bims-lifras 2021-07-25 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–07–25
nineteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

The Enigmatic Role of TP53 in Germ Cell Tumours: Are We Missing Something?
An updated quantitative model to classify missense variants in the TP53 gene: a novel multifactorial strategy.
A novel germline BRCA1 mutation identified in a family with hereditary breast and ovarian cancer syndrome.
Evaluation and comparison of hereditary Cancer guidelines in the population.
Clinicians Practicing Obstetrics and Gynecology are Uniquely Situated to Recognize DICER1 Syndrome.
Initial Findings from a High Genetic Risk Prostate Cancer Clinic.
Genetic Landscape of Male Breast Cancer.
Sequencing for germline mutations in Swedish breast cancer families reveals novel breast cancer risk genes.
Gynecological lesions in hereditary cancer predisposition syndromes.
Genetics of Myelodysplastic Syndromes.
Expanding the phenotype of E318K (c.952G > A) MITF germline mutation carriers: case series and review of the literature.
Genomes for Kids: The scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing.
Genetic syndromes predisposing to pediatric brain tumors.
Role of Splicing Regulatory Elements and In Silico Tools Usage in the Identification of Deep Intronic Splicing Variants in Hereditary Breast/Ovarian Cancer Genes.
The Genetic Analyses of French Canadians of Quebec Facilitate the Characterization of New Cancer Predisposing Genes Implicated in Hereditary Breast and/or Ovarian Cancer Syndrome Families.
Novel germline variant in the histone demethylase and transcription regulator KDM4C induces a multi-cancer phenotype.
Germline ERBB3 mutation in familial non-small cell lung carcinoma: Expanding ErbB's role in oncogenesis.
Generation of two heterozygous GATA2 CRISPR/Cas9-edited iPSC lines, R398W and R396Q, for modeling GATA2 deficiency.

Int J Mol Sci. 2021 Jul 02. pii: 7160. [Epub ahead of print]22(13):

The Enigmatic Role of TP53 in Germ Cell Tumours: Are We Missing Something?

Margaret Ottaviano, Emilio Francesco Giunta, Pasquale Rescigno, Ricardo Pereira Mestre, Laura Marandino, Marianna Tortora, Vittorio Riccio, Sara Parola, Milena Casula, Panagiotis Paliogiannis, Antonio Cossu, Ursula Maria Vogl, Davide Bosso, Mario Rosanova, Brunello Mazzola, Bruno Daniele, Giuseppe Palmieri, Giovannella Palmieri.

  The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since the introduction of cisplatin-based therapy, which to date remains the milestone for GCTs treatment. The exquisite cisplatin sensitivity has been mainly explained by the over-expression in GCTs of wild-type TP53 protein and the lack of TP53 somatic mutations; however, several other mechanisms seem to be involved, many of which remain still elusive. The findings about the role of TP53 in platinum-sensitivity and resistance, as well as the reported evidence of second cancers (SCs) in GCT patients treated only with surgery, suggesting a spectrum of cancer predisposing syndromes, highlight the need for a deepened understanding of the role of TP53 in GCTs. In the following report we explore the complex role of TP53 in GCTs cisplatin-sensitivity and resistance mechanisms, passing through several recent genomic studies, as well as its role in GCT patients with SCs, going through our experience of Center of reference for both GCTs and cancer predisposing syndromes.

Keywords:  Li-Fraumeni syndrome; TP53; bilateral testicular cancer; cancer predisposing syndrome; cisplatin resistance; germ cell tumour; germline mutations; somatic mutations; testicular cancer; thyroid cancer

DOI:  https://doi.org/10.3390/ijms22137160
Hum Mutat. 2021 Jul 17.

An updated quantitative model to classify missense variants in the TP53 gene: a novel multifactorial strategy.

Cristina Fortuno, Tina Pesaran, Jill Dolinsky, Amal Yussuf, Kelly McGoldrick, Sean V Tavtigian, David Goldgar, Amanda B Spurdle, Paul A James.

  Multigene panel testing has led to an increase in the number of variants of uncertain significance identified in the TP53 gene, associated with Li-Fraumeni syndrome. We previously developed a quantitative model for predicting pathogenicity of P53 missense variants based on the combination of calibrated bioinformatic information and somatic to germline ratio. Here, we extended this quantitative model for the classification of P53 predicted missense variants by adding new pieces of evidence (personal and family history parameters, loss-of-function results, population allele frequency, healthy individual status by age 60, and breast tumor pathology). We also annotated which missense variants might have an effect on splicing based on bioinformatic predictions. This updated model plus annotation led to the classification of 805 variants into a clinically relevant class, which correlated well with existing ClinVar classifications, and resolved a large number of conflicting and uncertain classifications. We propose this model as a reliable approach to TP53 germline variant classification and emphasize its use in contributing to optimise TP53-specific ACMG/AMP guidelines. This article is protected by copyright. All rights reserved.

Keywords:  TP53; multifactorial; quantitative model; variant classification

DOI:  https://doi.org/10.1002/humu.24264
Clin Med Insights Oncol. 2021 ;15 11795549211028569

A novel germline BRCA1 mutation identified in a family with hereditary breast and ovarian cancer syndrome.

Yanmei Wu, Xiaodong Pan, Juan Dou, Quan Zhang, Yuantong Li, Yuan Sheng, Xishui Liu.

  Pathogenic germline mutations occurring in the BRCA1 (MIM:113705) and BRCA2 (MIM: 600185), which always result in truncated protein or nonsense-mediated mRNA decay, have been identified to increase the risk of hereditary breast, ovarian, pancreatic, prostate, and melanoma cancers. Recent studies show that BRCA1/2 germline mutations also contribute to half of all hereditary breast and ovarian cancer (HBOC). In this case series, we reported a novel frameshift mutation of the BRCA1 gene. This novel frameshift mutation occurs in exon10 of BRCA1 and may result in a lack of the serine cluster domain and BRCA1 C-terminus domain, which mediates the function of BRCA1 in DNA repair and are responsible for activation function of BRCA1. The mutation was present in a Chinese hereditary male/female breast and ovarian cancer family characterized by a high incidence of breast cancer and/or ovarian cancer among the relatives and by a high incidence of triple negative breast cancer (TNBC). Our findings speculate that BRCA1 E1148Rfs*7 mutation may be related to the occurrence of HBOC and even TNBC. Interestingly, three cases of TNBC with this novel BRCA1 mutation in this case series showed a good disease-free survival, one of them has a disease-free survival up to 7 years. Therefore, further study is required to confirm that whether this mutation is associated with good prognosis of HBOC.

Keywords:  BRCA1 mutation; case series; family history; hereditary breast; ovarian and triple negative breast cancer; susceptibility

DOI:  https://doi.org/10.1177/11795549211028569
Hered Cancer Clin Pract. 2021 Jul 17. 19(1): 31

Evaluation and comparison of hereditary Cancer guidelines in the population.

Jordon B Ritchie, Cecelia Bellcross, Caitlin G Allen, Lewis Frey, Heath Morrison, Joshua D Schiffman, Brandon M Welch.

   BACKGROUND: Family health history (FHx) is an effective tool for identifying patients at risk of hereditary cancer. Hereditary cancer clinical practice guidelines (CPG) contain criteria used to evaluate FHx and to make recommendations for genetic consultation. Comparing different CPGs used to evaluate a common set of FHx provides insight into how well the CPGs perform, the extent of agreement across guidelines, and how well they identify patients who should consider a cancer genetic consultation.
METHODS: We compare the American College of Medical Genetics and Genomics (ACMG) and the National Comprehensive Cancer Networks (NCCN) (2019) CPG criteria for FHx collected by a chatbot and evaluated by ontologies and web services in a previous study. Collected FHx met criteria from seven groups: Gene Mutation, Breast and Ovarian, Li-Fraumeni syndrome (LFS), Colorectal and Endometrial, Relative Meets Criteria, ACMG Only Criteria, and NCCN Testing. CPG Criteria were coded and matched across 12 ACMG sub-guidelines and 6 NCCN sub-guidelines for comparison purposes.
RESULTS: The dataset contains 4915 records, of which 2221 met either ACMG or NCCN criteria and 2694 did not. There was significant overlap-1179 probands met both ACMG and NCCN criteria. The greatest similarities were for Gene Mutation and Breast and Ovarian criteria and the greatest disparity existed among Colorectal and Endometrial criteria. Only 156 positive gene mutations were reported and of the 2694 probands who did not meet criteria, 90.6% of them reported at least one cancer in their personal or family cancer history.
CONCLUSION: Hereditary cancer CPGs are useful for identifying patients at risk of developing cancer based on FHx. This comparison shows that with the aid of chatbots, ontologies, and web services, CPGs can be more efficiently applied to identify patients at risk of hereditary cancer. Additionally this comparison examines similarities and differences between ACMG and NCCN and shows the importance of using both guidelines when evaluating hereditary cancer risk.

Keywords:  Clinical practice guidelines; Family health history; Hereditary cancer; Risk assessment

DOI:  https://doi.org/10.1186/s13053-021-00188-9
J Pediatr Adolesc Gynecol. 2021 Jul 17. pii: S1083-3188(21)00256-4. [Epub ahead of print]

Clinicians Practicing Obstetrics and Gynecology are Uniquely Situated to Recognize DICER1 Syndrome.

Katherine G Hayes, Amanda V French.

  Pediatric gynecologic malignancies are rare, present with diverse pathologic findings, and can be associated with genetic syndromes such as Peutz-Jeghers, Lynch and Li-Fraumeni. DICER1 mutation is an emerging entity that has been demonstrated to cause a hereditary tumor predisposition syndrome. Previously, gynecologic manifestations of DICER1 syndrome have been described in single or small case reports with an array of pathologic findings. Here, we discuss pediatric and adolescent patients with gynecologic DICER1 associated tumors, outline the significance of DICER1, and suggest points of care where the syndrome may be diagnosed in the context of routine obstetric and gynecology practice. Patients presenting with a personal or family history suspicious for DICER1 syndrome should undergo both germline and somatic testing, as the presence of DICER1 mutations will impact both treatment and surveillance strategies.

Keywords:  Cancer surveillance; DICER; Pediatric malignancy; Rhabdomyosarcoma; Sex cord stromal tumor

DOI:  https://doi.org/10.1016/j.jpag.2021.07.007
Urology. 2021 Jul 16. pii: S0090-4295(21)00647-6. [Epub ahead of print]

Initial Findings from a High Genetic Risk Prostate Cancer Clinic.

Michael S Sessine, Sanjay Das, Bumsoo Park, Simpa S Salami, Samuel D Kaffenberger, Amy Kasputis, Marissa Solorzano, Mallory Luke, Randy A Vince, Deborah R Kaye, Tudor Borza, Elena M Stoffel, Erin Cobain, Sofia D Merajver, Michelle F Jacobs, Kara J Milliron, Laura Caba, Leander van Neste, Alison M Mondul, Todd M Morgan.

   OBJECTIVE: To improve prostate cancer screening for high-risk men, we developed an early detection clinic for patients at high genetic risk of developing prostate cancer. Despite the rapidly growing understanding of germline variants in driving aggressive prostate cancer and the increased availability of genetic testing, there is little evidence surrounding how best to screen these men.
METHODS: We are reporting on the first 45 patients enrolled, men between the ages of 35-75, primarily with known pathogenic germline variants in prostate cancer susceptibility genes. Screening consists of an intake lifestyle survey, PSA, DRE, and SelectMDx urine assay. A biopsy was recommended for any of the following indications: 1) abnormal DRE, 2) PSA above threshold, or 3) SelectMDx above threshold. The primary outcomes were number needed to screen, and number needed to biopsy to diagnose a patient with prostate cancer.
RESULTS: Patients enrolled in the clinic included those with BRCA1 (n=7), BRCA2 (n=16), Lynch Syndrome (n=6), and CHEK2 (n=4) known pathogenic germline variants. The median age and PSA were 58 (range 35-71) and 1.4 ng/ml (range 0.1-11.4 ng/ml), respectively. Twelve patients underwent a prostate needle biopsy and there were four positive biopsies for prostate cancer.
CONCLUSION: These early data support the feasibility of opening a dedicated clinic for men at high genetic risk of prostate cancer. This early report on the initial enrollment of our long-term study will help optimize early detection protocols and provide evidence for personalized prostate cancer screening in men with key pathogenic germline variants.

Keywords:  BRCA; Lynch Syndrome; Prostate cancer; genetics; pathogenic germline variants; prostate cancer prevention

DOI:  https://doi.org/10.1016/j.urology.2021.05.078
Cancers (Basel). 2021 Jul 15. pii: 3535. [Epub ahead of print]13(14):

Genetic Landscape of Male Breast Cancer.

Fernando Augusto Batista Campos, Etienne Rouleau, Giovana Tardin Torrezan, Dirce Maria Carraro, José Claudio Casali da Rocha, Higor Kassouf Mantovani, Leonardo Roberto da Silva, Cynthia Aparecida Bueno de Toledo Osório, Solange Moraes Sanches, Sandrine M Caputo, Elizabeth Santana Dos Santos.

  Male breast cancer (MBC) is now considered molecularly different from female breast cancer (FBC). Evidence from studies indicates that common genetic and epigenetic features of FBC are not shared with those diagnosed in men. Genetic predisposition is likely to play a significant role in the tumorigenesis of this rare disease. Inherited germline variants in BRCA1 and BRCA2 account for around 2% and 10% of MBC cases, respectively, and the lifetime risk of breast cancer for men harboring BRCA1 and BRCA2 mutations is 1.2% and 6.8%. As for FBC, pathogenic mutations in other breast cancer genes have also been recently associated with an increased risk of MBC, such as PALB2 and CHEK2 mutations. However, while multigene germline panels have been extensively performed for BC female patients, the rarity of MBC has resulted in limited data to allow the understanding of the magnitude of risk and the contribution of recently identified moderate penetrance genes of FBC for MBC predisposition. This review gathers available data about the germline genetic landscape of men affected by breast cancer, estimated risk associated with these genetic variants, and current guidelines for clinical management.

Keywords:  BRCA1; BRCA2; genetic testing; hereditary breast cancer; male breast cancer

DOI:  https://doi.org/10.3390/cancers13143535
Sci Rep. 2021 Jul 19. 11(1): 14737

Sequencing for germline mutations in Swedish breast cancer families reveals novel breast cancer risk genes.

Hafdis T Helgadottir, Jessada Thutkawkorapin, Kristina Lagerstedt-Robinson, Annika Lindblom.

Identifying genetic cancer risk factors will lead to improved genetic counseling, cancer prevention and cancer care. Analyzing families with a strong history of breast cancer (BC) has been a successful method to identify genes that contribute to the disease. This has led to discoveries of high-risk genes like the BRCA-genes. Nevertheless, many BC incidences are of unknown causes. In this study, exome sequencing on 59 BC patients from 24 Swedish families with a strong history of BC was performed to identify variants in known and novel BC predisposing genes. First, we screened known BC genes and identified two pathogenic variants in the BRIP1 and PALB2 genes. Secondly, to identify novel BC genes, rare and high impact variants and segregating in families were analyzed to identify 544 variants in novel BC candidate genes. Of those, 22 variants were defined as high-risk variants. Several interesting genes, either previously linked with BC or in pathways that when flawed could contribute to BC, were among the detected genes. The strongest candidates identified are the FANCM gene, involved in DNA double-strand break repair, and the RAD54L gene, involved in DNA recombination. Our study shows identifying pathogenic variants is challenging despite a strong family history of BC. Several interesting candidates were observed here that need to be further studied.

DOI: https://doi.org/10.1038/s41598-021-94316-z
Cesk Patol. 2021 ;57(2): 96-104

Gynecological lesions in hereditary cancer predisposition syndromes.

Pavel Dundr, David Cibula, Lenka Foretová, Milan Macek, Kateřina Kopečková, Luboš Petruželka, Kristýna Němejcová, Michaela Bártů, Jan Hojný, Nikola Hájková, Radek Jakša, Pavol Janega, Ivana Stružinská.

Hereditary tumor syndromes with a possible manifestation in the female internal genital tract represent a heterogeneous group of diseases. The two most common entities are the hereditary breast and ovarian cancer syndrome, and the Lynch syndrome. The less common syndromes include the rhabdoid tumor predisposition syndrome, Cowden syndrome, tuberous sclerosis complex, DICER1 syndrome, nevoid basal cell carcinoma syndrome, Peutz-Jeghers syndrome, von Hippel-Lindau disease, and hereditary leiomyomatosis and renal cell cancer syndrome. The goal of this manuscript is to provide a comprehensive overview of those hereditary tumor syndromes which can manifest in the area of the female genital system, with an emphasis on their summary, the characteristics of the tumors which can develop in association with these syndromes, and the approach to the processing of prophylactically removed tissues and organs. The issue of Lynch syndrome screening is also discussed.

Keywords: Lynch syndrome; Peutz-Jeghers syndrome; endometrial stromal tumors; female genital tract; hereditary breast and ovarian cancer syndrome; hereditary cancer predisposition syndromes; hereditary neoplastic syndromes; immunohistochemistry; mesenchymal uterine tumors; molecular classification; smooth muscle tumors; undifferentiated uterine sarcoma
Cancers (Basel). 2021 Jul 06. pii: 3380. [Epub ahead of print]13(14):

Genetics of Myelodysplastic Syndromes.

Caner Saygin, Lucy A Godley.

  Myelodysplastic syndrome (MDS) describes a heterogeneous group of bone marrow diseases, now understood to reflect numerous germline and somatic drivers, characterized by recurrent cytogenetic abnormalities and gene mutations. Precursor conditions including clonal hematopoiesis of indeterminate potential and clonal cytopenia of undetermined significance confer risk for MDS as well as other hematopoietic malignancies and cardiovascular complications. The future is likely to bring an understanding of those individuals who are at the highest risk of progression to MDS and preventive strategies to prevent malignant transformation.

Keywords:  clonal hematopoiesis; genetics; germline predisposition; myelodysplastic syndrome

DOI:  https://doi.org/10.3390/cancers13143380
Hered Cancer Clin Pract. 2021 Jul 21. 19(1): 32

Expanding the phenotype of E318K (c.952G > A) MITF germline mutation carriers: case series and review of the literature.

Leandro Jonata Carvalho Oliveira, Aline Bobato Lara Gongora, Fabiola Ambrosio Silveira Lima, Felipe Sales Nogueira Amorim Canedo, Carla Vanessa Quirino, Janina Pontes Pisani, Maria Isabel Achatz, Benedito Mauro Rossi.

   BACKGROUND: The microphthalmia-associated transcription factor gene (MITF) belongs to the MYC supergene family and plays an important role in melanocytes' homeostasis. Individuals harboring MITF germline pathogenic variants are at increased risk of developing cancer, most notably melanoma and renal cell carcinoma.
CASE PRESENTATION: We describe a cohort of ten individuals who harbor the same MITF c.952G > A (p.Glu 318Lys), or p.E318K, germline pathogenic variant. Six carriers developed at least one malignancy (4 cases of breast cancer; 1 cervical cancer; 1 colon cancer; 1 melanoma; 1 ovarian/fallopian tube cancer). A significant phenotypic heterogeneity was found among these individuals and their relatives. Breast cancer was, overall, the most frequent malignancy observed in this case series, with 13 occurrences of 60 (21.67 %) total cancer cases described among the probands and their relatives.
CONCLUSIONS: Our retrospective analysis data raise the hypothesis of a possible association of the MITF p.E318K pathogenic variant with an increased risk of breast cancer.

Keywords:  Breast cancer; Hereditary cancer; MITF; Multigene sequencing panel; c.952G > A; p.E318K

DOI:  https://doi.org/10.1186/s13053-021-00189-8
Cancer Discov. 2021 Jul 23. pii: candisc.1631.2020. [Epub ahead of print]

Genomes for Kids: The scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing.

Scott Newman, Joy Nakitandwe, Chimene A Kesserwan, Elizabeth M Azzato, David A Wheeler, Michael Rusch, Sheila Shurtleff, Dale J Hedges, Kayla V Hamilton, Scott G Foy, Michael N Edmonson, Andrew Thrasher, Armita Bahrami, Brent A Orr, Jeffery M Klco, Jiali Gu, Lynn W Harrison, Lu Wang, Michael R Clay, Annastasia Ouma, Antonina Silkov, Yanling Liu, Zhaojie Zhang, Yu Liu, Samuel W Brady, Xin Zhou, Ti-Cheng Chang, Manjusha Pande, Eric Davis, Jared Becksfort, Aman Patel, Mark R Wilkinson, Delaram Rahbarinia, Manish Kubal, Jamie L Maciaszek, Victor Pastor, Jay Knight, Alexander M Gout, Jian Wang, Zhaohui Gu, Charles G Mullighan, Rose B McGee, Emily A Quinn, Regina Nuccio, Roya Mostafavi, Elsie L Gerhardt, Leslie M Taylor, Jessica M Valdez, Stacy J Hines-Dowell, Alberto S Pappo, Giles Robinson, Liza-Marie Johnson, Ching-Hon Pui, David W Ellison, James R Downing, Jinghui Zhang, Kim E Nichols.

Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole genome (WGS), exome, and RNA sequencing, to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically-relevant (25%), and/or cancer predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors) and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor-normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers.

DOI: https://doi.org/10.1158/2159-8290.CD-20-1631
Neurooncol Pract. 2021 Aug;8(4): 375-390

Genetic syndromes predisposing to pediatric brain tumors.

Sameer Farouk Sait, Michael F Walsh, Matthias A Karajannis.

  The application of high-throughput sequencing approaches including paired tumor/normal sampling with therapeutic intent has demonstrated that 8%-19% of pediatric CNS tumor patients harbor a germline alteration in a classical tumor predisposition gene (NF1, P53). In addition, large-scale germline sequencing studies in unselected cohorts of pediatric neuro-oncology patients have demonstrated novel candidate tumor predisposition genes (ELP1 alterations in sonic hedgehog medulloblastoma). Therefore, the possibility of an underlying tumor predisposition syndrome (TPS) should be considered in all pediatric patients diagnosed with a CNS tumor which carries critical implications including accurate prognostication, selection of optimal therapy, screening, risk reduction, and family planning. The Pediatric Cancer Working Group of the American Association for Cancer Research (AACR) recently published consensus screening recommendations for children with the most common TPS. In this review, we provide an overview of the most relevant as well as recently identified TPS associated with the most frequently encountered pediatric CNS tumors with an emphasis on pathogenesis, genetic testing, clinical features, and treatment implications.

Keywords:  genetic predisposition; genetic syndromes; pediatric brain tumors

DOI:  https://doi.org/10.1093/nop/npab012
Eur J Cancer. 2021 Jul 17. pii: S0959-8049(21)00408-1. [Epub ahead of print]154 209-216

OncotypeDX© Recurrence Score in BRCA mutation carriers: a systematic review and meta-analysis.

Matthew G Davey, Vinitha Richard, Aoife J Lowery, Michael J Kerin.

   INTRODUCTION: There are limited data comparing the OncotypeDX© Recurrence Score (RS) among BRCA mutation carriers and patients with sporadic breast cancer.
AIM: To compare RS results among BRCA mutation carriers and patients with sporadic breast cancer in oestrogen receptor positive (ER+), human epidermal growth factor receptor-2 negative (HER2-) breast cancer.
METHODS: A systematic review was performed in accordance with PRISMA and MOOSE guidelines. Retrospective cohort studies comparing RS in BRCA mutation carriers and cases of sporadic cancer were included. Dichotomous variables were pooled as odds ratios (ORs) and associated 95% confidence intervals (CIs) using the Mantel-Haenszel method.
RESULTS: Five studies involving 4286 patients were included with a mean age of 60 years (range 22-85). Overall, 7.8% were BRCA mutation carriers (333/4286). The mean RS was 18.0 (range 0-71), and the mean RS in BRCA carriers was 25 (range 10-71) versus 18.4 in cases of sporadic disease (range 0-62). Patients with sporadic cancers were more likely to have RS < 18 (OR 0.27, 95% CI 0.14-0.51, P = 0.010). BRCA mutation carriers were more likely to have RS 18-30 (OR 1.74, 95% CI 1.28-2.37, P < 0.001) and RS > 30 (OR 3.71, 95% CI 2.55-5.40, P < 0.001).
CONCLUSION: There is an increased likelihood of high-risk RS among patients with known germline BRCA mutations when compared to patients developing sporadic ER+/HER2-early breast cancer. This study offers insight into genomic testing results within BRCA mutation carriers which may be useful in counselling patients with BRCA mutations in future practice.

Keywords:  BRCA; Breast cancer; Genomics; Hereditary breast cancer; Personalised medicine

DOI:  https://doi.org/10.1016/j.ejca.2021.06.032
Cancers (Basel). 2021 Jul 03. pii: 3341. [Epub ahead of print]13(13):

Role of Splicing Regulatory Elements and In Silico Tools Usage in the Identification of Deep Intronic Splicing Variants in Hereditary Breast/Ovarian Cancer Genes.

Alejandro Moles-Fernández, Joanna Domènech-Vivó, Anna Tenés, Judith Balmaña, Orland Diez, Sara Gutiérrez-Enríquez.

  The contribution of deep intronic splice-altering variants to hereditary breast and ovarian cancer (HBOC) is unknown. Current computational in silico tools to predict spliceogenic variants leading to pseudoexons have limited efficiency. We assessed the performance of the SpliceAI tool combined with ESRseq scores to identify spliceogenic deep intronic variants by affecting cryptic sites or splicing regulatory elements (SREs) using literature and experimental datasets. Our results with 233 published deep intronic variants showed that SpliceAI, with a 0.05 threshold, predicts spliceogenic deep intronic variants affecting cryptic splice sites, but is less effective in detecting those affecting SREs. Next, we characterized the SRE profiles using ESRseq, showing that pseudoexons are significantly enriched in SRE-enhancers compared to adjacent intronic regions. Although the combination of SpliceAI with ESRseq scores (considering ∆ESRseq and SRE landscape) showed higher sensitivity, the global performance did not improve because of the higher number of false positives. The combination of both tools was tested in a tumor RNA dataset with 207 intronic variants disrupting splicing, showing a sensitivity of 86%. Following the pipeline, five spliceogenic deep intronic variants were experimentally identified from 33 variants in HBOC genes. Overall, our results provide a framework to detect deep intronic variants disrupting splicing.

Keywords:  cryptic splice sites; hereditary breast ovarian cancer; in silico prediction tools; pseudoexons; spliceogenic deep intronic variants; splicing regulatory elements

DOI:  https://doi.org/10.3390/cancers13133341
Cancers (Basel). 2021 Jul 07. pii: 3406. [Epub ahead of print]13(14):

The Genetic Analyses of French Canadians of Quebec Facilitate the Characterization of New Cancer Predisposing Genes Implicated in Hereditary Breast and/or Ovarian Cancer Syndrome Families.

Caitlin T Fierheller, Wejdan M Alenezi, Patricia N Tonin.

  The French Canadian population of the province of Quebec has been recognized for its contribution to research in medical genetics, especially in defining the role of heritable pathogenic variants in cancer predisposing genes. Multiple carriers of a limited number of pathogenic variants in BRCA1 and BRCA2, the major risk genes for hereditary breast and/or ovarian cancer syndrome families, have been identified in French Canadians, which is in stark contrast to the array of over 2000 different pathogenic variants reported in each of these genes in other populations. As not all such cancer syndrome families are explained by BRCA1 and BRCA2, newly proposed gene candidates identified in other populations have been investigated for their role in conferring risk in French Canadian cancer families. For example, multiple carriers of distinct variants were identified in PALB2 and RAD51D. The unique genetic architecture of French Canadians has been attributed to shared ancestry due to common ancestors of early settlers of this population with origins mainly from France. In this review, we discuss the merits of genetically characterizing cancer predisposing genes in French Canadians of Quebec. We focused on genes that have been implicated in hereditary breast and/or ovarian cancer syndrome families as they have been the most thoroughly characterized cancer syndromes in this population. We describe how genetic analyses of French Canadians have facilitated: (i) the classification of variants in BRCA1 and BRCA2; (ii) the identification and classification of variants in newly proposed breast and/or ovarian cancer predisposing genes; and (iii) the identification of a new breast cancer predisposing gene candidate, RECQL. The genetic architecture of French Canadians provides a unique opportunity to evaluate new candidate cancer predisposing genes regardless of the population in which they were identified.

Keywords:  French Canadian; breast cancer; cancer predisposing gene; hereditary cancer syndrome; ovarian cancer

DOI:  https://doi.org/10.3390/cancers13143406
J Med Genet. 2021 Jul 19. pii: jmedgenet-2021-107747. [Epub ahead of print]

Novel germline variant in the histone demethylase and transcription regulator KDM4C induces a multi-cancer phenotype.

Riku Katainen, Iikki Donner, Maritta Räisänen, Davide Berta, Anna Kuosmanen, Eevi Kaasinen, Marja Hietala, Lauri A Aaltonen.

   BACKGROUND: Genes involved in epigenetic regulation are central for chromatin structure and gene expression. Specific mutations in these might promote carcinogenesis in several tissue types.
METHODS: We used exome, whole-genome and Sanger sequencing to detect rare variants shared by seven affected individuals in a striking early-onset multi-cancer family. The only variant that segregated with malignancy resided in a histone demethylase KDM4C. Consequently, we went on to study the epigenetic landscape of the mutation carriers with ATAC, ChIP (chromatin immunoprecipitation) and RNA-sequencing from lymphoblastoid cell lines to identify possible pathogenic effects.
RESULTS: A novel variant in KDM4C, encoding a H3K9me3 histone demethylase and transcription regulator, was found to segregate with malignancy in the family. Based on Roadmap Epigenomics Project data, differentially accessible chromatin regions between the variant carriers and controls enrich to normally H3K9me3-marked chromatin. We could not detect a difference in global H3K9 trimethylation levels. However, carriers of the variant seemed to have more trimethylated H3K9 at transcription start sites. Pathway analyses of ChIP-seq and differential gene expression data suggested that genes regulated through KDM4C interaction partner EZH2 and its interaction partner PLZF are aberrantly expressed in mutation carriers.
CONCLUSIONS: The apparent dysregulation of H3K9 trimethylation and KDM4C-associated genes in lymphoblastoid cells supports the hypothesis that the KDM4C variant is causative of the multi-cancer susceptibility in the family. As the variant is ultrarare, located in the conserved catalytic JmjC domain and predicted pathogenic by the majority of available in silico tools, further studies on the role of KDM4C in cancer predisposition are warranted.

Keywords:  epigenomics; gene expression; genetic predisposition to disease; genetic research; human genetics

DOI:  https://doi.org/10.1136/jmedgenet-2021-107747
Hum Mol Genet. 2021 Jul 19. pii: ddab172. [Epub ahead of print]

Germline ERBB3 mutation in familial non-small cell lung carcinoma: Expanding ErbB's role in oncogenesis.

Aideen M McInerney-Leo, Hui Yi Chew, Po-Ling Inglis, Paul J Leo, Shannon R Joseph, Caroline L Cooper, Satomi Okano, Tim Hassall, Lisa Anderson, Rayleen V Bowman, Michael Gattas, Jessica E Harris, Mhairi S Marshall, Janet G Shaw, Lawrie Wheeler, Ian A Yang, Matthew A Brown, Kwun M Fong, Fiona Simpson, Emma L Duncan.

INTRODUCTION: Lung cancer is the commonest cause of cancer deaths worldwide. Although strongly associated with smoking, predisposition to lung cancer is also heritable with multiple common risk variants identified. Rarely, dominantly inherited non-small-cell lung cancer (NSCLC) has been reported due to somatic mutations in EGFR/ErbB1 and ERBB2.
MATERIALS AND METHODS: Germline exome sequencing was performed in a multi-generation family with autosomal dominant NSCLC, including an affected child. Tumour samples were also sequenced. Full-length wild-type (wtErbB3) and mutant ERBB3 (mutErbB3) constructs were transfected into HeLa cells. Protein expression, stability, and sub-cellular localisation were assessed, and cellular proliferation, pAkt/Akt, and pERK levels determined.
RESULTS: A novel germline variant in ERBB3 (c.1946 T > G: p.Iso649Arg), coding for receptor tyrosine-protein kinase erbB-3 (ErbB3), was identified, with appropriate segregation. There was no loss-of-heterozygosity in tumour samples. Both wtErbB3 and mutErbB3 were stably expressed. MutErbB3-transfected cells demonstrated an increased ratio of the 80kD form (which enhances proliferation) compared to the full-length (180kD) form. MutErbB3 and wtErbB3 had similar punctate cytoplasmic localisation pre- and post-EGF stimulation; however, EGFR levels decreased faster post-stimulation in mutErbB3-transfected cells, suggesting more rapid processing of the mutErbB3/EGFR heterodimer. Cellular proliferation was increased in mutErbB3-transfected cells compared to wtErbB3 transfection. MutErbB3-transfected cells also showed decreased pAkt/tAkt ratios and increased pERK/tERK 30 minutes post-stimulation compared to wtErbB3 transfection, demonstrating altered signalling pathway activation. Cumulatively, these results support this mutation as tumorogenic.
CONCLUSIONS: This is the first reported family with a germline ERBB3 mutation causing heritable NSCLC, furthering understanding of the ErbB family pathway in oncogenesis.

DOI: https://doi.org/10.1093/hmg/ddab172
Stem Cell Res. 2021 Jun 27. pii: S1873-5061(21)00292-0. [Epub ahead of print]55 102445

Generation of two heterozygous GATA2 CRISPR/Cas9-edited iPSC lines, R398W and R396Q, for modeling GATA2 deficiency.

Julio Castaño, Damia Romero-Moya, Yvonne Richaud-Patin, Alessandra Giorgetti.

  Germline heterozygous GATA2 mutations underlie a complex disorder characterized by bone marrow failure, immunodeficiency and high risk to develop myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our understanding about GATA2 deficiency is limited due to the lack of relevant disease models. Here we generated high quality human induced pluripotent stem cell (iPSC) lines carrying two of the most recurrent germline GATA2 mutations (R389W and R396Q) associated with MDS, using CRISPR/Cas9. These hiPSCs represent an in vitro model to study the molecular and cellular mechanisms underlying GATA2 deficiency, when differentiated into blood progenitors.

Keywords:  GATA2 deficiency; Gene Editing; Induced Pluripotent stem cells

DOI:  https://doi.org/10.1016/j.scr.2021.102445