bims-lifras 2020-09-06 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2020–09–06
thirteen papers selected by
Joanna Zawacka-Pankau, University of Warsaw

Prevalence and clinical implications of germline predisposition gene mutations in patients with acute myeloid leukemia.
What 20 years of research has taught us about the TP53 p.R337H mutation.
Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland.
Prevalence of germline TP53 variants among early-onset breast cancer patients from Polish population.
Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario.
Reproductive decision-making in the context of hereditary cancer: the effects of an online decision aid on informed decision-making.
First report of a Mexican family with mutation in the CDH1 gene.
Age-dependent performance of BRAF mutation testing in Lynch syndrome diagnostics.
Hereditary Hematologic Malignancies.
Hereditary breast and ovarian cancer (HBOC): review of its molecular characteristics, screening, treatment, and prognosis.
A deep analysis using panel-based next-generation sequencing in an Ecuadorian pediatric patient with anaplastic astrocytoma: a case report.
Donor-derived myelodysplastic syndrome after allogeneic stem cell transplantation in a family with germline GATA2 mutation.
The Problem of TP53-Mutant MDS/AML.

Sci Rep. 2020 Aug 31. 10(1): 14297

Prevalence and clinical implications of germline predisposition gene mutations in patients with acute myeloid leukemia.

Borahm Kim, Woobin Yun, Seung-Tae Lee, Jong Rok Choi, Keon Hee Yoo, Hong Hoe Koo, Chul Won Jung, Sun Hee Kim.

Acute myeloid leukemia (AML) is one of the most common types of leukemia. With the recent advances in sequencing technology and the growing body of knowledge on the genetics of AML, there is increasing concern about cancer predisposing germline mutations as well as somatic mutations. As familial cases sharing germline mutations are constantly reported, germline predisposition gene mutations in patients with AML are gaining attention. We performed genomic sequencing of Korean patients diagnosed with AML to identify the prevalence and characteristics of germline predisposition mutations. Among 180 patients, germline predisposition mutations were identified in 13 patients (13/180, 7.2%, eight adults and five children). Germline mutations of BLM, BRCA1, BRCA2, CTC1, DDX41, ERCC4, ERCC6, FANCI, FANCM, PALB2, and SBDS were identified. Most of the mutations are in genes involved in DNA repair and genomic stability maintenance. Patients harboring germline mutations tended to have earlier onset of AML (p = 0.005), however, the presence of germline mutations did not showed significant association with other clinical characteristics or treatment outcome. Since each mutation was rare, further study with a larger number of cases would be needed to establish the effect of the mutations.

DOI: https://doi.org/10.1038/s41598-020-71386-z
Cancer. 2020 Aug 17.

What 20 years of research has taught us about the TP53 p.R337H mutation.

Emilia Modolo Pinto, Gerard P Zambetti.

  The p53 tumor suppressor transcriptionally regulates a myriad of genes involved in cell cycle control, DNA repair, cell survival, and cell metabolism and represents one of the most well-studied inhibitors of tumorigenesis. Since the discovery of TP53 in 1979, somatic mutations have been shown to be extremely common; more than 50% of human cancers carry loss-of-function mutations in TP53. Inherited or germline TP53 mutations are rare and are involved in complex hereditary cancer predisposition disorders, and affected family members can develop diverse tumor types and multiple primary cancers at young ages. In Brazil, a fascinating history of p53 and cancer predisposition began in the year 2000 with identification of the TP53 p.R337H mutation in close association with the development of adrenocortical tumors. In these past 20 years, much has been learned about the genetics and biochemistry of this mutation, which is widespread in Brazil because of a founder effect. This review highlights the contributions of TP53 p.R337H research over the last 20 years, the findings of which have sparked passionate debate among researchers worldwide, to understanding cancer predisposition in Brazilian individuals and families.

Keywords:   TP53 ; R337H; cancer predisposition; founder mutation; haplotype

DOI:  https://doi.org/10.1002/cncr.33143
Int J Cancer. 2020 Sep 01.

Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland.

Polish Hereditary Prostate Cancer Consortium

  In designing national strategies for genetic testing, it is important to define the full spectrum of pathogenic mutations in prostate cancer (PCa) susceptibility genes. To investigate the frequency of mutations in PCa susceptibility genes in Polish familial PCa cases, to estimate gene-related PCa risks and probability of aggressive disease, we analyzed the coding regions of 14 genes by exome sequencing in 390 men with familial prostate cancer and 308 cancer-free controls. We compared the mutation frequencies between PCa cases and controls. We also compared clinical characteristics of prostate cancers between mutation carriers and non-carriers. Of the 390 PCa cases, 76 men (19.5%) carried a mutation in BRCA1, BRCA2, NBN, ATM, CHEK2, HOXB13, MSH2 or MSH6 genes. No mutations were found in BRIP1, PTEN, TP53, MLH1, PMS2 and SPOP. Significant associations with familial PCa risk were observed for CHEK2, NBN, ATM, and HOXB13. High grade (Gleason 8-10) tumors were seen in 56% of BRCA2, NBN or ATM carriers, compared to 21% of patients who tested negative for mutations in these genes (OR = 4.7, 95%CI 2.0-10.7, P = 0.0003). In summary, approximately 20% of familial prostate cancer cases in Poland can be attributed to mutations in eight susceptibility genes. Carriers of mutations in BRCA2, NBN and ATM develop aggressive disease and may benefit from intensified screening and/or chemotherapy.

Keywords:  ATM; BRCA1; BRCA2; CHEK2; HOXB13; NBN; aggressive phenotype; hereditary; mutation; prostate cancer; sequencing

DOI:  https://doi.org/10.1002/ijc.33272
Breast Cancer. 2020 Sep 04.

Prevalence of germline TP53 variants among early-onset breast cancer patients from Polish population.

Emilia Rogoża-Janiszewska, Karolina Malińska, Bohdan Górski, Rodney J Scott, Cezary Cybulski, Wojciech Kluźniak, Marcin Lener, Anna Jakubowska, Jacek Gronwald, Tomasz Huzarski, Jan Lubiński, Tadeusz Dębniak.

   BACKGROUND: The objective of this study was to determine spectrum and prevalence of germline mutations in TP53 gene among Polish women with early-onset breast cancer (BC), which has not been determined until now.
METHODS: A cohort of 100 females with BC diagnosed ≤ 30 years of age and with a positive family history of cancer was used as a discovery cohort. 1880 women with BC ≤ 45 years old and a control group of 2000 healthy women were genotyped as a replication phase of this study.
RESULTS: Four heterozygous pathogenic missense mutations were detected in a group of 100 patients with early-onset breast cancer. On the basis of software prediction and available literature data, all these variants were defined as pathogenic. None of these TP53 variants were detected among 1880 breast cancer patients and 2000 healthy controls. No large mutations were found among early-onset cases using MLPA reaction.
CONCLUSION: Germline pathogenic TP53 variants were found in 4% early-onset Polish BC patients. No founder mutations were identified in Polish population. To improve the treatment and surveillance screening, the search for germline TP53 pathogenic variants is recommended for all female BC cases diagnosed ≤ 30 years old.

Keywords:  Cancer; Early-onset breast; Li-fraumeni; Mutation; TP53

DOI:  https://doi.org/10.1007/s12282-020-01151-7
J Cancer Res Clin Oncol. 2020 Sep 03.

Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario.

Jordan Lerner-Ellis, Chloe Mighton, Conxi Lazaro, Nicholas Watkins, Vanessa Di Gioacchino, Andrew Wong, Martin C Chang, George S Charames.

   PURPOSE: The aim of this study was to determine the diagnostic yield of multigene panel testing among patients referred with hereditary breast and ovarian cancer (HBOC).
METHODS: Patients who met provincial eligibility criteria were tested at the Advanced Molecular Diagnostic Laboratory at Mount Sinai Hospital, Toronto. Gene sequencing and exon-level copy number variant (CNV) analysis was performed. The referring physician had the opportunity to choose between several different gene panels based on patient phenotype. Cases were included in the analysis based on personal and family history of cancer and the type of panel ordered.
RESULTS: 3251 cases that received panel testing were included in this analysis. Overall, 9.1% (295) had a positive (pathogenic or likely pathogenic) result and 27.1% (882) had an inconclusive result (variant of uncertain significance). The genes with the highest prevalence of positive results were in BRCA2 (2.2%, 71/3235), BRCA1 (1.9%, 62/3235), and CHEK2 (1.4%, 40/2916). Of the positive cases, 9.8% (29) had a pathogenic or likely pathogenic variant in a gene associated with Lynch syndrome (MSH6, MSH2, MLH1, or PMS2).
CONCLUSIONS: Our overall positive yield is similar to that reported in the literature. The yield of inconclusive results was three times that of positive results. By testing more individuals in families with HBOC and through data-sharing efforts, the clinical significance of most variants may eventually be determined and panel testing for monogenic cancer predisposition syndromes will have greater utility.

Keywords:  Breast cancer; Genetic testing; Multigene panel testing; Next-generation sequencing; Ovarian cancer

DOI:  https://doi.org/10.1007/s00432-020-03377-6
J Community Genet. 2020 Sep 02.

Reproductive decision-making in the context of hereditary cancer: the effects of an online decision aid on informed decision-making.

Kelly Reumkens, Marly H E Tummers, Yil Severijns, Joyce J G Gietel-Habets, Sander M J van Kuijk, Cora M Aalfs, Christi J van Asperen, Margreet G E M Ausems, Margriet Collée, Charlotte J Dommering, Marleen Kets, Lizet E van der Kolk, Jan C Oosterwijk, Vivianne C G Tjan-Heijnen, Trudy van der Weijden, Christine E M de Die-Smulders, Liesbeth A D M van Osch.

  Individuals having a genetic predisposition to cancer and their partners face challenging decisions regarding their wish to have children. This study aimed to determine the effects of an online decision aid to support couples in making an informed decision regarding their reproductive options. A nationwide pretest-posttest study was conducted in the Netherlands among 131 participants between November 2016 and May 2018. Couples were eligible for participation if one partner had a pathogenic variant predisposing for an autosomal dominant hereditary cancer syndrome. Participants completed a questionnaire before use (T0), and at 3 months (T3) after use of the decision aid to assess the primary outcome measure informed decision-making, and the secondary outcome measures decisional conflict, knowledge, realistic expectations, level of deliberation, and decision self-efficacy. T0-T3 comparisons show an overall positive effect for all outcome measures (all ps < 0.05; knowledge (ES = - 1.05), decisional conflict (ES = 0.99), participants' decision self-efficacy (ES = -0.55), level of deliberation (ES = - 0.50), and realistic expectations (ES = - 0.44). Informed decision-making increased over time and 58.0% of the participants made an informed reproductive decision at T3. The online decision aid seems to be an appropriate tool to complement standard reproductive counseling to support our target group in making an informed reproductive decision. Use of the decision aid may lessen the negative psychological impact of decision-making on couples' daily life and wellbeing.

Keywords:  Decision aid; Hereditary cancer; Patient participation; Preimplantation genetic testing; Prenatal diagnosis

DOI:  https://doi.org/10.1007/s12687-020-00484-2
Mol Genet Genomic Med. 2020 Sep 04. e1208

First report of a Mexican family with mutation in the CDH1 gene.

Carmen Martínez Valenzuela, Edmundo Erbey Castelán-Maldonado, Octavio Carvajal-Zarrabal, Ana Laura Calderón-Garcidueñas.

   BACKGROUND: Germline mutations in E-cadherin (CDH1) gene are associated with autosomal-dominantly inherited cancer syndrome characterized by diffuse gastric cancer, lobular breast cancer, and in some families, cleft lip/palate. However, there may be generations in which these neoplasms do not occur at all in a family and later on, one or another carcinoma arises, which makes it difficult for physicians to think about hereditary origin.
METHODS: We report the first Mexican family with CDH1 mutation (variant c.377del).
RESULTS: An asymptomatic young woman underwent a search for mutations in susceptibility genes for breast cancer due to the history of this neoplasm in her mother and maternal aunt. A CDH1 mutation was detected. After an endoscopy, a diffuse gastric carcinoma was found. Later on, three generations of this family were studied. The findings are presented.
CONCLUSION: Medical communities should be aware of the contribution of this gene in the development of hereditary diffuse gastric carcinoma (HDGC) and breast cancer.

Keywords:  CDH1 gene; Mexican family; breast carcinoma; gastric carcinoma

DOI:  https://doi.org/10.1002/mgg3.1208
Int J Cancer. 2020 Sep 01.

Age-dependent performance of BRAF mutation testing in Lynch syndrome diagnostics.

German Consortium for Familial Intestinal Cancer

  BRAF V600E mutations have been reported as a marker of sporadic microsatellite-unstable (MSI) colorectal cancer (CRC). Current international diagnostic guidelines recommend BRAF mutation testing in MSI CRC patients to predict low risk of Lynch syndrome (LS). We evaluated the age-specific performance of BRAF testing in LS diagnostics. We systematically compared the prevalence of BRAF mutations in LS-associated CRCs and unselected MSI CRCs in different age groups as available from published studies, databases and population-based patient cohorts. Sensitivity/specificity analysis of BRAF testing for exclusion of LS and cost calculations were performed. Among 969 MSI CRCs from LS carriers in the literature and German HNPCC Consortium, 15 (1.6%) harbored BRAF mutations. 6/7 LS patients with BRAF-mutant CRC and reported age were < 50 years. Among 339/756 (44.8%) of BRAF mutations detected in unselected MSI CRC, only 2/339 (0.6%) BRAF mutations were detected in patients <50 years. The inclusion of BRAF testing led to high risk of missing LS patients and increased costs at age < 50 years. BRAF testing in patients <50 years carries a high risk of missing a hereditary cancer predisposition and is cost-inefficient. We suggest direct referral of MSI CRC patients <50 years to genetic counselling without BRAF testing. This article is protected by copyright. All rights reserved.

Keywords:  BRAF mutation testing; Lynch syndrome diagnostics; age; hereditary cancer syndrome; microsatellite-unstable colorectal cancer

DOI:  https://doi.org/10.1002/ijc.33273
Clin Lymphoma Myeloma Leuk. 2020 Sep;pii: S2152-2650(20)30451-1. [Epub ahead of print]20 Suppl 1 S27-S29

Hereditary Hematologic Malignancies.

Courtney DiNardo.



Keywords:  Inherited; cancer syndrome; germline; hereditary; predisposition

DOI:  https://doi.org/10.1016/S2152-2650(20)30451-1
Breast Cancer. 2020 Aug 29.

Hereditary breast and ovarian cancer (HBOC): review of its molecular characteristics, screening, treatment, and prognosis.

Reiko Yoshida.

  Breast cancer is a common cancer affecting a large number of patients. Notably, 5-10% of all breast cancer patients are genetically predisposed to cancers. Although the most common breast cancer susceptibility genes are BRCA1 and BRCA2, which are also associated with the risk of developing ovarian and pancreatic cancer, advances in next-generation sequencing (NGS) analysis technology enabled the discovery of several non-BRCA genes responsible for breast and ovarian cancers. Studies on hereditary breast and ovarian cancer (HBOC) involve not only determining the predisposition to developing cancer, but also considering the current treatment for breast cancer, prevention of next cancer, risk diagnosis, and adoption of protective measures for relatives. We present a comprehensive review of HBOC, which will be a useful resource in the clinical setting. Many hereditary tumors, including HBOC, are syndromes characterized by the development of different types of cancer in succession. Taking advantage of knowing predisposition of susceptibility to cancer, it is important to continue and update cancer management protocols, which includes the adoption of preventive measures, countermeasures, and treatments, to accurately assess and prevent the impact of cancer on the quality of life of the next generation of patients.

Keywords:  BRCA; BRCA1/2 mutations; HBOC; Hereditary breast and ovarian cancer

DOI:  https://doi.org/10.1007/s12282-020-01148-2
J Med Case Rep. 2020 Aug 31. 14(1): 136

A deep analysis using panel-based next-generation sequencing in an Ecuadorian pediatric patient with anaplastic astrocytoma: a case report.

Jennyfer M García-Cárdenas, Ana Karina Zambrano, Patricia Guevara-Ramírez, Santiago Guerrero, Gabriel Runruil, Andrés López-Cortés, Jorge P Torres-Yaguana, Isaac Armendáriz-Castillo, Andy Pérez-Villa, Verónica Yumiceba, Paola E Leone, César Paz-Y-Miño.

   BACKGROUND: Anaplastic astrocytoma is a rare disorder in children from 10 to 14 years of age, with an estimated 0.38 new cases per 100,000 people per year worldwide. Panel-based next-generation sequencing opens new possibilities for diagnosis and therapy of rare diseases such as this one. Because it has never been genetically studied in the Ecuadorian population, we chose to genetically characterize an Ecuadorian pediatric patient with anaplastic astrocytoma for the first time. Doing so allows us to provide new insights into anaplastic astrocytoma diagnosis and treatment.
CASE PRESENTATION: Our patient was a 13-year-old Mestizo girl with an extensive family history of cancer who was diagnosed with anaplastic astrocytoma. According to ClinVar, SIFT, and PolyPhen, the patient harbored 354 genomic alterations in 100 genes. These variants were mostly implicated in deoxyribonucleic acid (DNA) repair. The top five most altered genes were FANCD2, NF1, FANCA, FANCI, and WRN. Even though TP53 presented only five mutations, the rs11540652 single-nucleotide polymorphism classified as pathogenic was found in the patient and her relatives; interestingly, several reports have related it to Li-Fraumeni syndrome. Furthermore, in silico analysis using the Open Targets Platform revealed two clinical trials for pediatric anaplastic astrocytoma (studying cabozantinib, ribociclib, and everolimus) and 118 drugs that target the patient's variants, but the studies were not designed specifically to treat pediatric anaplastic astrocytoma.
CONCLUSIONS: Next-generation sequencing allows genomic characterization of rare diseases; for instance, this study unraveled a pathogenic single-nucleotide polymorphism related to Li-Fraumeni syndrome and identified possible new drugs that specifically target the patient's variants. Molecular tools should be implemented in routine clinical practice for early detection and effective preemptive intervention delivery and treatment.

Keywords:  High-grade gliomas; Li-Fraumeni syndrome; Pediatric anaplastic astrocytoma; TP53

DOI:  https://doi.org/10.1186/s13256-020-02451-4
Int J Hematol. 2020 Aug 31.

Donor-derived myelodysplastic syndrome after allogeneic stem cell transplantation in a family with germline GATA2 mutation.

Naoki Sakata, Munehiro Okano, Ryujin Masako, Ai Tanaka, Yuhei Yamashita, Takahiro Karasuno, Ken-Ichi Imadome, Mitsuru Okada, Keisuke Sugimoto.

  Germline GATA2 heterozygous mutations were identified as complex immunodeficiency and hematological syndromes characterized by cytopenia (monocytes, B-cells, NK-cells), susceptibility to mycobacterium, fungus, or Epstein-Barr virus (EBV) infection, and myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) development. Herein, we report a patient with AML who had a fatal infection after allogeneic hematopoietic stem cell transplantation (HSCT) due to impaired immune reconstitution associated with GATA2 mutation. A 15-year-old man was diagnosed with AML with monosomy 7. His family history was negative for immunodeficiency and hematological disorders. He attained complete remission after HSCT from an HLA-identical sister. Post-HSCT examinations performed 15 months later revealed pancytopenia, especially monocytopenia and the absence of B and NK cells, resulting in the occurrence of donor-type MDS. Twenty-one months after HSCT, he developed central nervous system aspergillosis and finally died of the disease. Two months later (24 months after PBSCT), the donor was diagnosed with persistent EBV infection accompanied by MDS with multilineage dysplasia. Genetic analysis of GATA2 revealed a novel heterozygous mutation (c.1023_1026dupCGCC) in both siblings. GATA2 mutations were highly prevalent among adolescent MDS/AML patients with monosomy 7. Therefore, the screening of GATA2 mutations in relatives is necessary when performing HSCT from a relative donor.

Keywords:  Allogeneic hematopoietic stem cell transplantation; Family donor; Germline GATA2 mutation; Poor outcome

DOI:  https://doi.org/10.1007/s12185-020-02980-0
Clin Lymphoma Myeloma Leuk. 2020 Sep;pii: S2152-2650(20)30465-1. [Epub ahead of print]20 Suppl 1 S65-S66

The Problem of TP53-Mutant MDS/AML.

David A Sallman.



Keywords:  APR-246; PDL1; azacitidine; magrolimab; minimal residual disease

DOI:  https://doi.org/10.1016/S2152-2650(20)30465-1