bims-lifras 2019-10-13 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2019–10–13
nine papers selected by
Joanna Zawacka-Pankau

TP53 mutations and relevance of expression of TP53 pathway genes in paediatric acute myeloid leukaemia.
Diseases Predisposing to Adrenocortical Malignancy (Li-Fraumeni Syndrome, Beckwith-Wiedemann Syndrome, and Carney Complex).
Genetic Screening and Personalized Prevention in Colorectal Cancer.
Identification of c.1531C>T Pathogenic Variant in the CDH1 Gene as a Novel Germline Mutation of Hereditary Diffuse Gastric Cancer.
Genetic Testing in Kidney Cancer Patients: Who, When, and How?
Prophylactic Surgery and Extended Oncologic Radicality in Gastric and Colorectal Hereditary Cancer Syndromes.
The predicted impact and cost-effectiveness of systematic testing of people with incident colorectal cancer for Lynch syndrome.
Enrichment of Heterozygous Germline RECQL4 Loss-of-Function Variants in Pediatric Osteosarcoma.
The missing heritability of familial colorectal cancer.

Br J Haematol. 2019 Oct 06.

TP53 mutations and relevance of expression of TP53 pathway genes in paediatric acute myeloid leukaemia.

David G J Cucchi, Costa Bachas, Kim Klein, Sander Huttenhuis, Christian M Zwaan, Gert J Ossenkoppele, Jeroen M W M Janssen, Gertjan L Kaspers, Jacqueline Cloos.

  Limited data are available on the incidence and impact of TP53 alterations and TP53 pathway deregulation in paediatric acute myeloid leukaemia (AML). We analysed TP53 alterations in bone marrow samples of 229 patients with de novo paediatric AML, and detected heterozygous missense exon mutations in two patients (1%) and 17p deletions of the TP53 gene in four patients (2%). These patients more frequently had complex karyotype (50% vs. 4%, P = 0·002) or adverse cytogenetic abnormalities, including complex karyotype (67% vs. 17%, P = 0·013), compared to TP53 wild-type. Differential expression of TP53 pathway genes was associated with poor survival, indicating a role for TP53 regulators and effector genes.

Keywords:   RRM2B ; TP53 ; acute myeloid leukaemia

DOI:  https://doi.org/10.1111/bjh.16229
Exp Suppl. 2019 ;111 149-169

Diseases Predisposing to Adrenocortical Malignancy (Li-Fraumeni Syndrome, Beckwith-Wiedemann Syndrome, and Carney Complex).

Anne Jouinot, Jérôme Bertherat.

  Adrenocortical malignancies can occur in the context of several tumor predisposition syndromes.The Carney complex (CNC) is responsible for the majority of primary pigmented nodular adrenal diseases and is more rarely associated with adrenocortical carcinoma (ACC). Other core manifestations of CNC include cardiac and cutaneous myxomas, lentiginosis, somatotroph pituitary adenomas, Sertoli tumors, melanocytic schwannoma, and thyroid, breast, and bone tumors. CNC is mostly due to germline inactivating mutations of PRKAR1A.The majority of childhood ACC are related to genetic predisposition. The Beckwith-Wiedemann syndrome (BWS) is an overgrowth and tumor predisposition syndrome due to genetic or epigenetic alterations at the 11p15 locus. Classical tumor spectrum of BWS includes embryonal tumors and childhood ACC. The Li-Fraumeni syndrome (LFS) is a devastating tumor predisposition syndrome, due to germline inactivating mutations of TP53, and characterized by a high, various, and early-onset cancer risk. LFS spectrum includes premenopausal breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumor, and ACC, accounting for 50-80% of pediatric cases. Finally, germline predisposition affects up to 10% of adult ACC patients, mostly in part of LFS and Lynch syndrome.This chapter focuses on the diagnosis, screening, and management of adrenal tumors in part of these tumor predisposition syndromes.

Keywords:  Beckwith–Wiedemann syndrome; Carney complex; Li–Fraumeni syndrome; adrenocortical carcinoma; primary micronodular adrenal hyperplasia

DOI:  https://doi.org/10.1007/978-3-030-25905-1_9
Visc Med. 2019 Aug;35(4): 226-230

Genetic Screening and Personalized Prevention in Colorectal Cancer.

Verena Steinke-Lange, Elke Holinski-Feder.

  Cancer per se is a genetic disease, either originating in germline mutations in cancer genes or in somatic mutations only present in the cancer cells. Therefore, personalized risk prediction, prevention, and treatment for cancer can be based on the results of genetic testing either in the germline or in the tumor. Surveillance regimens need to be based on appropriate risk assessment, which includes germline monogenic genetic testing - where appropriate - and in the future polygenic risk - possibly - for the general population. Treatment regimens should also include germline testing at least for cases suspicious of hereditary tumor diseases, followed by the analysis of somatic mutations within the tumor cell genome, raising a possible target for personalized therapy. Appropriate risk assessment is the key for suitable and, most importantly, individualized surveillance strategies especially in hereditary tumor syndromes. This concerns not only the patient but also the family members at risk. An overview about the different fields and aspects of genetic testing in colorectal cancer and its impact on personalized prevention will be given below.

Keywords:  Colorectal cancer; Genetic testing; Hereditary tumor syndromes

DOI:  https://doi.org/10.1159/000501941
Int J Mol Sci. 2019 Oct 09. pii: E4980. [Epub ahead of print]20(20):

Identification of c.1531C>T Pathogenic Variant in the CDH1 Gene as a Novel Germline Mutation of Hereditary Diffuse Gastric Cancer.

Enrique Norero, M Alejandra Alarcon, Christopher Hakkaart, Tomas de Mayo, Cecilia Mellado, Marcelo Garrido, Gloria Aguayo, Marcela Lagos, Javiera Torres, Alfonso Calvo, Parry Guilford, Alejandro H Corvalan.

  Germline pathogenic variants in the CDH1 gene are a well-established cause of hereditary diffuse gastric cancer (HDGC) syndrome. The aim of this study was to characterize CDH1 mutations associated with HDGC from Chile, a country with one of the highest incidence and mortality rates in the world for gastric cancer (GC). Here, we prospectively include probands with family history/early onset of diffuse-type of GC. The whole coding sequence of the CDH1 gene was sequenced from genomic DNA in all patients, and a multidisciplinary team managed each family member with a pathogenic sequence variant. Thirty-six cases were included (median age 44 years/male 50%). Twenty-seven (75%) patients had diffuse-type GC at ≤50 years of age and 19 (53%) had first or second-degree family members with a history of HDGC. Two cases (5.5%) carried a non-synonymous germline sequence variant in the CDH1 gene: (a) The c.88C>A missense variant was found in a family with three diffuse-type GC cases; and (b) c.1531C>T a nonsense pathogenic variant was identified in a 22-year-old proband with no previous family history of HDGC. Of note, six family members carry the same nonsense pathogenic variant. Prophylactic gastrectomy in the proband's sister revealed stage I signet-ring cell carcinoma. The finding of 1531C>T pathogenic variant in the CDH1 in proband with no previous family history of HDGC warrants further study to uncover familial clustering of disease in CDH1 negative patients. This finding may be particularly relevant in high incidence countries, such as the case in this report.

Keywords:  CDH1; HDGC; prophylactic gastrectomy

DOI:  https://doi.org/10.3390/ijms20204980
Eur Urol Focus. 2019 Oct 05. pii: S2405-4569(19)30281-0. [Epub ahead of print]

Genetic Testing in Kidney Cancer Patients: Who, When, and How?

Sandy T Lui, Brian Shuch.

  There are more than a dozen recognized hereditary forms of kidney cancer. While classic syndromic forms are readily recognizable, more recently described conditions are subtler because of lower penetrance. Adequate counseling and implementation of risk assessment before or after management are important aspects of clinical care. Germline testing to assess hereditary risk has rapidly evolved thanks to multigene panel testing, which can be performed quickly and at relatively low cost. This review discusses what is known about germline risk assessment, namely which individuals should be tested and when and how, and covers many of the uncertainties around this process. PATIENT SUMMARY: More than a dozen genes have been linked to predisposition to kidney cancer. We review genetic testing in terms of who should be tested and when and how the testing should be carried out. Results from genetic tests can help in tailoring screening and surgical management and in selecting the most suitable chemotherapy.

Keywords:  Gene; Germline; Hereditary; Kidney cancer; Predisposition; Renal cell carcinoma

DOI:  https://doi.org/10.1016/j.euf.2019.09.005
Visc Med. 2019 Aug;35(4): 231-239

Prophylactic Surgery and Extended Oncologic Radicality in Gastric and Colorectal Hereditary Cancer Syndromes.

Holger Eduard Vogelsang.

  Prophylactic surgery for high-penetrance hereditary gastric and colorectal cancer can be a primary prophylaxis of cancer and a secondary oncologic prevention. As early cancer is often detected in the resected organ, there has been no prophylaxis of cancer but cancer treatment. Extended oncological radicality with removal of the complete organ is a tertiary prevention as metachronous cancer is avoided. The indication for prophylactic surgery or extended oncological radicality is presented regarding hereditary and familial gastric and colorectal cancer. Hereditary diffuse type gastric cancer (E-cadherin mutation) and familial adenomatous polyposis coli (APC or MYH mutation) are well-accepted indications for prophylactic surgery with a variety of considerations regarding phenotype, genotype, associated diseases, age, timing, extent, and technique of surgery. Not so much prophylactic surgery as extended oncologic radicality can be considered in familial gastric and colorectal cancer as well as Lynch or hereditary nonpolyposis colorectal cancer syndrome (HNPCC). Clinical, molecular, and technical progress leads to less invasive and risk-adapted surgical and nonsurgical interventions, expanding the variety of individualized treatment options.

Keywords:  Colorectal cancer; Gastric cancer; Hereditary; Prophylactic surgery

DOI:  https://doi.org/10.1159/000501919
Med J Aust. 2019 Oct 08.

The predicted impact and cost-effectiveness of systematic testing of people with incident colorectal cancer for Lynch syndrome.

Yoon-Jung Kang, James Killen, Michael Caruana, Kate Simms, Natalie Taylor, Ian M Frayling, Tristan Snowsill, Nicola Huxley, Veerle Mh Coupe, Suzanne Hughes, Victoria Freeman, Alex Boussioutas, Alison H Trainer, Robyn L Ward, Gillian Mitchell, Finlay A Macrae, Karen Canfell.

   OBJECTIVES: To evaluate the health impact and cost-effectiveness of systematic testing for Lynch syndrome (LS) in people with incident colorectal cancer (CRC) in Australia.
DESIGN, SETTING, PARTICIPANTS: We investigated the impact of LS testing strategies in a micro-simulation model (Policy1-Lynch), explicitly modelling the cost of testing all patients diagnosed with incident CRC during 2017, with detailed modelling of outcomes for patients identified as LS carriers (probands) and their at-risk relatives throughout their lifetimes. For people with confirmed LS, we modelled ongoing colonoscopic surveillance.
MAIN OUTCOME MEASURES: Cost-effectiveness of six universal tumour testing strategies (testing for DNA mismatch repair deficiencies) and of universal germline gene panel testing of patients with incident CRC; impact on cost-effectiveness of restricting testing by age at CRC diagnosis (all ages, under 50/60/70 years) and of colonoscopic surveillance interval (one, two years).
RESULTS: The cost-effectiveness ratio of universal tumour testing strategies (annual colonoscopic surveillance, no testing age limit) compared with no testing ranged from $28 915 to $31 904/life-year saved (LYS) (indicative willingness-to-pay threshold: $30 000-$50 000/LYS). These strategies could avert 184-189 CRC deaths with an additional 30 597-31 084 colonoscopies over the lifetimes of 1000 patients with incident CRC with LS and 1420 confirmed LS carrier relatives (164-166 additional colonoscopies/death averted). The most cost-effective strategy was immunohistochemistry and BRAF V600E testing (incremental cost-effectiveness ratio [ICER], $28 915/LYS). Universal germline gene panel testing was not cost-effective compared with universal tumour testing strategies (ICER, $2.4 million/LYS). Immunohistochemistry and BRAF V600E testing was cost-effective at all age limits when paired with 2-yearly colonoscopic surveillance (ICER, $11 525-$32 153/LYS), and required 4778-15 860 additional colonoscopies to avert 46-181 CRC deaths (88-103 additional colonoscopies/death averted).
CONCLUSIONS: Universal tumour testing strategies for guiding germline genetic testing of people with incident CRC for LS in Australia are likely to be cost-effective compared with no testing. Universal germline gene panel testing would not currently be cost-effective.

Keywords:  Cancer; Colonoscopy; Cost-benefit analysis; Digestive system neoplasms; Early detection of cancer; Genetic testing; Health policy; Neoplasms, epidemiology; Preventive health services; Public health

DOI:  https://doi.org/10.5694/mja2.50356
Cold Spring Harb Mol Case Stud. 2019 Oct 11. pii: mcs.a004218. [Epub ahead of print]

Enrichment of Heterozygous Germline RECQL4 Loss-of-Function Variants in Pediatric Osteosarcoma.

Jamie L Maciaszek, Ninad Oak, Wenan Chen, Kayla V Hamilton, Rose B McGee, Regina Nuccio, Roya Mostafavi, Stacy Hines-Dowell, Lynn Harrison, Leslie Taylor, Elsie L Gerhardt, Annastasia Ouma, Michael N Edmonson, Aman Patel, Joy Nakitandwe, Alberto S Pappo, Elizabeth M Azzato, Sheila A Shurtleff, David W Ellison, James R Downing, Melissa M Hudson, Leslie L Robison, Victor Santana, Scott Newman, Jinghui Zhang, Zhaoming Wang, Gang Wu, Kim E Nichols, Chimene A Kesserwan.

  Patients harboring germline pathogenic bi-allelic variants in genes involved in the recognition and repair of DNA damage are known to have a substantially increased cancer risk. Emerging evidence suggests that individuals harboring heterozygous variants in these same genes may also be at heightened, albeit lesser, risk for cancer. Herein, we sought to determine whether heterozygous variants in RECQL4, the gene encoding an essential DNA helicase that is defective in children with the autosomal recessive cancer predisposing condition Rothmund-Thomson syndrome (RTS), are associated with increased risk for childhood cancer. To address this question, we interrogated germline sequence data from 4,435 pediatric cancer patients at St. Jude Children's Research Hospital and 1,127 from the National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database and identified 24 (0.43%) who harbored loss-of-function (LOF) RECQL4 variants, including five of 249 (2.0%) with osteosarcoma (OS). These RECQL4 variants were significantly over-represented in children with OS, the cancer most frequently observed in patients with RTS, as compared to 134,187 non-cancer controls in the Genome Aggregation Database (gnomAD v2.1; P = 0.00087, odds ratio [OR] = 7.1, 95% CI, 2.9-17). Nine of the 24 (38%) individuals possessed the same c.1573delT (p.Cys525Alafs) variant located in the highly conserved DNA helicase domain, suggesting that disruption of this domain is central to oncogenesis. Altogether these data expand our understanding of the genetic factors predisposing to childhood cancer and reveal a novel association between heterozygous RECQL4 LOF variants and development of pediatric OS.

Keywords:  Craniopharyngioma; Hodgkin lymphoma; Osteosarcoma; Pre-B-cell acute lymphoblastic leukemia; T-cell acute lymphoblastic leukemias

DOI:  https://doi.org/10.1101/mcs.a004218
Mutagenesis. 2019 Oct 12. pii: gez027. [Epub ahead of print]

The missing heritability of familial colorectal cancer.

Stephanie A Schubert, Hans Morreau, Noel F C C de Miranda, Tom van Wezel.

Pinpointing heritability factors is fundamental for the prevention and early detection of cancer. Up to one-quarter of colorectal cancers (CRCs) occur in the context of familial aggregation of this disease, suggesting a strong genetic component. Currently, only less than half of the heritability of CRC can be attributed to hereditary syndromes or common risk loci. Part of the missing heritability of this disease may be explained by the inheritance of elusive high-risk variants, polygenic inheritance, somatic mosaicism, as well as shared environmental factors, among others. A great deal of the missing heritability in CRC is expected to be addressed in the coming years with the increased application of cutting-edge next-generation sequencing technologies, routine multigene panel testing and tumour-focussed germline predisposition screening approaches. On the other hand, it will be important to define the contribution of environmental factors to familial aggregation of CRC incidence. This review provides an overview of the known genetic causes of familial CRC and aims at providing clues that explain the missing heritability of this disease.

DOI: https://doi.org/10.1093/mutage/gez027