bims-lifras 2020-07-05 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2020–07–05
twelve papers selected by
Joanna Zawacka-Pankau, University of Warsaw

Hereditary vs Familial Pancreatic Cancer: Associated Genetic Syndromes and Clinical Perspective.
Characteristics and Clinical Outcomes of Individuals at High Risk for Pancreatic Cancer: A Descriptive Analysis from a Comprehensive Cancer Center.
The role of PARP inhibitors in germline BRCA-associated pancreatic ductal adenocarcinoma.
Tumoural soft tissue calcification in Down syndrome: association with heterozygous germline SAMD9 mutation and hyperactive type I interferon signaling.
Germline Mutations in DNA Repair Genes in Patients With Metastatic Castration-resistant Prostate Cancer.
Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
Inherited Thrombocytopenia Caused by Germline ANKRD26 Mutation Should Be Considered in Young Patients With Suspected Myelodysplastic Syndrome.
Two independent families with strongly suspected hereditary diffuse gastric cancer based on the probands' endoscopic findings.
Digenic inheritance of MSH6 and MUTYH variants in familial colorectal cancer.
Field Study of the Possible Effect of Parental Irradiation on the Germline of Children Born to Cleanup Workers and Evacuees of the Chornobyl Accident.
Expression of a germline variant in the N-terminal domain of the human DNA glycosylase NTHL1 induces cellular transformation without impairing enzymatic function or substrate specificity.
Germinal defects of SDHx genes in patients with isolated pituitary adenoma.

Oncology (Williston Park). 2020 Jun 10. 34(6): 196-201

Hereditary vs Familial Pancreatic Cancer: Associated Genetic Syndromes and Clinical Perspective.

Mehmet Sitki Copur, Geoffrey A Talmon, Whitney Wedel, Jonathan D Hart, Shaheed Merani, Luciano M Vargasi.

Pancreatic ductal adenocarcinoma (PDAC) is a disease marked by high rates of mortality; it is mostly incurable at the time of diagnosis. Only about 7% of patients survive 5 years after diagnosis. Diagnosis at a late stage and rapid progression with minimal response to available treatments are the main reasons for this poor outcome. It is crucial to identify individuals at high risk of developing PDAC so preventive and early detection measures can be employed. Approximately 10% to 15% of PDAC cases have a hereditary or familial basis. In the majority of PDAC cases, no main causative gene has been identified, but several known germline pathogenic mutations have been shown to be related to an increased risk of this cancer. The presence of 2 or more patients with pancreatic cancer within the circle of first-degree relatives, without the presence of a causative germline mutation, is defined as familial pancreatic cancer; this accounts for 4% to 10% of PDAC. Based on the growing evidence supporting the benefit of germline genetic testing in patients with PDAC, both the American Society of Clinical Oncology and the National Comprehensive Cancer Network recently updated their guidelines to include recommendations around genetic testing for patients with pancreatic cancer. However, there is no general consensus on the group of patients and individuals who should be studied and screened. We present a demonstrative case and review the available data on hereditary and familial PDAC.
Gastrointest Disord (Basel). 2019 Mar;1(1): 106-119

Characteristics and Clinical Outcomes of Individuals at High Risk for Pancreatic Cancer: A Descriptive Analysis from a Comprehensive Cancer Center.

Griffin P J McNamara, Karla N Ali, Shraddha Vyas, Tri Huynh, Monica Nyland, Deanna Almanza, Christine Laronga, Jason Klapman, Jennifer B Permuth.

  Pancreatic cancer (PC), a leading cause of cancer-related deaths in the United States, is typically diagnosed at an advanced stage. To improve survival, there is an unmet need to detect pre-malignant lesions and early invasive disease. Prime populations to study for early detection efforts include cohorts of high risk individuals (HRI): those with increased risk to develop pre-malignant pancreatic cysts and PC because of a familial or hereditary predisposition to the disease and those in the general population of sporadic cases who are incidentally found to harbor a pre-malignant pancreatic cyst. The objective of this study was to describe the characteristics and clinical outcomes of cohorts of HRI identified at Moffitt Cancer Center. We set out to determine the uptake of screening, the prevalence and characteristics of solid and cystic pancreatic lesions detected via screening or as incidental findings, and the age at which lesions were detected. Of a total of 329 HRI, roughly one-third were found to have pancreatic lesions, most of which constituted pre-malignant cysts known as intraductal papillary mucinous neoplasms. Individuals with the highest genetic risk for PC were found to have smaller cysts at a much earlier age than sporadic cases with incidental findings; however, many individuals at high genetic risk did not have abdominal imaging reports on file. We also identified a subset of HRI at moderate genetic risk for PC that were found to have cystic and solid pancreatic lesions as part of a diagnostic work-up rather than a screening protocol. These findings suggest the pancreatic research community should consider expanding criteria for who should be offered screening. We also emphasize the importance of continuity of care between cancer genetics and gastrointestinal oncology clinics so that HRI are made aware of the opportunities related to genetic counseling, genetic testing, and screening.

Keywords:  familial pancreatic cancer; intraductal papillary mucinous neoplasm; mucinous cystic neoplasm; mutation carriers; pancreatic cancer; pancreatic intraepithelial neoplasm

DOI:  https://doi.org/10.3390/gidisord1010008
Clin Adv Hematol Oncol. 2020 Mar;18(3): 168-179

The role of PARP inhibitors in germline BRCA-associated pancreatic ductal adenocarcinoma.

Gordon T Moffat, Eileen M O'Reilly.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that remains a challenge to treat. In pursuit of personalized medicine, researchers continue active exploration of the genetic and molecular framework of PDAC to apply novel therapeutics and enhance outcomes. In patients who have PDAC, germline mutations-such as those in the BRCA1/2 and PALB2 genes-are predominantly associated with the DNA damage response and repair pathway. On the basis of studies completed in patients with BRCA-mutated advanced breast and ovarian cancer, the poly(ADP-ribose) polymerase (PARP) inhibitors have been evaluated for safety, tolerability, and efficacy in patients with advanced PDAC who are carrying germline BRCA gene mutations. Results have demonstrated meaningful activity and identified BRCA as a predictive and targetable biomarker in PDAC, and have also identified the role of olaparib as a maintenance therapy in PDAC. On the basis of the principle of synthetic lethality, and to avert resistance to PARP inhibitors, clinical trials of combination therapy with PARP inhibitors and platinum-based chemotherapy have been conducted with an early signal. As we continue to explore the role of PARP inhibitors in the management of PDAC, recent clinical trials are studying the effectiveness of PARP inhibitors in combination with immunotherapy, targeted inhibitors, and angiogenesis inhibitors. The next steps are to understand the role of PARP inhibitors beyond germline BRCA in other homologous recombination repair gene mutations and in other subgroups of patients with PDAC.
Rheumatology (Oxford). 2020 Jun 28. pii: keaa301. [Epub ahead of print]

Tumoural soft tissue calcification in Down syndrome: association with heterozygous germline SAMD9 mutation and hyperactive type I interferon signaling.

Nikolaus Deigendesch, Julia R Hirsiger, Marc B Bigler, Adhideb Ghosh, Dorothee Harder, Annaïse Jauch, Joaquin M Espinosa, Mike Recher, Alexander Navarini, Thomas Daikeler, Christoph T Berger.

DOI: https://doi.org/10.1093/rheumatology/keaa301
In Vivo. 2020 Jul-Aug;34(4):34(4): 1773-1778

Germline Mutations in DNA Repair Genes in Patients With Metastatic Castration-resistant Prostate Cancer.

Klaudia Holeckova, Katarina Baluchova, Mark Hives, Ludovit Musak, Jan Kliment, Maria Skerenova.

   BACKGROUND/AIM: The aim of this study was to analyse the genetic profiles of metastatic castration-resistant prostate cancer (mCRPC) by using next generation sequencing to identify variants with pathogenic potential in nine DNA repair genes - BRCA1, BRCA2, RAD50, RAD51, RAD51C/D, ATM and ATR.
MATERIALS AND METHODS: Isolated genomic DNA from peripheral blood of 50 patients with mCRPC was used for the sequencing of 111 genes associated with hereditary cancer on an Illumina platform. Identified variants were tested in Integrative Genomic Viewer, their clinical significance confirmed in databases and their potential impact on protein function predicted by in silico tools.
RESULTS: From nine analysed DNA repair genes, we identified 14 relevant variants; three pathogenic variants - BRCA2 (rs80359306), RAD50 (rs786201531) and ATM (rs1555099760), and eleven other variants with pathogenic potential.
CONCLUSION: The pathogenic variants identified in this study are located in evolutionarily conserved regions of proteins and are highly likely to affect DNA repair efficiency.

Keywords:  DNA repair genes; Prostate cancer; germline mutations; next generation sequencing

DOI:  https://doi.org/10.21873/invivo.11971
JAMA Oncol. 2020 Jul 02.

Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

and the CIMBA Group

Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population.
Objective: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers.
Design, Setting, and Participants: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected.
Main Outcomes and Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview.
Results: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier.
Conclusions and Relevance: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.

DOI: https://doi.org/10.1001/jamaoncol.2020.2134
J Investig Med High Impact Case Rep. 2020 Jan-Dec;8:8 2324709620938941

Inherited Thrombocytopenia Caused by Germline ANKRD26 Mutation Should Be Considered in Young Patients With Suspected Myelodysplastic Syndrome.

Tariq Kewan, Ryan Noss, Lucy A Godley, Heesun J Rogers, Hetty E Carraway.

  Thrombocytopenia 2 (THC2) is an autosomal dominant disorder characterized by ankyrin repeat domain 26 mutation and moderate thrombocytopenia. THC2 exposes patients to a low risk of bleeding and an increased likelihood of myelodysplastic syndrome/acute myeloid leukemia. Germline evaluation for a genetic disorder should be considered when a patient presents with isolated thrombocytopenia and associated dysmegakaryopoiesis. In this case report, we present a male patient who presented with isolated thrombocytopenia but was ultimately confirmed to have an inherited THC2 thrombocytopenia/myelodysplastic syndrome. Given the rarity of the disease, no clear guidelines on how to follow THC2 patients over the long term have been established. We recommend a monthly complete blood count and clinical visits every 3 months at a minimum.

Keywords:  ANKRD26; acute leukemia; germline mutations; myelodysplastic syndrome; thrombocytopenia 2

DOI:  https://doi.org/10.1177/2324709620938941
Clin J Gastroenterol. 2020 Jun 27.

Two independent families with strongly suspected hereditary diffuse gastric cancer based on the probands' endoscopic findings.

Moriya Iwaizumi, Hidetaka Yamada, Misaki Fukue, Yasuhiko Maruyama, Ayano Sonoda, Mitsushige Sugimoto, Kenji Koda, Ryoji Kushima, Masato Maekawa, Haruhiko Sugimura.

  Hereditary diffuse gastric cancer (HDGC) is the most famous of hereditary gastric cancer syndromes with an autosomal dominant inheritance pattern, and its diagnosis can be made by identifying a pathogenic germline variant in CDH1. We report two independent families that were strongly suspected of having HDGC based on endoscopic findings (multiple tiny, pale areas) obtained in the probands; the probands were pathologically diagnosed as having signet ring cell carcinoma (SRCC) and were genetically confirmed to have a pathogenic CDH1 germline variant. Although the updated International Gastric Cancer Linkage Consortium (IGCLC)'s clinical guidelines for HDGC (2015) state that screening/surveillance endoscopy should be performed (Cambridge protocol), the endoscopic findings obtained in the two presently reported families suggest that pale areas should be suspected as indicating the presence of SRCCs, and biopsies should be performed in addition to obtaining a precise family history in cases suspected of having HDGC.

Keywords:  CDH1; Endoscopic findings; Gastric cancer; HDGC; Hereditary diffuse gastric cancer

DOI:  https://doi.org/10.1007/s12328-020-01163-y
Genes Chromosomes Cancer. 2020 Jul 02.

Digenic inheritance of MSH6 and MUTYH variants in familial colorectal cancer.

Stephanie A Schubert, Dina Ruano, Yvonne Tiersma, Mark Drost, Niels de Wind, Maartje Nielsen, Liselotte P van Hest, Hans Morreau, Noel F C C de Miranda, Tom van Wezel.

  We describe a family severely affected by colorectal cancer (CRC) where whole-exome sequencing identified the coinheritance of the germline variants encoding MSH6 p.Thr1100Met and MUTYH p.Tyr179Cys in, at least, three CRC patients diagnosed before 60 years of age. Digenic inheritance of monoallelic MSH6 variants of uncertain significance and MUTYH variants has been suggested to predispose to Lynch syndrome-associated cancers, however cosegregation with disease in the familial setting has not yet been established. The identification of individuals carrying multiple potential cancer risk variants is expected to rise with the increased application of whole-genome sequencing and large multigene panel testing in clinical genetic counseling of familial cancer patients. Here we demonstrate the coinheritance of monoallelic variants in MSH6 and MUTYH consistent with cosegregation with CRC, further supporting a role for digenic inheritance in cancer predisposition. This article is protected by copyright. All rights reserved.

Keywords:  Lynch syndrome; MSH6; MUTYH; digenic inheritance; familial colorectal cancer; whole-exome sequencing

DOI:  https://doi.org/10.1002/gcc.22883
Am J Epidemiol. 2020 Jul 02. pii: kwaa095. [Epub ahead of print]

Field Study of the Possible Effect of Parental Irradiation on the Germline of Children Born to Cleanup Workers and Evacuees of the Chornobyl Accident.

Dimitry Bazyka, Maureen Hatch, Natalia Gudzenko, Elizabeth K Cahoon, Vladimir Drozdovitch, Mark P Little, Vadim Chumak, Elena Bakhanova, David Belyi, Victor Kryuchkov, Ivan Golovanov, Kiyohiko Mabuchi, Iryna Illienko, Yuri Belayev, Clara Bodelon, Mitchell J Machiela, Amy Hutchinson, Meredith Yeager, Amy Berrington Gonzalez, Stephen J Chanock.

  Although transgenerational effects of ionizing radiation exposure have long been a concern, human research to date has been confined to studies of disease phenotype in groups exposed to high dose and high dose rates, such as the Japanese atomic bomb survivors. Transgenerational effects of parental irradiation can be addressed using powerful new genomic technologies. In collaboration with the National Research Center for Radiation Medicine (NRCRM) Ukraine, the US National Cancer Institute, in 2014-2018, conducted a genomic alterations study among children born in selected regions in Ukraine post Chornobyl accident to cleanup workers and/or evacuees exposed to low dose rate radiation. To investigate whether parental exposure is associated with germline mutations and genomic alterations in the offspring, we are collecting biospecimens from father-mother-offspring to study de novo mutations, minisatellite mutations, copy number changes, structural variants, genomic insertions and deletions, methylation profiles and telomere length. Genomic alterations are examined in relation to parental gonadal dose reconstructed using questionnaire and measurement data. Subjects are being recruited in exposure categories that will allow examining parental origin, duration and timing of exposure in relation to conception. Here we describe the study methodology, results of recruitment and provide descriptive information on the first 150 families (mother-father-child(ren).

Keywords:  Chornobyl (Chernobyl); Ukraine; genetic risk; germline mutations; low dose rate radiation; parent-offspring constellations; preconception exposure

DOI:  https://doi.org/10.1093/aje/kwaa095
Oncotarget. 2020 Jun 16. 11(24): 2262-2272

Expression of a germline variant in the N-terminal domain of the human DNA glycosylase NTHL1 induces cellular transformation without impairing enzymatic function or substrate specificity.

Carolyn G Marsden, Pawel Jaruga, Erdem Coskun, Robyn L Maher, David S Pederson, Miral Dizdaroglu, Joann B Sweasy.

  Oxidatively-induced DNA damage, widely accepted as a key player in the onset of cancer, is predominantly repaired by base excision repair (BER). BER is initiated by DNA glycosylases, which locate and remove damaged bases from DNA. NTHL1 is a bifunctional DNA glycosylase in mammalian cells that predominantly removes oxidized pyrimidines. In this study, we investigated a germline variant in the N-terminal domain of NTHL1, R33K. Expression of NTHL1 R33K in human MCF10A cells resulted in increased proliferation and anchorage-independent growth compared to NTHL1 WT-expressing cells. However, wt-NTHL1 and R33K-NTHL1 exhibited similar substrate specificity, excision kinetics, and enzyme turnover in vitro and in vivo. The results of this study indicate an important function of R33 in BER that is disrupted by the R33K mutation. Furthermore, the cellular transformation induced by R33K-NTHL1 expression suggests that humans harboring this germline variant may be at increased risk for cancer incidence.

Keywords:  NTHL1; base excision repair; cellular transformation; germline variant

DOI:  https://doi.org/10.18632/oncotarget.27548
Eur J Endocrinol. 2020 Jul 01. pii: EJE-20-0054.R2. [Epub ahead of print]

Germinal defects of SDHx genes in patients with isolated pituitary adenoma.

Grégory Mougel, Arnaud Lagarde, Frederique Albarel, Wassim Essamet, Perrine Luigi, Céline Mouly, Magaly Vialon, Thomas Cuny, Frédéric Castinetti, Alexandru Saveanu, Thierry Brue, Anne Barlier, Pauline Romanet.

INTRODUCTION: TThe '3PAs' syndrome, associating pituitary adenoma (PA) and pheochromocytoma/paraganglioma (PPGL), is sometimes associated with mutations in PPGL-predisposing genes such as SDHx or MAX. In '3PAs' syndrome, PAs can occur before PPGL, suggesting a new gateway into SDHx/MAX-related diseases.
OBJECTIVE: To determine the SDHx/MAX mutation prevalence in patients with isolated PAs and characterize PAs of patients with SDHx/MAX mutations.
DESIGN: Genes involved in PAs (AIP/MEN1/CDKN1B) or PPGLs (SDHx/MAX) were sequenced in patients with isolated PAs. We then conducted a review of cases of PA in the setting of '3PAs' syndrome.
RESULTS: 263 patients were recruited. Seven (likely) pathogenic variants were found in AIP, 2 in MEN1, 2 in SDHA, and 1 in SDHC. The prevalence of SDHx mutations reached 1.1% (3/263). Of 31 reported patients with PAs harbouring SDHx/MAX mutations (28 published cases and 3 cases reported here), 6/31 (19%) developed PA before PPGL, and 8/31 (26%) had isolated PA. The age of onset was later than in patients with AIP/MEN1 mutations. PAs were mainly macroprolactinomas and showed intracytoplasmic vacuoles seen on histopathology.
CONCLUSIONS: We discovered SDHx mutations in patients bearing PA who had no familial or personal history of PPGL. However, the question of incidental association remains unresolved and data to determine the benefit of SDHx/MAX screening in these patients is lacking. We recommend that patients with isolated PA should be carefully examined for a family history of PPGLs. A family history of PPGL, as well as the presence of intracytoplasmic vacuoles in PA, requires SDHx/MAX genetic testing of patients.

DOI: https://doi.org/10.1530/EJE-20-0054