Role of POLE and POLD1 in familial cancer Mur, Pilar; García-Mulero, Sandra; Del Valle, Jesús ...
Genetics in medicine,
12/2020, Letnik:
22, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and ...exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study.
POLE and POLD1 were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case-control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation.
Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies <1%, were identified. One ED variant (POLE p.Met294Arg) was classified as likely pathogenic, four as likely benign, and seven as variants of unknown significance. The most commonly associated tumor types were colorectal, endometrial and ovarian cancers. Loss-of-function and outside-ED variants are likely not pathogenic for this syndrome.
Polymerase proofreading-associated syndrome constitutes 0.1-0.4% of familial cancer cases, reaching 0.3-0.7% when only CRC and polyposis are considered. ED variant interpretation is challenging and should include multiple pieces of evidence.
Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (
and
. BRCA1-associated ring domain 1 ...(
), nuclear partner of
, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of
truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive
screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous
truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating
variants with overall risk (odds ratio (OR) = 3.78; CI = 2.10-6.48;
= 1.16 × 10
). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18; CI = 2.10-7.70;
= 5.45 × 10
). Furthermore, deleterious
variants were enriched among triple-negative BC patients (OR = 5.40; CI = 1.77-18.15;
= 0.001) compared to other BC subtypes. Our results support the role of
as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors.
Background: Data on the clinical patterns and histopathology of SARS-CoV-2 related skin lesions, as well as on their relationship with the severity of COVID-19 are limited. Methods and Materials: ...Retrospective analysis of a prospectively collected cohort of patients with SARS-CoV-2 infection in a teaching hospital in Barcelona, Spain, from 1 April to 1 May 2020. Clinical, microbiological and therapeutic characteristics, clinicopathological patterns of skin lesions, and direct immunofluorescence and immunohistochemical findings in skin biopsies were analyzed. Results: Fifty-eight out of the 2761 patients (2.1%) either consulting to the emergency room or admitted to the hospital for COVID-19 suspicion during the study period presented COVID-19 related skin lesions. Cutaneous lesions could be categorized into six patterns represented by the acronym “GROUCH”: Generalized maculo-papular (20.7%), Grover’s disease and other papulo-vesicular eruptions (13.8%), livedo Reticularis (6.9%), Other eruptions (22.4%), Urticarial (6.9%), and CHilblain-like (29.3%). Skin biopsies were performed in 72.4%, including direct immunofluorescence in 71.4% and immunohistochemistry in 28.6%. Patients with chilblain-like lesions exhibited a characteristic histology and were significantly younger and presented lower rates of systemic symptoms, radiological lung infiltrates and analytical abnormalities, and hospital and ICU admission compared to the rest of patients. Conclusion: Cutaneous lesions in patients with COVID-19 appear to be relatively rare and varied. Patients with chilblain-like lesions have a characteristic clinicopathological pattern and a less severe presentation of COVID-19.
Multigene panels provide a powerful tool for analyzing several genes simultaneously. We evaluated the frequency of pathogenic variants (PV) in customized predefined panels according to clinical ...suspicion by phenotype and compared it to the yield obtained in the analysis of our clinical research gene panel. We also investigated mutational yield of opportunistic testing of BRCA1/2 and mismatch repair (MMR) genes in all patients. A total of 1,205 unrelated probands with clinical suspicion of hereditary cancer were screened for germline mutations using panel testing. Overall, 1,048 females and 157 males were analyzed, mean age at cancer diagnosis was 48; 883 had hereditary breast/ovarian cancer‐suspicion, 205 hereditary nonpolyposis colorectal cancer (HNPCC)‐suspicion, 73 adenomatous‐polyposis‐suspicion and 44 with other/multiple clinical criteria. At least one PV was found in 150 probands (12%) analyzed by our customized phenotype‐driven panel. Tumoral MMR deficiency predicted for the presence of germline MMR gene mutations in patients with HNPCC‐suspicion (46/136 vs. 0/56 in patients with and without MMR deficiency, respectively). Opportunistic testing additionally identified five MSH6, one BRCA1 and one BRCA2 carriers (0.6%). The analysis of the extended 24‐gene panel provided 25 additional PVs (2%), including in 4 out of 51 individuals harboring MMR‐proficient colorectal tumors (2 CHEK2 and 2 ATM). Phenotype‐based panels provide a notable rate of PVs with clinical actionability. Opportunistic testing of MMR and BRCA genes leads to a significant straightforward identification of MSH6, BRCA1 and BRCA2 mutation carriers, and endorses the model of opportunistic testing of genes with clinical utility within a standard genetic counseling framework.
What's new?
Multigene panels offer a powerful tool for analyzing several cancer‐related genes with a single test. But which genes are actually useful in guiding medical decisions in the clinic? In this study, the authors analyzed several customized, phenotype‐driven diagnostic gene panels. These yielded a notable rate of pathogenic variants with clear clinical actionability. The study also found that opportunistic testing of MMR and BRCA genes leads to a significant, straightforward identification of MSH6, BRCA1 and BRCA2 mutation carriers. This approach could be applied within a standard genetic counseling framework.
We describe a family in which four siblings exhibited multiple or classic colonic polyposis with or without colorectal carcinoma (CRC). One female developed three primary tumors, including CRC and ...carcinomas of the ovary and breast. Whole‐exome sequencing of germline DNA from affected and unaffected individuals revealed a novel missense mutation in the exonuclease domain of POLE (c.833C>A; p.Thr278Lys) associated with a highly penetrant, autosomal‐dominant inheritance pattern. Functional studies in yeast and demonstration of a high mutational burden in the available tumors confirmed the pathogenicity of the novel variant. Prominent POLE‐deficient somatic mutational signatures were seen in the CRCs, but in contrast, a mutational signature typical of concomitant tumoral loss of POLE and mismatch‐repair function (POLE‐exo*/MSI) was noted in the breast cancer. The breast cancer also showed distinctive pathological characteristics that reflect the presence of both the germline POLE variant and the secondary somatic MMR alterations.
In a family of four siblings with colonic polyposis and colonic and extracolonic tumors, we found a novel variant in POLE gene (c.833C>A; p.Thr278Lys) that we proved to be pathogenic by functional assays in yeast and high mutational burden in tumors. Prominent POLE‐deficient somatic mutational signatures were seen in the CRCs, but a mutational signature typical of concomitant tumoral loss of POLE and mismatch repair function (POLE‐exo*/MSI) was noted in the breast cancer.
BACKGROUND Mutations in breast cancer BRCA1/2 genes increase breast and ovarian cancer risk and are transmitted with an autosomal dominant pattern. Opinion about reproductive decisions among ...individuals undergoing BRCA1/2 testing in our institutions is unknown. MATERIALS AND METHODS Individuals (n = 77) undergoing BRCA1/2 testing were included in a prospective multicentre study to assess the clinical impact of genetic testing. Demographic and clinical information, psychological status and opinion about reproductive decisions were collected in two questionnaires administered prior to testing. Opinion regarding the use of assisted reproduction techniques for hereditary cancer susceptibility among health care professionals was also collected. RESULTS Twenty-eight individuals (36%) reported that they would decide to have children, regardless of their result. In case of a mutation, 9 (12%) believed that they would decide not to have children, 42 (55%) would consider prenatal diagnosis (PND), 37 (48%) would consider preimplantation genetic diagnosis (PGD) and 23 (30%) would consider adoption. Fifty-seven (74%) and 47 (61%) reported that they considered it ethical to offer PND or PGD, respectively, to BRCA+ patients. Individuals older than 40 years were more likely to consider PND or PGD than younger subjects (P = 0.02 and 0.05, respectively). Individuals with cancer compared with those without a diagnosis of malignancy were more likely to consider PGD (61 versus 30%, P = 0.02) and to consider that it was ethical to offer it (74 versus 44%, P = 0.02). Most health care professionals were in favour of PND and PGD for individuals with hereditary cancer susceptibility (58 and 61%, respectively). CONCLUSIONS BRCA1/2 genetic results could influence an individual's decisions regarding reproduction. Health care professionals who serve individuals undergoing BRCA testing should incorporate patient education regarding the potential impact of such testing on family planning.
RAD51C and RAD51D are involved in DNA repair by homologous recombination. Germline pathogenic variants (PVs) in these genes are associated with an increased risk of ovarian and breast cancer. ...Understanding the homologous recombination deficiency (HRD) status of tumors from patients with germline PVs in RAD51C/D could guide therapeutic decision-making and improve survival.
To characterize the clinical and tumor characteristics of germline RAD51C/D PV carriers, including the evaluation of HRD status.
This retrospective cohort study included 91 index patients plus 90 relatives carrying germline RAD51C/D PV (n = 181) in Spanish hospitals from January 1, 2014, to December 31, 2021. Genomic and functional HRD biomarkers were assessed in untreated breast and ovarian tumor samples (n = 45) from June 2022 to February 2023.
Clinical and pathologic characteristics were assessed using descriptive statistics. Genomic HRD by genomic instability scores, functional HRD by RAD51, and gene-specific loss of heterozygosity were analyzed. Associations between HRD status and tumor subtype, age at diagnosis, and gene-specific loss of heterozygosity in RAD51C/D were investigated using logistic regression or the t test.
A total of 9507 index patients were reviewed, and 91 patients (1.0%) were found to carry a PV in RAD51C/D; 90 family members with a germline PV in RAD51C/D were also included. A total of 157 of carriers (86.7%) were women and 181 (55.8%) had received a diagnosis of cancer, mainly breast cancer or ovarian cancer. The most prevalent PVs were c.1026+5_1026+7del (11 of 56 19.6%) and c.709C>T (9 of 56 16.1%) in RAD51C and c.694C>T (20 of 35 57.1%) in RAD51D. In untreated breast cancer and ovarian cancer, the prevalence of functional and genomic HRD was 55.2% (16 of 29) and 61.1% (11 of 18) for RAD51C, respectively, and 66.7% (6 of 9) and 90.0% (9 of 10) for RAD51D. The concordance between HRD biomarkers was 91%. Tumors with the same PV displayed contrasting HRD status, and age at diagnosis did not correlate with the occurrence of HRD. All breast cancers retaining the wild-type allele were estrogen receptor positive and lacked HRD.
In this cohort study of germline RAD51C/D breast cancer and ovarian cancer, less than 70% of tumors displayed functional HRD, and half of those that did not display HRD were explained by retention of the wild-type allele, which was more frequent among estrogen receptor-positive breast cancers. Understanding which tumors are associated with RAD51C/D and HRD is key to identify patients who can benefit from targeted therapies, such as PARP (poly adenosine diphosphate-ribose polymerase) inhibitors.
Objective: Medical applications have special features (interpretation of results in medical metrics, experiment reproducibility and dealing with complex data) that require the development of ...particular tools. The eXiT*CBR framework is proposed to support the development of and experimentation with new case-based reasoning (CBR) systems for medical diagnosis. Method: Our framework offers a modular, heterogeneous environment that combines different CBR techniques for different application requirements. The graphical user interface allows easy navigation through a set of experiments that are pre-visualized as plots (receiver operator characteristics (ROC) and accuracy curves). This user-friendly navigation allows easy analysis and replication of experiments. Used as a plug-in on the same interface, eXiT*CBR can work with any data mining technique such as determining feature relevance. Results: The results show that eXiT*CBR is a user-friendly tool that facilitates medical users to utilize CBR methods to determine diagnoses in the field of breast cancer, dealing with different patterns implicit in the data. Conclusions: Although several tools have been developed to facilitate the rapid construction of prototypes, none of them has taken into account the particularities of medical applications as an appropriate interface to medical users. eXiT*CBR aims to fill this gap. It uses CBR methods and common medical visualization tools, such as ROC plots, that facilitate the interpretation of the results. The navigation capabilities of this tool allow the tuning of different CBR parameters using experimental results. In addition, the tool allows experiment reproducibility
Purpose
To describe the incidences of hypogonadism, hypertension, and dyslipidaemia in patients with stage 1 seminoma (S1S) testicular cancer (TC) treated with a risk-adapted strategy.
Methods
A ...retrospective analysis from 2000 to 2020 was conducted. Active surveillance (AS), carboplatin one cycle, and carboplatin two cycles were offered according to risk factors. Cumulative incidences and relapse-free survival (RFS) were estimated.
Results
Of the 145 patients, 8 (5.4%) were excluded due to bilateral TC or hypogonadism at diagnosis. Median follow-up time was 8.2 years. Eighty-four, 30, and 33 patients were treated with AS, carboplatin one cycle, and carboplatin two cycles, respectively. In the overall population, the 5-year and 10-year cumulative incidences were 1.6% and 5.3% for hypogonadism; 2.0% and 8.6% for hypertension; and 12.4% and 25.1% for dyslipidaemia. No statistically significant differences were found in the incidences among the three adjuvant strategies. Five-year and 10-year RFS were 85.9% and 83.3% for AS; 92.4% and 84.0% for carboplatin one cycle; and 96.7% at both times for carboplatin two cycles.
Conclusion
There were no statistically differences in cumulative incidences of hypogonadism, hypertension, and dyslipidaemia in S1S patients treated with a risk-adapted strategy.
•Immune checkpoint inhibitors emerged as a the predominant 2L treatment, leading to a substantial decrease in the utilization of chemotherapies beyond the 1L.•Despite the introduction of immune ...checkpoint inhibitors, treatment attrition rates remained elevated, with approximately only half of patients undergoing ICIs the post-ICIs era.•When comparing the outcomes of patients treated before and after the introduction of ICIs, we did not observe higher rates of either a 2-year OS or an increase in the number of patients receiving 3L therapies.
Metastatic urothelial carcinoma (mUC) is a lethal disease with limited treatment options. We aimed to compare the treatment patterns and outcomes of patients with mUC who were treated before and after the introduction of immune checkpoint inhibitors (ICIs) at a tertiary hospital in Barcelona.
Single-center retrospective study from 2004 to 2021. Access to ICIs began in December 2014. We analyzed differences in clinical characteristics and survival outcomes, such as overall survival (OS), progression-free survival (PFS), and restricted mean survival time (RMST).
A total of 206 patients were included. The median follow-up was 48.6 months. Ninety and 116 patients were treated during the pre-ICIs and the post-ICIs eras, respectively. We found high treatment attrition rates, with no differences in the number of patients who received second-line (48%) and third-line (26%) therapies between the two eras. In the second-line, ICIs became the predominant therapy (58%), leading to a 30% reduction in the utilisation of platinum-based ChT and non-platinum ChT. Innovative approaches including ICIs in the first-line treatment (18%) and targeted therapies in the third-line setting (34%) were observed. We found no differences in the median OS, 2-year OS, or 24-month RMST between the two periods.
ICIs have emerged as a transformative treatment option, reshaping the treatment landscape. Nevertheless, substantial attrition rates from first-line to subsequent lines of systemic therapies might impede the potential impact of ICIs on long-term survival outcomes across the entire population.
Immune checkpoint inhibitors now serve as a novel treatment option for patients facing metastatic urothelial carcinoma, particularly in the second-line setting, thereby changing the treatment paradigm. Nonetheless, the substantial attrition rates during the transition from the first-line to subsequent lines of systemic therapy may hinder the potential impact of immune checkpoint inhibitors on long-term survival outcomes for the broader population.
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