bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023–04–09
six papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Prevalence and Risk Factors of Germline Pathogenic Variants in Pancreatic Ductal Adenocarcinoma.
  2. Universal genetic testing for women with newly diagnosed breast cancer in the context of multidisciplinary team care.
  3. Comprehensive profiling of pathogenic germline large genomic rearrangements in a pan-cancer analysis.
  4. A novel BRCA1 splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in ATM: A case report.
  5. Assessment of Factors Associated With the Evaluation of Children for Leukemia Predisposition Syndromes: A Retrospective Single-center Study.
  6. Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort.
  1. Cancer Res Treat. 2023 Apr 03.
    Prevalence and Risk Factors of Germline Pathogenic Variants in Pancreatic Ductal Adenocarcinoma.
    Kum Hei Ryu, Sunhwa Park, Jung Won Chun, Eunhae Cho, Jongmun Choi, Dong-Eun Lee, Hyoeun Shim, Yun-Hee Kim, Sung-Sik Han, Sang-Jae Park, Sang Myung Woo, Sun-Young Kong.
       Purpose: The genetic attribution for pancreatic ductal adenocarcinoma (PDAC) has been reported as 5-10%. However, the incidence of germline pathogenic variants (PVs) in Korean PDAC patients has not been thoroughly investigated. Therefore we studied to identify the risk factors and prevalence of PV for future treatment strategies in PDAC.
    Materials and Methods: Total of 300 (155 male) patients with a median age of 65 years (33-90) were enrolled in National Cancer Center in Korea. Cancer predisposition genes, clinicopathologic characteristics, and family history of cancer were analyzed.
    Results: PVs were detected in 20 patients (6.7%, median age 65) in ATM (n=7, 31.8%), BRCA1 (n=3, 13.6%), BRCA2 (n=3), and RAD51D (n=3). Each one patient showed TP53, PALB2, PMS2, RAD50, MSH3 and SPINK1 PV. Among them, two likely PVs were in ATM and RAD51D, respectively. Family history of various types of cancer including pancreatic cancer (n=4) were found in 12 patients. Three patients with ATM PVs and a patient with three germline PVs (BRCA2, MSH3, and RAD51D) had first-degree relatives with pancreatic cancer. Familial pancreatic cancer history and PVs detection had a significant association (4/20, 20% vs. 16/264, 5.7%, p=0.03).
    Conclusion: Our study demonstrated that germline PVs in ATM, BRCA1, BRCA2, and RAD51D are most frequent in Korean PDAC patients and it is comparable to those of different ethnic groups. Although this study did not show guidelines for germline predisposition gene testing in patients with PDAC in Korea, it would be emphasized the need for germline testing for all PDAC patients.
    Keywords:  Germline pathogenic variant; Pancreatic ductal adenocarcinoma; Prevalence; Risk factors
    DOI:  https://doi.org/10.4143/crt.2023.291
  2. Med J Aust. 2023 Apr 02.
    Universal genetic testing for women with newly diagnosed breast cancer in the context of multidisciplinary team care.
    Dilanka L De Silva, Lesley Stafford, Anita R Skandarajah, Michelle Sinclair, Lisa Devereux, Kirsten Hogg, Maira Kentwell, Allan Park, Luxi Lal, Magnus Zethoven, Madawa W Jayawardana, Fiona Chan, Phyllis N Butow, Paul A James, G Bruce Mann, Ian G Campbell, Geoffrey J Lindeman.
       OBJECTIVE: To determine the feasibility of universal genetic testing of women with newly diagnosed breast cancer, to estimate the incidence of pathogenic gene variants and their impact on patient management, and to evaluate patient and clinician acceptance of universal testing.
    DESIGN, SETTING, PARTICIPANTS: Prospective study of women with invasive or high grade in situ breast cancer and unknown germline status discussed at the Parkville Breast Service (Melbourne) multidisciplinary team meeting. Women were recruited to the pilot (12 June 2020 - 22 March 2021) and expansion phases (17 October 2021 - 8 November 2022) of the Mutational Assessment of newly diagnosed breast cancer using Germline and tumour genomICs (MAGIC) study.
    MAIN OUTCOME MEASURES: Germline testing by DNA sequencing, filtered for nineteen hereditary breast and ovarian cancer genes that could be classified as actionable; only pathogenic variants were reported. Surveys before and after genetic testing assessed pilot phase participants' perceptions of genetic testing, and psychological distress and cancer-specific worry. A separate survey assessed clinicians' views on universal testing.
    RESULTS: Pathogenic germline variants were identified in 31 of 474 expanded study phase participants (6.5%), including 28 of 429 women with invasive breast cancer (6.5%). Eighteen of the 31 did not meet current genetic testing eligibility guidelines (probability of a germline pathogenic variant ≥ 10%, based on CanRisk, or Manchester score ≥ 15). Clinical management was changed for 24 of 31 women after identification of a pathogenic variant. Including 68 further women who underwent genetic testing outside the study, 44 of 542 women carried pathogenic variants (8.1%). Acceptance of universal testing was high among both patients (90 of 103, 87%) and clinicians; no decision regret or adverse impact on psychological distress or cancer-specific worry were reported.
    CONCLUSION: Universal genetic testing following the diagnosis of breast cancer detects clinically significant germline pathogenic variants that might otherwise be missed because of testing guidelines. Routine testing and reporting of pathogenic variants is feasible and acceptable for both patients and clinicians.
    Keywords:  Breast neoplasms; Cancer; Cancer genes; Genetic counselling; Genetic testing; Pathology, molecular; Sequence analysis
    DOI:  https://doi.org/10.5694/mja2.51906
  3. Mol Oncol. 2023 Apr 04.
    Comprehensive profiling of pathogenic germline large genomic rearrangements in a pan-cancer analysis.
    Zhe Sun, Chujie Bai, Miaoyi Su, Haimeng Tang, Xiaoying Wu, Yue Wang, Hua Bao, Xunbiao Liu, Xue Wu, Yang Shao, Bei Xu.
      The presence of large genomic rearrangements (LGRs) has been heavily investigated in breast and ovarian cancer. However, correlations between LGRs and cancer types beyond these two have not been extensively profiled, likely due to the highly inefficient methods of detecting these types of alterations. This study utilized next-generation sequencing (NGS) to analyze and classify the germline LGR profile in 17,025 cancer patients across 22 cancer types. We characterized newly identified LGRs based on predicted pathogenicity and took a closer look at genes that acquire both germline and somatic mutations within our samples. The detection method for LGRs was validated using droplet digital polymerase chain reaction (ddPCR) assay of commonly investigated LGR genes. In total, 15,659 samples from across 22 cancer types were retained for analysis after filtering. We observed that, in our cohort, the cancer types with the highest proportion of germline LGRs were ovarian cancer (4.7%), renal cell carcinoma (2.5%), breast cancer (2%), glioma (1.8%) and thyroid carcinoma (1.8%). Annotation of detected germline variants revealed several genes - MSH2, FANCA and PMS2 - that contain novel LGRs. We observed co-occurrences between germline LGRs in MSH2 and somatic single nucleotide variants/insertion and deletions (SNVs/InDels) in BRCA2, KTM2B, KDM5A, CHD8 and HNF1A. Furthermore, our analysis showed that samples with pathogenic and likely pathogenic germline LGRs tended to also have higher mutational burden, chromosomal instability, and microsatellite instability ratio compared to samples with pathogenic germline SNVs/InDels. In this study, we demonstrated the prevalence of pathogenic germline LGRs beyond breast and ovarian cancer. The profiles of these pathogenic or likely-pathogenic alterations will fuel further investigations and highlight new understanding of LGRs across multiple cancer types.
    Keywords:  double-hit hypothesis; large genomic rearrangement; next generation sequencing; pathogenic germline mutation
    DOI:  https://doi.org/10.1002/1878-0261.13430
  4. Front Oncol. 2023 ;13 1102184
    A novel BRCA1 splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in ATM: A case report.
    Mara Colombo, Patrizia Mondini, Elisa Minenza, Claudia Foglia, Annamaria Mosconi, Carmen Molica, Lorenza Pistola, Vienna Ludovini, Paolo Radice.
      The widespread adoption of gene panel testing for cancer predisposition is leading to the identification of an increasing number of individuals with clinically relevant allelic variants in two or more genes. The potential combined effect of these variants on cancer risks is mostly unknown, posing a serious problem for genetic counseling in these individuals and their relatives, in whom the variants may segregate singly or in combination. We report a female patient who developed triple-negative high grade carcinoma in the right breast at the age of 36 years. The patient underwent bilateral mastectomy followed by combined immunotherapy and chemotherapy (IMpassion030 clinical trial). Two years later she developed a skin recurrence on the right anterior chest wall. Despite intensive treatment, the patient died at 40-year-old due to disease progression. Gene panel testing of patient's DNA revealed the presence of a protein truncating variant in ATM [c.1672G>T; p.(Gly558Ter)] and of a not previously reported variant in the BRCA1 exon 22 donor splice site [c.5406+6T>C], whose clinical significance was unknown. The analysis of patient's RNA revealed the up-regulation of two alternative BRCA1 mRNA isoforms derived from skipping of exon 22 and of exons 22-23. The corresponding predicted protein products, p.(Asp1778GlyfsTer27) and p.(Asp1778_His1822del) are both expected to affect the BRCA1 C Terminus (BRCT) domain. The two variants were observed to co-occur also in the proband's brother who, in addition, was heterozygous for a common variant (c.4837A>G) mapped to BRCA1 exon 16. This allowed to ascertain, by transcript-specific amplification, the lack of functional mRNA isoforms expressed by the c.5406+6T>C allele and provided evidence to classify the BRCA1 variant as pathogenic, according to the guidelines of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium. To our knowledge, excluding two cases detected following the screening of population specific recurrent variants, only one ATM/BRCA1 double heterozygote has been reported in the literature, being the case here described the one with the youngest age at cancer onset. The systematic collection of cases with pathogenic variants in more than one cancer predisposition gene is needed to verify if they deserve ad hoc counseling and clinical management.
    Keywords:  ATM; BRCA1; case report; double heterozygote; spliceogenic variant
    DOI:  https://doi.org/10.3389/fonc.2023.1102184
  5. J Pediatr Hematol Oncol. 2023 Mar 16.
    Assessment of Factors Associated With the Evaluation of Children for Leukemia Predisposition Syndromes: A Retrospective Single-center Study.
    Kristen R D'Aquila, Elena Kessler, Kristine L Cooper, Andrea Durst, Julia Meade.
      Five to 10% of children with cancer are thought to have a cancer predisposition syndrome (CPS). Referral guidelines for leukemia predisposition syndromes are limited and vague, requiring the treating provider to determine whether patients should have a genetics evaluation. We evaluated referrals to the pediatric cancer predisposition clinic (CPP), the prevalence of CPS in those who elected to pursue germline genetic testing, and assessed for associations between a patient's medical history and the diagnosis of a CPS. Data were obtained via chart review of children diagnosed with leukemia or myelodysplastic syndrome between November 1, 2017, and November 30, 2021. A total of 22.7% of pediatric leukemia patients were referred for evaluation in the CPP. Of the participants evaluated with germline genetic testing, the prevalence of a CPS was 25%. Our study was able to find a CPS in different malignancies, including acute lymphoblastic leukemia, acute myeloid leukemia, and myelodysplastic syndrome. We did not find associations between a participant with an abnormal CBC before diagnosis or hematology visit and the diagnosis of a CPS. Our study supports that a genetic evaluation should be available to all children with leukemia as medical and family history alone is not predictors of a CPS.
    DOI:  https://doi.org/10.1097/MPH.0000000000002626
  6. J Med Genet. 2023 Apr 05. pii: jmg-2022-108982. [Epub ahead of print]
    Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort.
    Ulrik Kristoffer Stoltze, Mathis Hildonen, Thomas Van Overeem Hansen, Jon Foss-Skiftesvik, Anna Byrjalsen, Malene Lundsgaard, Laura Pignata, Karen Grønskov, Asuman Z Tumer, Kjeld Schmiegelow, Jesper Sune Brok, Karin A W Wadt.
       BACKGROUND: Studies suggest that Wilms tumours (WT) are caused by underlying genetic (5%-10%) and epigenetic (2%-29%) mechanisms, yet studies covering both aspects are sparse.
    METHODS: We performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes.
    RESULTS: Of 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes (FBXW7, WT1 and REST). Only one patient had a family history of WT (3 cases), segregating with the REST variant. Epigenetic testing revealed one (4%) additional patient (female) with uniparental disomy of chromosome 11 and Beckwith-Wiedemann syndrome (BWS). We observed a tendency of higher methylation of the BWS-related imprinting centre 1 in patients with WT than in healthy controls. Three patients (13%, all female) with bilateral tumours and/or features of BWS had higher birth weights (4780 g vs 3575 g; p=0.002). We observed more patients with macrosomia (>4250 g, n=5, all female) than expected (OR 9.98 (95% CI 2.56 to 34.66)). Genes involved in early kidney development were enriched in our constrained gene analysis, including both known (WT1, FBXW7) and candidate (CTNND1, FRMD4A) WT predisposition genes. WT predisposing variants, BWS and/or macrosomia (n=8, all female) were more common in female patients than male patients (p=0.01).
    CONCLUSION: We find that most females (57%) and 33% of all patients with WT had either a genetic or another indicator of WT predisposition. This emphasises the need for scrutiny when diagnosing patients with WT, as early detection of underlying predisposition may impact treatment, follow-up and genetic counselling.
    Keywords:  DNA methylation; biological evolution; genetics; medical oncology; pediatrics
    DOI:  https://doi.org/10.1136/jmg-2022-108982
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:18.