0.02). Current BMI of 26.5 kg/m2 or greater was associated with an increased risk of ovarian cancer in BRCA1 mutation carriers, compared with those with a BMI less than 20.8 kg/m2 (Q4 vs. Q1 HR, 2.13; 95% CI, 1.04-4.36; P = 0.04). There were no significant associations between height or BMI at age 18 and risk of ovarian cancer. CONCLUSIONS: Adult weight gain is a risk factor for ovarian cancer in women with a BRCA1 or BRCA2 mutation. IMPACT: These findings emphasize the importance of maintaining a healthy body weight throughout adulthood in women at high risk for ovarian cancer.

15.
J Clin Oncol ; 39(29): 3207-3216, 2021 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-34383599

RESUMO

PURPOSE: Childhood cancer survivors (CCS) are at risk of developing subsequent malignant neoplasms (SMNs) resulting from exposure to prior therapies. CCS with underlying cancer predisposition syndromes are at additional genetic risk of SMN development. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) tool identifies children with cancer at increased likelihood of having a cancer predisposition syndrome, guiding clinicians through a series of Yes or No questions that generate a recommendation for or against genetic evaluation. We evaluated MIPOGG's ability to predict SMN development in CCS. METHODS: Using the provincial cancer registry (Ontario, Canada), and adopting a nested case-control approach, we identified CCS diagnosed and/or treated for a primary malignancy before age 18 years (1986-2015). CCS who developed an SMN (cases) were matched, by primary cancer and year of diagnosis, with CCS who did not develop an SMN (controls) over the same period (1:5 ratio). Potential predictors for SMN development (chemotherapy, radiation, and MIPOGG output) were applied retrospectively using clinical data pertaining to the first malignancy. Conditional logistic regression models estimated hazard ratios and 95% CIs associated with each covariate, alone and in combination, for SMN development. RESULTS: Of 13,367 children with a primary cancer, 317 (2.4%) developed an SMN and were matched to 1,569 controls. A MIPOGG output recommending evaluation was significantly associated with SMN development (hazard ratio 1.53; 95% CI, 1.06 to 2.19) in a multivariable model that included primary cancer therapy exposures. MIPOGG was predictive of SMN development, showing value in nonhematologic malignancies and in CCS not exposed to radiation. CONCLUSION: MIPOGG has additional value for SMN prediction beyond treatment exposures and may be beneficial in decision making for enhanced individualized SMN surveillance strategies for CCS.

16.
17.
Clin Cancer Res ; 27(20): 5465-5471, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34261697

RESUMO

The MRN complex, composed of MRE11A, RAD50, and NBN, mediates vital molecular functions to maintain genomic stability and hence protect against related disorders. Germline mutations in the MRN genes predispose to three different syndromes: ataxia-telangiectasia-like disorder (MRE11A deficiency), Nijmegen breakage syndrome (NBS; NBN deficiency), and NBS-like disorder (RAD50 deficiency). The potential cancer component of these syndromes in addition to the close physical and functional proximity of the MRN complex to BRCA1 has promoted the MRN genes as candidate risk genes for developing breast cancer. This notion has been challenged by independent large-scale population-based studies. Despite having their two-decade old candidacy as breast cancer genes close to being refuted, it has recently been reported that the MRN genes rise to have potential new roles in clonal hematopoiesis. In this article, we discuss the history and current status of MRN genes' clinical utility in breast cancer and then focus on their recently uncovered and less understood roles in clonal hematopoiesis that likely predispose to health-related disorders such as hematologic malignancies and/or cardiovascular morbid events.

18.
Cancer Genet ; 258-259: 1-6, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34218100

RESUMO

Knowledge of the genetic landscape of a specific population group is vital for population-specific diagnosis and treatment of familial breast cancer. Although BRCA-related diagnostic testing has long been implemented in South Africa, the genotyping approach previously failed for the SA Indian population as it was based on other SA population groups. Because this population is uniquely admixed, the lack of population-specific data resulted in the implementation of comprehensive mutation screens for BRCA1/2. A total of 223 female patients were screened for clinically actionable variants. High-resolution melting analysis (HRMA) was used to screen 88 patients for DNA alterations in the coding and splice site boundaries of BRCA1 exons 2-9, BRCA1 exons 11-23, BRCA2 exons 2-9 and BRCA2 exons 12-27. The protein truncation test (PTT) was used to screen the three larger exons (BRCA1 exon 10 and BRCA2 exons 10 and 11) for protein termination changes. Multiplex ligation-dependent probe amplification (MLPA) was used to determine the presence of larger indels and possible copy number differences. Next Generation Sequencing (NGS) was performed on the remaining 135 samples. All potential variants were confirmed by performing Sanger DNA sequencing. The search revealed 28 different pathogenic heterozygotic variants, together with nine variants of unknown significance (VUS). The results suggested that the SA Indian population represents a different genetic admixture compared to that of mainland India, as only five pathogenic variants corresponded to those reported for mainland India. Familial breast cancer testing for SA Indian patients should therefore be performed as comprehensively as possible as the pathogenic variants seem to be family- rather than population-specific. Furthermore, predictive testing of family members will contribute to relieve the financial burden on the country's healthcare system, as increased surveillance and appropriate management could prevent disease.

20.
Eur Thyroid J ; 10(3): 257-261, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34178712

RESUMO

Introduction: With the use of ultrasonography for the evaluation of thyroid and nonthyroid neck diseases, the incidental discovery of previously unsuspected thyroid nodules/nonpalpable lesions has increased. Intrathyroidal thymus arises due to aberrant thymic migration during embryogenesis. It is thought to be rare, fulfils the classiccriteria for diagnosis of an incidentaloma and it can be mistaken for a thyroid nodule. Multinodular goiter is the main endocrine manifestation of DICER1 syndrome, a tumor predisposition syndrome. Careful thyroid examination including ultrasound is thus necessary for DICER1 syndrome patients. Case Report: A 4-year-old prepubertal boy was referred to the pediatric endocrinology department following an earlier diagnosis of pleuropulmonary blastoma (PPB) type III, which is a hallmark component of DICER1 syndrome. The patient underwent surgery followed by chemotherapy. Genetic analysis identified a germline DICER1 pathogenic variant (c.2062C>T, p.R688*)in the child and in 5 relatives. A second somatic DICER1 RNase IIIb hotspot mutation(c.5438A>G, p.E1813G) was identified in DNA extracted from the proband's PPB. He had no goiter on clinical examination, but a heterogenous, well-delineated, avascular, solid and hypoechogenic lesion with pseudomicrocalcifications was observed in the right lobe (4.1 × 3.1 × 2.6 mm), suggestive of thyroid neoplasia. Diagnostic work-up and a 3-year follow-up excluded thyroid neoplasia and confirmed the diagnosis of an intrathyroid benign thymic lesion. Discussion and Conclusion: This case exemplifies that thyroid incidentalomas in DICER1 syndrome patients should be viewed with great suspicion, but that not all thyroid disorders are indeed DICER1-related in these patients.

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