bims-lifras 2020-08-30 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2020–08–30
nine papers selected by
Joanna Zawacka-Pankau, University of Warsaw

Germline DNMT3A mutation in familial acute myeloid leukaemia.
Report of a germline double heterozygote in MSH2 and PALB2.
Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2.
Prevalence and molecular characteristics of DNA mismatch repair deficient endometrial cancer in a Japanese hospital-based population.
Germline biallelic MCM8 variants are associated with early-onset Lynch-like syndrome.
Tumor Testing for Somatic and Germline BRCA1/BRCA2 Variants in Ovarian Cancer Patients in the Context of Strong Founder Effects.
Genetic Counseling for Hereditary Gastric and Pancreatic Cancer in High-Risk Gastrointestinal Cancer Clinics: An Effective Strategy.
DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives.
Pathogenic germline variants in patients with features of hereditary renal cell carcinoma: evidence for further locus heterogeneity.

Epigenetics. 2020 Aug 28. 1-10

Germline DNMT3A mutation in familial acute myeloid leukaemia.

Courtney D DiNardo, Hannah C Beird, Marcos Estecio, Swanand Hardikar, Koichi Takahashi, Sarah A Bannon, Gautam Borthakur, Elias Jabbour, Curtis Gumbs, Joseph D Khoury, Mark Routbort, Ting Gong, Kimie Kondo, Hagop Kantarjian, Guillermo Garcia-Manero, Taiping Chen, P Andrew Futreal.

  Acute myeloid leukaemia (AML) is a heterogeneous myeloid malignancy characterized by recurrent clonal events, including mutations in epigenetically relevant genes such as DNMT3A, ASXL1, IDH1/2, and TET2. Next-generation sequencing analysis of a mother and son pair who both developed adult-onset diploid AML identified a novel germline missense mutation DNMT3A p.P709S. The p.P709S protein-altering variant resides in the highly conserved catalytic DNMT3A methyltransferase domain. Functional studies demonstrate that the p.P709S variant confers dominant negative effects when interacting with wildtype DNMT3A. LINE-1 pyrosequencing and reduced representation bisulphite sequencing (RBBS) analysis demonstrated global DNA hypomethylation in germline samples, not present in the leukaemic samples. Somatic acquisition of IDH2 p.R172K mutations, in concert with additional acquired clonal DNMT3A events in both patients at the time of AML diagnosis, confirms the important pathogenic interaction of epigenetically active genes, and implies a strong selection and regulation of methylation in leukaemogenesis. Improved characterization of germline mutations may enable us to better predict malignant clonal evolution, improving our ability to provide customized treatment or future preventative strategies.

Keywords:  AML; DNMT3A; germline; hereditary; predisposition

DOI:  https://doi.org/10.1080/15592294.2020.1809871
Mol Genet Genomic Med. 2020 Aug 27. e1242

Report of a germline double heterozygote in MSH2 and PALB2.

Konstantinos Agiannitopoulos, Eirini Papadopoulou, Georgios N Tsaousis, Georgia Pepe, Stavroula Kampouri, Eleni Patsea, George Lypas, George Nasioulas.

   BACKGROUND: Carriers with pathogenic variants in MSH2 have increased risk to develop colorectal, endometrium, ovarian, and other types of cancer. The PALB2 is associated with breast, ovarian, pancreatic, and prostate cancer. We describe the case of a 42-year-old female diagnosed with endometrial cancer at the age of 42 years with a strong family history of colorectal cancer, which was referred to our private diagnostic laboratory for genetic testing.
METHODS: In this study, we performed next-generation sequencing (NGS) using an amplicon based 26 genes panel. The presence of multi-exonic copy number variations (CNVs) was investigated by computational analysis and Multiplex Ligation-dependent Probe Amplification (MLPA).
RESULTS: A gross deletion of the genomic region encompassing exons 11-16 of the MSH2 and the loss-of-function variant c.757_758delCT, p.(Leu253Ilefs*3) in the PALB2 were identified in the proband.
CONCLUSIONS: Multigene analysis using NGS technology allows the identification of pathogenic variants in genes that would normally not be tested based on the patient diagnosis. In our case these results explained not only the personal and/or family history of cancer but also allowed the surveillance for prevention of other cancer types. Moreover, the detection of large genomic rearrangements should be routinely included in hereditary cancer testing.

Keywords:   MSH2 ; PALB2 ; NGS; endometrial cancer; pathogenic variant

DOI:  https://doi.org/10.1002/mgg3.1242
Cancers (Basel). 2020 Aug 25. pii: E2415. [Epub ahead of print]12(9):

Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2.

Daniele Fanale, Lorena Incorvaia, Clarissa Filorizzo, Marco Bono, Alessia Fiorino, Valentina Calò, Chiara Brando, Lidia Rita Corsini, Nadia Barraco, Giuseppe Badalamenti, Antonio Russo, Viviana Bazan.

  Patients with unilateral breast cancer (UBC) have an increased risk of developing bilateral breast cancer (BBC). The annual risk of contralateral BC is about 0.5%, but increases by up to 3% in BRCA1 or BRCA2 pathogenic variant (PV) carriers. Our study was aimed to evaluate whether all BBC patients should be offered multi-gene panel testing, regardless their cancer family history and age at diagnosis. We retrospectively collected all clinical information of 139 BBC patients genetically tested for germline PVs in different cancer susceptibility genes by NGS-based multi-gene panel testing. Our investigation revealed that 52 (37.4%) out of 139 BBC patients harbored germline PVs in high- and intermediate-penetrance breast cancer (BC) susceptibility genes including BRCA1, BRCA2, PTEN, PALB2, CHEK2, ATM, RAD51C. Nineteen out of 53 positively tested patients harbored a PV in a known BC susceptibility gene (no-BRCA). Interestingly, in the absence of an analysis performed via multi-gene panel, a significant proportion (14.4%) of PVs would have been lost. Therefore, offering a NGS-based multi-gene panel testing to all BBC patients may significantly increase the detection rates of germline PVs in other cancer susceptibility genes beyond BRCA1/2, avoiding underestimation of the number of individuals affected by a hereditary tumor syndrome.

Keywords:  ATM; BRCA1; BRCA2; CHECK2; PALB2; PTEN; bilateral breast cancer; breast cancer; germline pathogenic variants; multi-gene panel testing

DOI:  https://doi.org/10.3390/cancers12092415
Jpn J Clin Oncol. 2020 Aug 26. pii: hyaa142. [Epub ahead of print]

Prevalence and molecular characteristics of DNA mismatch repair deficient endometrial cancer in a Japanese hospital-based population.

Azusa Yamamoto, Tatsuro Yamaguchi, Okihide Suzuki, Tetsuya Ito, Noriyasu Chika, Nao Kamae, Jun-Ichi Tamaru, Tomonori Nagai, Hiroyuki Seki, Tomio Arai, Tetsuhiko Tachikawa, Kiwamu Akagi, Hidetaka Eguchi, Yasushi Okazaki, Hideyuki Ishida.

   BACKGROUND: The prevalence and molecular characteristics of defective DNA mismatch repair endometrial cancers in the Japanese population have been underexplored. Data supporting clinical management of patients with Lynch-like syndrome and germline variant of uncertain significance of mismatch repair genes are still lacking.
METHODS: Immunohistochemistry of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary endometrial cancers in 395 women with a median age of 59 years. Genetic and/or epigenetic alterations of the mismatch repair genes were also investigated.
RESULTS: Loss of expression of one or more mismatch repair proteins was observed in 68 patients (17.2%). A total of 17 out of 68 patients (25%, 4.3% of all cases) were identified as candidates for genetic testing for Lynch syndrome after excluding 51 patients with MLH1 hypermethylated cancer. Fourteen of these 17 patients subjected to genetic testing were found to have Lynch syndrome (n = 5), germline variant of uncertain significance (n = 2) or Lynch-like syndrome (n = 7). Compared with patients with Lynch syndrome, those with germline variant of uncertain significance and Lynch-like syndrome tended to demonstrate an older age at the time of endometrial cancer diagnosis (P = 0.07), less fulfillment of the revised Bethesda guidelines (P = 0.09) and lower prevalence of Lynch syndrome-associated tumors in their first-degree relatives (P = 0.01).
CONCLUSIONS: This study provides useful information for management in patients with DNA mismatch repair endometrial cancer. Specifically, cancer surveillance as recommended in patients with Lynch syndrome might not be necessary in patients with germline variant of uncertain significance and Lynch-like syndrome and their relatives.

Keywords:  Lynch syndrome; Lynch-like syndrome; colorectal cancer; defective MMR; endometrial cancer

DOI:  https://doi.org/10.1093/jjco/hyaa142
JCI Insight. 2020 Aug 25. pii: 140698. [Epub ahead of print]

Germline biallelic MCM8 variants are associated with early-onset Lynch-like syndrome.

Mariano Golubicki, Laia Bonjoch, José G Acuña-Ochoa, Marcos Díaz-Gay, Jenifer Muñoz, Miriam Cuatrecasas, Teresa Ocaña, Soledad Iseas, Guillermo Mendez, Daniel Cisterna, Stephanie A Schubert, Maartje Nielsen, Tom van Wezel, Yael Goldberg, Eli Pikarsky, Juan Robbio, Enrique Roca, Antoni Castells, Francesc Balaguer, Marina Antelo, Sergi Castellví-Bel.

  Lynch syndrome is the most common colorectal cancer (CRC) hereditary form and it is characterized by DNA mismatch repair (MMR) deficiency. The term Lynch-like syndrome (LLS) is used for patients with MMR-deficient tumors and neither germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM, nor MLH1 somatic methylation. Biallelic somatic inactivation or cryptic germline MMR variants undetected during genetic testing have been proposed to be involved. Sixteen patients with early-onset LLS CRC were selected for germline and tumor whole-exome sequencing. Two potentially pathogenic germline MCM8 variants were detected in a LLS male patient with fertility problems. A knockout cellular model for MCM8 was generated by CRISPR-Cas9 and detected genetic variants were produced by mutagenesis. DNA damage, microsatellite instability and mutational signatures were monitored. DNA damage was evident for MCM8KO cells and the analyzed genetic variants. Microsatellite instability and mutational signatures in MCM8KO cells were compatible with the involvement of MCM8 in MMR. Replication in an independent familial cancer cohort detected additional carriers. Unexplained MMR-deficient CRC cases, even showing somatic biallelic MMR inactivation, may be caused by underlying germline defects in genes different than the MMR genes. We suggest MCM8 as a new gene involved in CRC germline predisposition with a recessive pattern of inheritance.

Keywords:  Colorectal cancer; DNA repair; Gastroenterology; Genetic diseases; Genetics

DOI:  https://doi.org/10.1172/jci.insight.140698
Front Oncol. 2020 ;10 1318

Tumor Testing for Somatic and Germline BRCA1/BRCA2 Variants in Ovarian Cancer Patients in the Context of Strong Founder Effects.

Ana Peixoto, Pedro Pinto, Joana Guerra, Manuela Pinheiro, Catarina Santos, Carla Pinto, Rui Santos, Carla Escudeiro, Carla Bartosch, Rita Canário, Ana Barbosa, Alfredo Gouveia, Almerinda Petiz, Miguel Henriques Abreu, Susana Sousa, Deolinda Pereira, João Silva, Manuel R Teixeira.

  Deleterious variants in the BRCA1/BRCA2 genes and homologous recombination deficiency (HRD) status are considered strong predictors of response to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). The introduction of PARPi in clinical practice for the treatment of patients with advanced ovarian cancer imposed changes in the molecular diagnosis of BRCA1/BRCA2 variants. BRCA1/BRCA2 tumor testing by next-generation sequencing (NGS) can detect simultaneously both somatic and germline variants, allowing the identification of more patients with higher likelihood of benefiting from PARPi. Our main goal was to determine the frequency of somatic and germline BRCA1/BRCA2 variants in a series of non-mucinous OC, and to define the best strategy to be implemented in a routine diagnostic setting for the screening of germline/somatic variants in these genes, including the BRCA2 c.156_157insAlu Portuguese founder variant. We observed a frequency of 19.3% of deleterious variants, 13.3% germline, and 5.9% somatic. A higher prevalence of pathogenic variants was observed in patients diagnosed with high-grade serous ovarian cancer (23.2%). Considering the frequencies of the c.3331_3334del and the c.2037delinsCC BRCA1 variants observed in this study (73% of all BRCA1 pathogenic germline variants identified) and the limitations of NGS to detect the BRCA2 c.156_157insAlu variant, it might be cost-effective to test for these founder variants with a specific test prior to tumor screening of the entire coding regions of BRCA1 and BRCA2 by NGS in patients of Portuguese ancestry.

Keywords:  BRCA1/BRCA2; NGS; PARPi; founder variants; ovarian cancer; tumor testing

DOI:  https://doi.org/10.3389/fonc.2020.01318
Cancers (Basel). 2020 Aug 23. pii: E2386. [Epub ahead of print]12(9):

Genetic Counseling for Hereditary Gastric and Pancreatic Cancer in High-Risk Gastrointestinal Cancer Clinics: An Effective Strategy.

Joan Llach, Lorena Moreno, Ariadna Sánchez, Cristina Herrera-Pariente, Teresa Ocaña, Miriam Cuatrecasas, Liseth Rivero-Sánchez, Rebeca Moreira, Mireia Díaz, Gerhard Jung, Maria Pellisé, Antoni Castells, Francesc Balaguer, Sabela Carballal, Leticia Moreira.

  The identification of high-risk groups of gastric (GC) and pancreatic adenocarcinoma (PC) due to a hereditary basis could imply a benefit in the affected families by establishing personalized preventive strategies. We aimed at assessing the diagnostic yield of GC/PC hereditary syndromes in individuals evaluated based on specific clinical criteria. In total, 77 unrelated individuals (45 from GC group/32 from PC group) were recruited: 51 (66.2%) cancer diagnosis ≤60 years, 3 (4%) with personal history of GC/PC and other cancer and 23 (29.8%) due to family history. Immunohistochemical analysis of DNA mismatch repair proteins was performed in 38 (49.3%) available tumors, being pathological in one (2%) GC. A genetic analysis was performed if clinical criteria of hereditary syndrome were fulfilled, identifying a mutation in 10/22 (45.5%) families [7/16 (43.7%) with GC and 3/6 (50%) with PC] and 19 (24.7%) fulfilled criteria of familial cancer. Diagnosis of cancer <40 years and personal history of other cancers were independent risk factors of a hereditary syndrome [OR:11.3 (95%IC 1.9-67); p = 0.007 and OR:17.4 (95% IC 2.5-119.9); p = 0.004; respectively]. The selection of patients based on clinical criteria leads to high diagnostic yield, detecting a causative germline mutation in almost half of the cases; therefore, both meticulous genetic counseling and use of multi-gen panels is crucial.

Keywords:  familial cancer; gastric cancer; genetic counselling; hereditary cancer; pancreatic cancer

DOI:  https://doi.org/10.3390/cancers12092386
Gut. 2020 Aug 27. pii: gutjnl-2019-319984. [Epub ahead of print]

DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives.

Lukas Perkhofer, Johann Gout, Elodie Roger, Fernando Kude de Almeida, Carolina Baptista Simões, Lisa Wiesmüller, Thomas Seufferlein, Alexander Kleger.

  Complex rearrangement patterns and mitotic errors are hallmarks of most pancreatic ductal adenocarcinomas (PDAC), a disease with dismal prognosis despite some therapeutic advances in recent years. DNA double-strand breaks (DSB) bear the greatest risk of provoking genomic instability, and DNA damage repair (DDR) pathways are crucial in preserving genomic integrity following a plethora of damage types. Two major repair pathways dominate DSB repair for safeguarding the genome integrity: non-homologous end joining and homologous recombination (HR). Defective HR, but also alterations in other DDR pathways, such as BRCA1, BRCA2, ATM and PALB2, occur frequently in both inherited and sporadic PDAC. Personalised treatment of pancreatic cancer is still in its infancy and predictive biomarkers are lacking. DDR deficiency might render a PDAC vulnerable to a potential new therapeutic intervention that increases the DNA damage load beyond a tolerable threshold, as for example, induced by poly (ADP-ribose) polymerase inhibitors. The Pancreas Cancer Olaparib Ongoing (POLO) trial, in which olaparib as a maintenance treatment improved progression-free survival compared with placebo after platinum-based induction chemotherapy in patients with PDAC and germline BRCA1/2 mutations, raised great hopes of a substantially improved outcome for this patient subgroup. This review summarises the relationship between DDR and PDAC, the prevalence and characteristics of DNA repair mutations and options for the clinical management of patients with PDAC and DNA repair deficiency.

Keywords:  DNA damage; chemotherapy; pancreatic cancer

DOI:  https://doi.org/10.1136/gutjnl-2019-319984
Genes Chromosomes Cancer. 2020 Aug 23.

Pathogenic germline variants in patients with features of hereditary renal cell carcinoma: evidence for further locus heterogeneity.

Philip S Smith, Hannah West, James Whitworth, Bruce Castle, Francis H Sansbury, Anne Y Warren, Emma R Woodward, Marc Tischkowitz, Eamonn R Maher.

Inherited renal cell carcinoma(RCC) is associated with multiple familial cancer syndromes but most individuals with features of non-syndromic inherited RCC do not harbour variants in the most commonly tested renal cancer predisposition genes (CPGs). We investigated whether undiagnosed cases might harbour mutations in CPGs that are not routinely tested for by testing 118 individuals with features suggestive of inherited RCC (family history of RCC, two or more primary RCC aged <60 years, or early onset RCC≤46 years) for the presence of pathogenic variants in a large panel of CPGs. All individuals had been pre-screened for pathogenic variants in the major RCC genes. We detected pathogenic or likely pathogenic (P/LP) variants of potential clinical relevance in 16.1% (19/118) of individuals, including P/LP variants in BRIP1 (N=4), CHEK2 (n=3), MITF (n=1) and BRCA1 (n=1). Though the power to detect rare variants was limited by sample size the frequency of truncating variants in BRIP1, 4/118, was significantly higher than in controls (P=5.92E-03). These findings suggest that the application of genetic testing for larger inherited cancer gene panels in patients with indicators of a potential inherited RCC can increase the diagnostic yield for P/LP variants. However, the clinical utility of such a diagnostic strategy requires validation and further evaluation and in particular confirmation of rarer RCC genotype-phenotype associations is required. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/gcc.22893