bims-lifras 2021-11-28 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021‒11‒28
eleven papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

Quantification of Discordant Variant Interpretations in a Large Family-Based Study of Li-Fraumeni Syndrome.
Universal Germline Testing of Unselected Cancer Patients Detects Pathogenic Variants Missed by Standard Guidelines without Increasing Healthcare Costs.
Germline Testing Data Validate Inferences of Mutational Status for Variants Detected From Tumor-Only Sequencing.
Identification and Characterization of New Alu Element Insertion in the BRCA1 Exon 14 Associated with Hereditary Breast and Ovarian Cancer.
Adrenocortical Tumors in Children With Constitutive Chromosome 11p15 Paternal Uniparental Disomy: Implications for Diagnosis and Treatment.
Brain Cancers in Genetic Syndromes.
Variants of uncertain significance (VUS) in cancer predisposing genes: What are we learning from multigene panels?
RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant.
Monoallelic deleterious MUTYH germline variants as a driver for tumorigenesis.
Rare germline variants in the AXIN2 gene in families with colonic polyposis and colorectal cancer.
Pathogenic BRCA2 germline variants in combined hepatocellular-cholangiocarcinoma.

JCO Precis Oncol. 2021 ;pii: PO.21.00320. [Epub ahead of print]5

Quantification of Discordant Variant Interpretations in a Large Family-Based Study of Li-Fraumeni Syndrome.

Megan N Frone, Douglas R Stewart, Sharon A Savage, Payal P Khincha.

PURPOSE: The use of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines has improved germline variant classification concordance, but discrepancies persist, sometimes directly affecting medical management. We evaluated variant discordance between and within families with germline TP53 variants in the National Cancer Institute's Li-Fraumeni syndrome longitudinal cohort study.MATERIALS AND METHODS: Germline TP53 genetic testing results were obtained from 421 individuals in 140 families. A discordant test result was defined as a report of pathogenicity that differed between two clinical testing laboratories, between a testing laboratory and the ClinVar database, or between either the laboratory or ClinVar database and variant classification by internal study review.
RESULTS: There were 141 variants in 140 families (one family had two different TP53 variants). Fifty-four families had discordant interpretations (54 of 140, 39%). Sixteen families had discordant classifications leading to clinically important differences in medical management (16 of 140, 11%). Interfamilial discordance was observed between four families (two different variants). Intrafamilial discordance was observed within six families. One family experienced both intrafamilial and interfamilial discordance.
CONCLUSION: This large single-gene study found discordant germline TP53 variant interpretations in 39% of families studied; 11% had a variant with the potential to significantly affect medical management. This finding is especially concerning in patients with Li-Fraumeni syndrome because of their exceedingly high risks of multiple cancers and intensive cancer screening and risk-reducing recommendations. Centralized data sharing, gene-specific variant curation guidelines, and provider education for consistent variant interpretation are essential for optimal patient care.

DOI: https://doi.org/10.1200/PO.21.00320
Cancers (Basel). 2021 Nov 10. pii: 5612. [Epub ahead of print]13(22):

Universal Germline Testing of Unselected Cancer Patients Detects Pathogenic Variants Missed by Standard Guidelines without Increasing Healthcare Costs.

Adrienne T Perkins, Derrick Haslem, Jessica Goldsberry, Katherine Shortt, Laura Sittig, Sharanya Raghunath, Christopher Giauque, Shawnee Snow, Gail Fulde, Bryce Moulton, David Jones, Lincoln Nadauld.

  PURPOSE: To accurately ascertain the frequency of pathogenic germline variants (PGVs) in a pan-cancer patient population with universal genetic testing and to assess the economic impact of receiving genetic testing on healthcare costs.METHODS: In this prospective study, germline genetic testing using a 105-gene panel was administered to an unselected pan-cancer patient population irrespective of eligibility by current guidelines. Financial records of subjects were analyzed to assess the effect of PGV detection on cost of care one year from the date of testing.
RESULTS: A total of 284 patients participated in this study, of which 44 patients (15%) tested positive for a PGV in 14 different cancer types. Of the patients with PGVs, 23 patients (52%) were ineligible for testing by current guidelines. Identification of a PGV did not increase cost of care.
CONCLUSION: Implementation of universal genetic testing for cancer patients in the clinic, beyond that specified by current guidelines, is necessary to accurately assess and treat hereditary cancer syndromes and does not increase healthcare costs.

Keywords:  germline testing; healthcare costs; hereditary cancer; pathogenic germline variants; precision oncology

DOI:  https://doi.org/10.3390/cancers13225612
JCO Precis Oncol. 2021 ;pii: PO.21.00279. [Epub ahead of print]5

Germline Testing Data Validate Inferences of Mutational Status for Variants Detected From Tumor-Only Sequencing.

Nahed Jalloul, Israel Gomy, Samantha Stokes, Alexander Gusev, Bruce E Johnson, Neal I Lindeman, Laura Macconaill, Shridar Ganesan, Judy E Garber, Hossein Khiabanian.

Pathogenic germline variants (PGVs) in cancer susceptibility genes are usually identified through germline testing of DNA from blood or saliva: their detection can affect treatment options and potential risk-reduction strategies for patient relatives. PGV can also be identified in tumor sequencing assays, which, when performed without patient-matched normal specimens, render determination of variants' germline or somatic origin critical.METHODS: Tumor-only sequencing data from 1,608 patients were retrospectively analyzed to infer germline versus somatic status of variants using an information-theoretic, gene-independent approach. Loss of heterozygosity was also determined. Predicted mutational models were compared with clinical germline testing results. Statistical measures were computed to evaluate performance.
RESULTS: Tumor-only sequencing detected 3,988 variants across 70 cancer susceptibility genes for which germline testing data were available. We imputed germline versus somatic status for > 75% of all detected variants, with a sensitivity of 65%, specificity of 88%, and overall accuracy of 86% for pathogenic variants. False omission rate was 3%, signifying minimal error in misclassifying true PGV. A higher portion of PGV in known hereditary tumor suppressors were found to be retained with loss of heterozygosity in the tumor specimens (72%) compared with variants of uncertain significance (58%).
CONCLUSION: Analyzing tumor-only data in the context of specimens' tumor cell content allows precise, systematic exclusion of somatic variants and suggests a balance between type 1 and 2 errors for identification of patients with candidate PGV for standard germline testing. Although technical or systematic errors in measuring variant allele frequency could result in incorrect inference, misestimation of specimen purity could result in inferring somatic variants as germline in somatically mutated tumor suppressor genes. A user-friendly bioinformatics application facilitates objective analysis of tumor-only data in clinical settings.

DOI: https://doi.org/10.1200/PO.21.00279
Genes (Basel). 2021 Oct 29. pii: 1736. [Epub ahead of print]12(11):

Identification and Characterization of New Alu Element Insertion in the BRCA1 Exon 14 Associated with Hereditary Breast and Ovarian Cancer.

Ahmed Bouras, Melanie Leone, Valerie Bonadona, Marine Lebrun, Alain Calender, Nadia Boutry-Kryza.

  Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant cancer predisposition syndrome characterized by an increased risk of breast and ovarian cancers. Germline pathogenic variants in BRCA1 are found in about 7-10% of all familial breast cancers and 10% of ovarian cancers. Alu elements are the most abundant mobile DNA element in the human genome and are known to affect the human genome by different mechanisms leading to human disease. We report here the detection, by next-generation sequencing (NGS) analysis coupled with a suitable bioinformatics pipeline, of an AluYb8 element in exon 14 of the BRCA1 gene in a family with HBOC history first classified as BRCA-negative by Sanger sequencing and first NGS analysis. The c.4475_c.4476insAluYb8 mutation impacts splicing and induces the skipping of exon 14. As a result, the produced mRNA contains a premature stop, leading to the production of a short and likely non-functional protein (pAla1453Glyfs*10). Overall, our study allowed us to identify a novel pathogenic variant in BRCA1 and showed the importance of bioinformatics tool improvement and versioning.

Keywords:  AluYb8; BRCA1; hereditary breast and ovarian cancer; next-generation sequencing; retrotransposon

DOI:  https://doi.org/10.3390/genes12111736
Front Endocrinol (Lausanne). 2021 ;12 756523

Adrenocortical Tumors in Children With Constitutive Chromosome 11p15 Paternal Uniparental Disomy: Implications for Diagnosis and Treatment.

Emilia Modolo Pinto, Carlos Rodriguez-Galindo, Catherine G Lam, Robert E Ruiz, Gerard P Zambetti, Raul C Ribeiro.

  Pediatric adrenocortical tumors (ACTs) are rare and heterogeneous. Approximately 50% of children with ACT carry a germline TP53 variant; however, the genetic underpinning of remaining cases has not been elucidated. In patients having germline TP53 variants, loss of maternal chromosome 11 and duplication of the paternal copy [paternal uniparental disomy, (UPD)] occurs early in tumorigenesis and explains the overexpression of IGF2, the hallmark of pediatric ACT. Beckwith-Wiedemann syndrome (BWS) is also associated with overexpression of IGF2 due to disruption of the 11p15 loci, including segmental UPD. Here, we report six children with ACT with wild type TP53 and germline paternal 11p15 UPD. Median age of five girls and one boy was 3.2 years (range 0.5-11 years). Two patients met the criteria for BWS before diagnosis of ACT. However, ACT was the first and only manifestation of paternal 11p15 UPD in four children. Tumor weight ranged from 21.5 g to 550 g. Despite poor prognostic features at presentation, such as pulmonary metastasis, bilateral adrenal involvement, and large tumors, all patients are alive 8-21 years after cancer diagnosis. Our observations suggest that children with ACT and wild type TP53, irrespective of their age, should be screened for germline abnormalities in chromosome 11p15.

Keywords:  Beckwith-Wiedemann syndrome; TP53; UPD; adrenocortical cancer; chromosome 11p15; hemihypertrophia

DOI:  https://doi.org/10.3389/fendo.2021.756523
Curr Neurol Neurosci Rep. 2021 Nov 22. 21(11): 64

Brain Cancers in Genetic Syndromes.

Edina Komlodi-Pasztor, Jaishri O Blakeley.

  PURPOSE OF REVIEW: Although genetic conditions that cause primary central nervous system tumors are rare, their pathophysiology influences both treatment and surveillance. This article reviews the most frequently occurring genetic conditions associated with brain cancers and highlights the most recent therapeutic approaches in the treatment of Lynch syndrome (and other disorders of the mismatch repair system), neurofibromatosis 1, and Li-Fraumeni syndrome.RECENT FINDINGS: Recent advances in molecular diagnostics have considerably improved the ability to diagnose genetic conditions in people with primary brain tumors. The common application of next-generation sequencing analyses of tissue increases the frequency with which clinicians are forced to address the possibility of an underlying genetic condition based on tissue molecular findings. Clinicians must be aware of the clinical presentation of genetic conditions predisposing to brain tumors in order to discern which patients are appropriate for germline genetic testing. Advances in therapeutics for specific genetic variants are increasingly available, and accurately diagnosing an underlying genetic condition may directly impact patient outcomes.

Keywords:  Brain cancer; Genetic syndromes; Li–Fraumeni syndrome; Lynch syndrome; Mismatch repair system; Neurofibromatosis 1

DOI:  https://doi.org/10.1007/s11910-021-01149-4
Eur J Med Genet. 2021 Nov 20. pii: S1769-7212(21)00266-4. [Epub ahead of print] 104400

Variants of uncertain significance (VUS) in cancer predisposing genes: What are we learning from multigene panels?

Emanuela Lucci-Cordisco, Simona Amenta, Arianna Panfili, Jesús Del Valle, Gabriel Capellá, Marta Pineda, Maurizio Genuardi.

  One of the main factors influencing the clinical utility of genetic tests for cancer predisposition is the ability to provide actionable classifications (ie pathogenic or benign). However, a large fraction of the variants identified in cancer predisposing genes (CPGs) are of uncertain significance (VUS), and cannot be used for clinical purposes either to identify individuals at risk or to drive treatment. Here we analyze the current status of VUS identification in a subset of 24 CPGs included by the American College of Medical Genetics/Association for Molecular Pathology in the list of genes that should be considered for the return of incidental findings. To this purpose we retrieved published literature using different search strings according to the frequency of the condition and we extracted corresponding data from ClinVar. The total number of VUS has not decreased with time, due to widespread multigene panel testing, and the relative yield of VUS compared to pathogenic variants is higher in more recent studies, which tend to involve series not selected for the presence of specific high risk criteria. In addition, only few studies adopt gene specific interpretation criteria when these are available. Despite the large yield of VUS associated with multigene testing, the data obtained from such studies can be very useful for variant classification, especially for those variants that are more likely to be benign, since these are expected to be detected more frequently in a population that does not show gene specific manifestations. In addition, wider use of gene specific interpretation criteria should be promoted in order to optimize the interpretation process.

Keywords:  Clinical utility; Genetic testing; Hereditary cancer; Variant interpretation

DOI:  https://doi.org/10.1016/j.ejmg.2021.104400
Sci Rep. 2021 Nov 25. 11(1): 22948

RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant.

Paula Rofes, Marta Pineda, Lídia Feliubadaló, Mireia Menéndez, Rafael de Cid, Carolina Gómez, Eva Montes, Gabriel Capellá, Joan Brunet, Jesús Del Valle, Conxi Lázaro.

Case-control studies have shown an association of BARD1 with hereditary breast and/or ovarian cancer (HBOC) predisposition. BARD1 alternatively spliced isoforms are abundant and some are highly expressed in different cancer types. In addition, a number of BARD1 germline pathogenic variants have been reported among HBOC patients. In previous reports, BARD1 c.1977A>G variant has been classified as pathogenic since it produces a frameshift transcript lacking exons 2 to 9. In the present study, we sought to validate the mRNA splicing results previously published and to contribute with new evidence to refine the classification of this substitution according to ACMG/AMP guidelines. The presence of the variant was screened in patients and controls. RT-PCR was performed in order to compare the transcriptional profiles of two variant carriers and ten non-carrier controls. In addition, allele-specific expression was assessed. No differences in variant frequency were detected between patients and controls. The RNA assay confirmed the presence of the shorter transcript lacking exons 2-9, but it was detected both in carriers and non-carriers. Furthermore, allelic imbalance was discarded and no significant differences in the proportion of full-length and shorter transcript were detected between carriers and controls. The shorter transcript detected corresponds to BARD1 isoform η, constituted by exons 1, 10 and 11. Our results support that this transcript is a constitutive splicing product rather than an aberrant transcript caused by BARD1 c.1977A>G variant, and for this reason this variant should be considered as likely benign following ACMG/AMP guidelines.

DOI: https://doi.org/10.1038/s41598-021-02465-y
J Pathol. 2021 Nov 23.

Monoallelic deleterious MUTYH germline variants as a driver for tumorigenesis.

Rodrigo Araujo Sequeira Barreiro, Jorge Sabbaga, Benedito M Rossi, Maria Isabel W Achatz, Fabiana Bettoni, Anamaria A Camargo, Paula F Asprino, Pedro A F Galante.

  MUTYH encodes a glycosylase involved in the base excision repair of DNA. Biallelic pathogenic germline variants in MUTYH cause an autosomal recessive condition known as MUTYH-associated adenomatous polyposis and consequently increase the risk of colorectal cancer. However, reports of increased cancer risk in individuals carrying only one defective MUTYH allele are controversial and based on studies involving few individuals. Here, we describe a comprehensive investigation of monoallelic pathogenic MUTYH germline variants in 10,389 cancer patients across 33 different tumour types and 117,000 healthy individuals. Our results indicate that monoallelic pathogenic MUTYH germline variants can lead to tumorigenesis through a mechanism of somatic loss of heterozygosity of the functional MUTYH allele in the tumour. We confirmed that the frequency of monoallelic pathogenic MUTYH germline variants is higher in individuals with cancer than in the general population, although this frequency is not homogeneous among tumour types. We also demonstrated that the MUTYH mutational signature is present only in tumours with loss of the functional allele and found that the characteristic MUTYH base substitution (C>A) increases stop-codon generation. We identified key genes that are affected during tumorigenesis. In conclusion, we propose that carriers of the monoallelic pathogenic MUTYH germline variant are at a higher risk of developing tumours, especially those with frequent loss of heterozygosity events, such as adrenal adenocarcinoma, although the overall risk is still low. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords:  MUTYH; adrenal; cancer; heterozygosity; loss of heterozygosity; monoallelic; mutational signature

DOI:  https://doi.org/10.1002/path.5829
Fam Cancer. 2021 Nov 24.

Rare germline variants in the AXIN2 gene in families with colonic polyposis and colorectal cancer.

James M Chan, Mark Clendenning, Sharelle Joseland, Peter Georgeson, Khalid Mahmood, Romy Walker, Julia Como, Jihoon E Joo, Susan Preston, Ryan A Hutchinson, Bernard J Pope, Andrew Metz, Catherine Beard, Rebecca Purvis, Julie Arnold, Varnika Vijay, Galina Konycheva, Nathan Atkinson, Susan Parry, Mark A Jenkins, Finlay A Macrae, Christophe Rosty, Ingrid M Winship, Daniel D Buchanan.

  Germline loss-of-function variants in AXIN2 are associated with oligodontia and ectodermal dysplasia. The association between colorectal cancer (CRC) and colonic polyposis is less clear despite this gene now being included in multi-gene panels for CRC. Study participants were people with genetically unexplained colonic polyposis recruited to the Genetics of Colonic Polyposis Study who had a rare germline AXIN2 gene variant identified from either clinical multi-gene panel testing (n=2) or from whole genome/exome sequencing (n=2). Variant segregation in relatives and characterisation of tumour tissue were performed where possible. Four different germline pathogenic variants in AXIN2 were identified in four families. Five of the seven carriers of the c.1049delC, p.Pro350Leufs*13 variant, two of the six carriers of the c.1994dupG, p.Asn666Glnfs*41 variant, all three carriers of c.1972delA, p.Ser658Alafs*31 variant and the single proband carrier of the c.2405G>C, p.Arg802Thr variant, which creates an alternate splice form resulting in a frameshift mutation (p.Glu763Ilefs*42), were affected by CRC and/or polyposis. Carriers had a mean age at diagnosis of CRC/polyposis of 52.5 ± 9.2 years. Colonic polyps were typically pan colonic with counts ranging from 5 to >100 (median 12.5) comprising predominantly adenomatous polyps but also serrated polyps. Two CRCs from carriers displayed evidence of a second hit via loss of heterozygosity. Oligodontia was observed in carriers from two families. Germline AXIN2 pathogenic variants from four families were associated with CRC and/or polyposis in multiple family members. These findings support the inclusion of AXIN2 in CRC and polyposis multigene panels for clinical testing.

Keywords:  AXIN2; Colonic polyposis; Colorectal cancer; Ectodermal dysplasia; Oligodontia

DOI:  https://doi.org/10.1007/s10689-021-00283-9
Pathol Int. 2021 Nov 22.

Pathogenic BRCA2 germline variants in combined hepatocellular-cholangiocarcinoma.

Hongjie Li, Xuchen Zhang, Karin E Finberg, Zenta Walther, Dhanpat Jain, Joanna Gibson.

DOI: https://doi.org/10.1111/pin.13188