bims-lifras 2023-02-12 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2023–02–12
fourteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Genetic susceptibility in children, adolescents, and young adults diagnosed with soft-tissue sarcomas.
Hereditary Diffuse Gastric Cancer.
Germline pathogenic variants in 786 neuroblastoma patients.
Common activities and predictive gene signature identified for genetic hypomorphs of TP53.
Novel Candidate loci and Pathogenic Germline Variants Involved in Familial Hematological Malignancies Revealed by Whole-Exome Sequencing.
Germline TP53 pathogenic variants and breast cancer: A narrative review.
Is Reflex Germline BRCA1/2 Testing Necessary in Women Diagnosed with Non-Mucinous High-Grade Epithelial Ovarian Cancer Aged 80 Years or Older?
Functional damaging germline variants in ETV6, IKZF1, PAX5 and RUNX1 predisposing to B-cell precursor acute lymphoblastic leukemia.
Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome.
Genetic Predisposition to Colorectal Cancer: How Many and Which Genes to Test?
Germline cancer gene expression quantitative trait loci are associated with local and global tumor mutations.
Role of psychological background in cancer susceptibility genetic testing distress: It is not only about a positive result.
Comprehensive Analysis of Germline Drivers in Endometrial Cancer.
Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma.

Eur J Med Genet. 2023 Feb 08. pii: S1769-7212(23)00024-1. [Epub ahead of print] 104718

Genetic susceptibility in children, adolescents, and young adults diagnosed with soft-tissue sarcomas.

Julia Würtemberger, Tim Ripperger, Christian Vokuhl, Sebastian Bauer, Irene Teichert-von Lüttichau, Eva Wardelmann, Charlotte Niemeyer, Christian P Kratz, Brigitte Schlegelberger, Simone Hettmer.

  Soft tissue sarcomas (STS) may arise as a consequence of germline variants in cancer predisposition genes (CPGs). We believe that elucidating germline sarcoma predisposition is critical for understanding disease biology and therapeutic requirements. Participation in surveillance programs may allow for early tumor detection, early initiation of therapy and, ultimately, better outcomes. Among children, adolescents, and adults diagnosed with soft-tissue sarcomas and examined as part of published germline sequencing studies, pathogenic/likely pathogenic variants in CPGs were reported in 7-33% of patients. (Likely) pathogenic germline variants were detected most frequently in TP53, NF1 and BRCA1/2. In this review, we describe reported associations between soft tissue sarcomas and germline variants in CPGs, with mention of locally aggressive and benign soft tissue tumors that have important associations with cancer predisposition syndromes. We also discuss recommendations for diagnostic germline genetic testing. Testing for sarcoma-predisposing germline variants should be considered as part of the routine clinical workup and care of any child, adolescent, or adult diagnosed with STS and take into account consequences for the whole family.

Keywords:  Cancer predisposition genes; Cancer susceptibility; Germline genetic testing; Soft-tissue sarcomas; Soft-tissue tumors

DOI:  https://doi.org/10.1016/j.ejmg.2023.104718
Gastroenterology. 2023 Feb 03. pii: S0016-5085(23)00110-5. [Epub ahead of print]

Hereditary Diffuse Gastric Cancer.

Lyvianne Decourtye-Espiard, Parry Guilford.

  Hereditary Diffuse Gastric Cancer (HDGC) is a dominantly-inherited cancer syndrome characterized by a high incidence of diffuse gastric cancer (DGC) and lobular breast cancer (LBC). HDGC is caused by germline mutations in two genes involved in the epithelial adherens junction complex, CDH1 and CTNNA1. Here, we discuss the genetics of HDGC and the variability of its clinical phenotype, in particular the variable penetrance of advanced DGC and LBC, both within and between families. We review the pathology of the disease, the mechanism of tumor initiation and its natural history. Finally, we describe current best practice for the clinical management of HDGC including emerging genetic testing criteria for the identification of new families, methods for endoscopic surveillance, the complications associated with prophylactic surgery, post-operative quality of life and the emerging field of HDGC chemoprevention.

Keywords:  CDH1; CTNNA1; Hereditary Diffuse Gastric Cancer; cancer predisposition

DOI:  https://doi.org/10.1053/j.gastro.2023.01.038
medRxiv. 2023 Jan 25. pii: 2023.01.23.23284864. [Epub ahead of print]

Germline pathogenic variants in 786 neuroblastoma patients.

Penn Medicine BioBank

Importance: Neuroblastoma accounts for 12% of childhood cancer deaths. The genetic contribution of rare pathogenic germline variation in patients without a family history remains unclear.
Objective: To define the prevalence, spectrum, and clinical significance of pathogenic germline variation in cancer predisposition genes (CPGs) in neuroblastoma patients.
Design Setting and Participants: Germline DNA sequencing was performed on the peripheral blood from 786 neuroblastoma patients unselected for family history. Rare variants mapping to CPGs were evaluated for pathogenicity and the percentage of cases harboring pathogenic (P) or likely pathogenic (LP) variants was quantified. The frequency of CPG P-LP variants in neuroblastoma cases was compared to two distinct cancer-free control cohorts to assess enrichment. Matched tumor DNA sequencing was evaluated for "second hits" at CPGs and germline DNA array data from 5,585 neuroblastoma cases and 23,505 cancer-free control children was analyzed to identify rare germline copy number variants (CNVs) affecting genes with an excess burden of P-LP variants in neuroblastoma. Neuroblastoma patients with germline P-LP variants were compared to those without P-LP variants to test for association with clinical characteristics, tumor features, and patient survival.
Main Outcomes and Measures: Rare variant prevalence, pathogenicity, enrichment, and association with clinical characteristics, tumor features, and patient survival.
Results: We observed 116 P-LP variants in CPGs involving 13.9% (109/786) of patients, representing a significant excess burden of P-LP variants compared to controls (9.1%; P = 5.14 × 10 -5 , Odds Ratio: 1.60, 95% confidence interval: 1.27-2.00). BARD1 harbored the most significant burden of P-LP variants compared to controls (1.0% vs. 0.03%; P = 8.18 × 10 -7 ; Odds Ratio: 32.30, 95% confidence interval: 6.44-310.35). Rare germline CNVs disrupting BARD1 were also identified in neuroblastoma patients (0.05%) but absent in controls (P = 7.08 × 10 -3 ; Odds Ratio: 29.47, 95% confidence interval: 1.52 - 570.70). Overall, P-LP variants in DNA repair genes in this study were enriched in cases compared to controls (8.1% vs. 5.7%; P = 0.01; Odds Ratio: 1.45, 95% confidence interval: 1.08-1.92). Neuroblastoma patients harboring a germline P-LP variant had a worse overall survival when compared to patients without P-LP variants (P = 8.6 × 10 -3 ), and this remained significant in a multivariate Cox proportional-hazards model (P = 0.01).
Conclusions and Relevance: Neuroblastoma patients harboring germline P-LP variants in CPGs have worse overall survival and BARD1 is an important predisposition gene affected by both common and rare pathogenic variation. Germline sequencing should be performed for all neuroblastoma patients at diagnosis to inform genetic counseling and support future longitudinal and mechanistic studies. Patients with a germline P-LP variant should be closely monitored, regardless of risk group assignment.
Key Points:
Question: What is the prevalence and clinical significance of germline pathogenic variants in cancer predisposition genes (CPGs) in neuroblastoma patients?
Findings: Among 786 neuroblastoma patients with germline DNA sequencing, 13.9% harbored a pathogenic (P) or likely pathogenic (LP) variant in a CPG. The number of patients with germline P-LP variants in BARD1 and other DNA repair genes was significantly greater than observed in two cancer-free control cohorts. The presence of a germline P-LP variant was independently predictive of worse overall survival.
Meaning: Germline sequencing should be performed for all neuroblastoma patients at diagnosis to inform genetic counseling and frequency of clinical follow-up. Centralization of these data will facilitate longitudinal and mechanistic studies needed to identify specific actionable events and improve patient outcomes.

DOI: https://doi.org/10.1101/2023.01.23.23284864
Proc Natl Acad Sci U S A. 2023 Feb 14. 120(7): e2212940120

Common activities and predictive gene signature identified for genetic hypomorphs of TP53.

Jessica C Leung, Julia I-Ju Leu, Alexandra Indeglia, Toshitha Kannan, Nicole L Clarke, Nicole A Kirven, Harsh Dweep, David Garlick, Thibaut Barnoud, Andrew V Kossenkov, Donna L George, Maureen E Murphy.

  Missense mutations that inactivate p53 occur commonly in cancer, and germline mutations in TP53 cause Li Fraumeni syndrome, which is associated with early-onset cancer. In addition, there are over two hundred germline missense variants of p53 that remain uncharacterized. In some cases, these germline variants have been shown to encode lesser-functioning, or hypomorphic, p53 protein, and these alleles are associated with increased cancer risk in humans and mouse models. However, most hypomorphic p53 variants remain un- or mis-classified in clinical genetics databases. There thus exists a significant need to better understand the behavior of p53 hypomorphs and to develop a functional assay that can distinguish hypomorphs from wild-type p53 or benign variants. We report the surprising finding that two different African-centric genetic hypomorphs of p53 that occur in distinct functional domains of the protein share common activities. Specifically, the Pro47Ser variant, located in the transactivation domain, and the Tyr107His variant, located in the DNA binding domain, both share increased propensity to misfold into a conformation specific for mutant, misfolded p53. Additionally, cells and tissues containing these hypomorphic variants show increased NF-κB activity. We identify a common gene expression signature from unstressed lymphocyte cell lines that is shared between multiple germline hypomorphic variants of TP53, and which successfully distinguishes wild-type p53 and a benign variant from lesser-functioning hypomorphic p53 variants. Our findings will allow us to better understand the contribution of p53 hypomorphs to disease risk and should help better inform cancer risk in the carriers of p53 variants.

Keywords:  NF-kB; cancer; gene signature; mutant p53; p53

DOI:  https://doi.org/10.1073/pnas.2212940120
Cancers (Basel). 2023 Feb 02. pii: 944. [Epub ahead of print]15(3):

Novel Candidate loci and Pathogenic Germline Variants Involved in Familial Hematological Malignancies Revealed by Whole-Exome Sequencing.

Cristina Andrés-Zayas, Julia Suárez-González, María Chicano-Lavilla, Mariana Bastos Oreiro, Gabriela Rodríguez-Macías, Patricia Font López, Santiago Osorio Prendes, Gillen Oarbeascoa Royuela, Patricia García Ramírez, Rocío Nieves Salgado, Ignacio Gómez-Centurión, Diego Carbonell Muñoz, Paula Muñiz, Mi Kwon, José Luis Díez-Martín, Ismael Buño, Carolina Martínez-Laperche.

  The familial occurrence of hematological malignancies has been underappreciated. Recent studies suggest that up to 15% of adults with myeloid neoplasms carry germline pathogenic variants in cancer-predisposing genes. This study aimed to identify the underlying germline predisposition variant in patients with a strong family or personal onco-hematological history using whole exome sequencing on sixteen uncharacterized individuals. It was carried out in two groups of patients, one with samples available from two affected relatives (Cohort A) and one with available samples from the index case (Cohort B). In Cohort A, six families were characterized. Two families shared variants in genes associated with DNA damage response and involved in cancer development (CHEK2 and RAD54L). Pathogenic or likely pathogenic germline variants were also found in novel candidate genes (NFATC2 and TC2N). In two families, any relevant pathogenic or likely pathogenic genomic variants were identified. In Cohort B, four additional index cases were analyzed. Three of them harbor clinically relevant variants in genes with a probable role in the development of inherited forms of hematological malignancies (GATA1, MSH4 and PRF1). Overall, whole exome sequencing is a useful approach to achieve a further characterization of these patients and their mutational spectra. Moreover, further investigations may help improve optimization for disease management of affected patients and their families.

Keywords:  cancer susceptibility; germline mutation; hematological malignancies; predisposition syndromes; whole-exome sequencing

DOI:  https://doi.org/10.3390/cancers15030944
Cancer Treat Rev. 2023 Jan 31. pii: S0305-7372(23)00013-0. [Epub ahead of print]114 102522

Germline TP53 pathogenic variants and breast cancer: A narrative review.

Eva Blondeaux, Luca Arecco, Kevin Punie, Rossella Graffeo, Angela Toss, Carmine De Angelis, Lucia Trevisan, Giulia Buzzatti, Sabine C Linn, Peter Dubsky, Mara Cruellas, Ann H Partridge, Judith Balmaña, Shani Paluch-Shimon, Matteo Lambertini.

  Approximately 10% of breast cancers are associated with the inheritance of a pathogenic variant (PV) in one of the breast cancer susceptibility genes. Multiple breast cancer predisposing genes, including TP53, are responsible for the increased breast cancer risk. Tumor protein-53 (TP53) germline PVs are associated with Li-Fraumeni syndrome, a rare autosomal dominant inherited cancer predisposition syndrome associated with early-onset pediatric and multiple primary cancers such as soft tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinomas and leukemias. Women harboring a TP53 PV carry a lifetime risk of developing breast cancer of 80-90%. The aim of the present narrative review is to provide a comprehensive overview of the criteria for offering TP53 testing, prevalence of TP53 carriers among patients with breast cancer, and what is known about its prognostic and therapeutic implications. A summary of the current indications of secondary cancer surveillance and survivorship issues are also provided. Finally, the spectrum of TP53 alteration and testing is discussed. The optimal strategies for the treatment of breast cancer in patients harboring TP53 PVs poses certain challenges. Current guidelines favor the option of performing mastectomy rather than lumpectomy to avoid adjuvant radiotherapy and subsequent risk of radiation-induced second primary malignancies, with careful consideration of radiation when indicated post-mastectomy. Some studies suggest that patients with breast cancer and germline TP53 PV might have worse survival outcomes compared to patients with breast cancer and wild type germline TP53 status. Annual breast magnetic resonance imaging (MRI) and whole-body MRI are recommended as secondary prevention.

Keywords:  Breast cancer; Prognosis; TP53; Treatment

DOI:  https://doi.org/10.1016/j.ctrv.2023.102522
Cancers (Basel). 2023 Jan 25. pii: 730. [Epub ahead of print]15(3):

Is Reflex Germline BRCA1/2 Testing Necessary in Women Diagnosed with Non-Mucinous High-Grade Epithelial Ovarian Cancer Aged 80 Years or Older?

Robert D Morgan, George J Burghel, Nicola Flaum, Michael Bulman, Philip Smith, Andrew R Clamp, Jurjees Hasan, Claire L Mitchell, Zena Salih, Emma R Woodward, Fiona Lalloo, Emma J Crosbie, Richard J Edmondson, Helene Schlecht, Gordon C Jayson, D Gareth R Evans.

  Women diagnosed with non-mucinous high-grade epithelial ovarian cancer (EOC) in England are often reflex-tested for germline and tumour BRCA1/2 variants. The value of germline BRCA1/2 testing in women diagnosed aged ≥80 is questionable. We performed an observational study of all women diagnosed with non-mucinous high-grade EOC who underwent germline and tumour BRCA1/2 testing by the North West of England Genomic Laboratory Hub. A subgroup of women also underwent germline testing using a panel of homologous recombination repair (HRR) genes and/or tumour testing for homologous recombination deficiency (HRD) using Myriad's myChoice® companion diagnostic. Seven-hundred-two patients successfully underwent both germline and tumour BRCA1/2 testing. Of these, 48 were diagnosed with non-mucinous high-grade EOC aged ≥80. In this age group, somatic BRCA1/2 pathogenic/likely pathogenic variants (PV/LPVs) were detected nine times more often than germline BRCA1/2 PV/LPVs. The only germline PV reported in a patient aged ≥80 was detected in germline and tumour DNA (BRCA2 c.4478_4481del). No patient aged ≥80 had a germline PV/LPVs in a non-BRCA1/2 HRR gene. Thirty-eight percent of patients aged ≥80 had a tumour positive for HRD. Our data suggest that tumour BRCA1/2 and HRD testing is adequate for patients diagnosed with non-mucinous high-grade EOC aged ≥80, with germline BRCA1/2 testing reserved for women with a tumour BRCA1/2 PV/LPVs.

Keywords:  BRCA1; BRCA2; epithelial ovarian cancer; germline; somatic

DOI:  https://doi.org/10.3390/cancers15030730
Eur J Med Genet. 2023 Feb 08. pii: S1769-7212(23)00031-9. [Epub ahead of print] 104725

Functional damaging germline variants in ETV6, IKZF1, PAX5 and RUNX1 predisposing to B-cell precursor acute lymphoblastic leukemia.

Rabea Wagener, Sarah Elitzur, Triantafyllia Brozou, Arndt Borkhardt.

  Recent genome-wide studies have demonstrated that a significant proportion of children with cancer carry predisposing germline variants, with varying incidence according to cancer type. In general, there is a lower incidence of underlying germline predisposing variants among patients with B-cell acute lymphoblastic leukemia (B-ALL) compared to other types of cancer, but higher rates may be found in patients with specific leukemia subtypes. Two categories of ALL-predisposing variants have been described: common polymorphisms, conferring low-penetrance ALL susceptibility, and rare variants, conferring high-penetrance ALL susceptibility. Variants in genes encoding hematopoietic transcription factors are an example of the latter, and include ETV6, IKZF1, PAX5 and RUNX1. Here, we present an overview of the germline variants detected in patients with B-ALL in these four genes and a summary of functional studies analyzing the impacts of these variants upon protein function, and hence their effects with regard to leukemia predisposition. Furthermore, we review specific clinical characteristics of patients with B-ALL, including specific features of the patient or family history and associated somatic genetic characteristics, which are suggestive of underlying germline alterations in one of these genes. This review may be of assistance in the interpretation of patient genetic germline findings, made even more challenging by the absence of a suggestive family history or by an unknown familial cancer history. Despite a low incidence of underlying germline alterations in ETV6, IKZF1, PAX5 and RUNX1 in patients with B-ALL, identification of an underlying ALL predisposition syndrome is relevant to the clinical management of patients and their relatives, as the latter are also at risk of developing cancer.

Keywords:  Cancer predisposition; Familial B-ALL; Genetic alterations; Hematopoietic transcription factors

DOI:  https://doi.org/10.1016/j.ejmg.2023.104725
Front Mol Biosci. 2023 ;10 1119900

Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome.

Laia Bonjoch, Yasmin Soares de Lima, Marcos Díaz-Gay, Isabella Dotti, Jenifer Muñoz, Leticia Moreira, Sabela Carballal, Teresa Ocaña, Miriam Cuatrecasas, Oswaldo Ortiz, Antoni Castells, Maria Pellisé, Francesc Balaguer, Azucena Salas, Ludmil B Alexandrov, Sergi Castellví-Bel.

  Serrated polyposis syndrome (SPS) is one of the most frequent polyposis syndromes characterized by an increased risk for developing colorectal cancer (CRC). Although SPS etiology has been mainly associated with environmental factors, germline predisposition to SPS could also be relevant for cases with familial aggregation or a family history of SPS/CRC. After whole-exome sequencing of 39 SPS patients from 16 families, we identified a heterozygous germline frameshift variant in the POLD1 gene (c.1941delG, p.(Lys648fs*46)) in a patient with SPS and CRC. Tumor presented an ultra-hypermutated phenotype and microsatellite instability. The POLD1 germline variant segregated in three additional SPS-affected family members. We attempted to create yeast and cellular models for this variant but were no viable. Alternatively, we generated patient-derived organoids (PDOs) from healthy rectal tissue of the index case, as well as from a control donor. Then, we challenged PDOs with a DNA-damaging agent to induce replication stress. No significant differences were observed in the DNA damage response between control and POLD1-Lys648fs PDOs, nor specific mutational signatures were observed. Our results do not support the pathogenicity of the analyzed POLD1 frameshift variant. One possible explanation is that haplosufficiency of the wild-type allele may be compensating for the absence of expression of the frameshift allele. Overall, future work is required to elucidate if functional consequences could be derived from POLD1 alterations different from missense variants in their proofreading domain. To our knowledge, our study presents the first organoid model for germline POLD1 variants and establishes the basis for its use as a model for disease in SPS, CRC and other malignancies.

Keywords:  POLD1; functional genomics; gene editing; genetic predisposition to disease; serrated polyposis syndrome

DOI:  https://doi.org/10.3389/fmolb.2023.1119900
Int J Mol Sci. 2023 Jan 21. pii: 2137. [Epub ahead of print]24(3):

Genetic Predisposition to Colorectal Cancer: How Many and Which Genes to Test?

Francesca Rebuzzi, Paola Ulivi, Gianluca Tedaldi.

  Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and familial adenomatous polyposis are the best-known genetic diseases associated with hereditary colorectal cancer. However, some other genetic disorders confer an increased risk of colorectal cancer, such as Li-Fraumeni syndrome (TP53 gene), MUTYH-associated polyposis (MUTYH gene), Peutz-Jeghers syndrome (STK11 gene), Cowden syndrome (PTEN gene), and juvenile polyposis syndrome (BMPR1A and SMAD4 genes). Moreover, the recent advances in molecular techniques, in particular Next-Generation Sequencing, have led to the identification of many new genes involved in the predisposition to colorectal cancers, such as RPS20, POLE, POLD1, AXIN2, NTHL1, MSH3, RNF43 and GREM1. In this review, we summarized the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and into the associated genetic disorders. Furthermore, we discussed the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.

Keywords:  Next-Generation Sequencing; cancer predisposition; cancer risk; gene panels; hereditary colorectal cancer

DOI:  https://doi.org/10.3390/ijms24032137
Cancer Res. 2023 Feb 06. pii: CAN-22-2624. [Epub ahead of print]

Germline cancer gene expression quantitative trait loci are associated with local and global tumor mutations.

Yuxi Liu, Alexander Gusev, Peter Kraft.

Somatic mutations drive cancer development and are relevant to patient responses to treatment. Emerging evidence shows that variations in the somatic genome can be influenced by the germline genetic background. However, the mechanisms underlying these germline-somatic associations remain largely obscure. We hypothesized that germline variants can influence somatic mutations in a nearby cancer gene ("local impact") or a set of recurrently mutated cancer genes across the genome ("global impact") through their regulatory effect on gene expression. To test this hypothesis, tumor targeted sequencing data from 12,413 patients across 11 cancer types in the Dana-Farber Profile cohort were integrated with germline cancer gene expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression Project. Variants that upregulate ATM expression were associated with a decreased risk of somatic ATM mutations across 8 cancer types. GLI2, WRN, and CBFB eQTL were associated with global tumor mutational burden of cancer genes in ovarian cancer, glioma, and esophagogastric carcinoma, respectively. An EPHA5 eQTL was associated with mutations in cancer genes specific to colorectal cancer, and eQTL related to expression of APC, WRN, GLI1, FANCA, and TP53 were associated with mutations in genes specific to endometrial cancer. These findings provide evidence that germline-somatic associations are mediated through expression of specific cancer genes, opening new avenues for research on the underlying biological processes.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2624
J Genet Couns. 2023 Feb 07.

Role of psychological background in cancer susceptibility genetic testing distress: It is not only about a positive result.

Adrià López-Fernández, Guillermo Villacampa, Mònica Salinas, Elia Grau, Esther Darder, Estela Carrasco, Ares Solanes, Angela Velasco, Maite Torres, Elisabet Munté, Silvia Iglesias, Sara Torres-Esquius, Noemí Tuset, Orland Diez, Conxi Lázaro, Joan Brunet, Sergi Corbella, Judith Balmaña.

  Clinical and familial factors predict psychological distress after genetic testing for cancer susceptibility. However, the contribution of an individual's psychological background to such distress is unclear. This study aims to analyze the psychological impact of genetic testing and to identify the profile of individuals at higher risk. This is a longitudinal multicenter study of individuals undergoing genetic testing for cancer susceptibility. Demographic, clinical, genetic, familial, and psychological (personality types, cancer worry) characteristics were assessed by validated questionnaires the day of genetic testing. Distress, uncertainty, and positive experience perception (MICRA scale) were evaluated at the results disclosure visit, and 3 and 12 months afterwards. Multivariate analysis was performed. A total of 714 individuals were included. A high neuroticism score, high baseline cancer worry, and a positive genetic test result were independently associated with higher psychological impact (p-value < 0.05). The highest risk profile (10% of the cohort) included women with high level of neuroticism and a positive result. Uncertainty was mainly associated with a high level of neuroticism, regardless of the genetic test result. A holistic approach to personalized germline genetic counseling should include the assessment of personality dimensions.

Keywords:  genetic counseling; genetic testing; hereditary cancer; neuroticism; personality traits; psychological impact

DOI:  https://doi.org/10.1002/jgc4.1687
J Natl Cancer Inst. 2023 Feb 06. pii: djad016. [Epub ahead of print]

Comprehensive Analysis of Germline Drivers in Endometrial Cancer.

Sushmita Gordhandas, Eric Rios-Doria, Karen A Cadoo, Amanda Catchings, Anna Maio, Yelena Kemel, Margaret Sheehan, Megha Ranganathan, Dina Green, Anjali Aryamvally, Angela G Arnold, Erin Salo-Mullen, Beryl Manning-Geist, Tiffany Sia, Pier Selenica, Arnaud Da Cruz Paula, Chad Vanderbilt, Maksym Misyura, Mario M Leitao, Jennifer J Mueller, Vicky Makker, Maria Rubinstein, Claire F Friedman, Qin Zhou, Alexia Iasonos, Alicia Latham, Maria I Carlo, Yonina R Murciano-Goroff, Marie Will, Michael F Walsh, Shirin Issa Bhaloo, Lora H Ellenson, Ozge Ceyhan-Birsoy, Michael F Berger, Mark E Robson, Nadeem Abu-Rustum, Carol Aghajanian, Kenneth Offit, Zsofia Stadler, Britta Weigelt, Diana L Mandelker, Ying L Liu.

   BACKGROUND: We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features.
METHODS: Germline assessment of ≥ 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal MSK-IMPACT sequencing from 1/1/15-6/30/21. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using non-parametric tests.
RESULTS: Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high-penetrance, 39 [17%] moderate-penetrance, and 117 [51%] low/recessive/uncertain-penetrance). Compared to those without gPVs, patients with gPVs were younger (P=.002), more often White (P=.009), less obese (P=.025) and had differences in distribution of tumor histology (P=.017) and molecular subtype (P<.001). Among 231 gPVs, 74 (32%) exhibited biallelic inactivation within tumors. For high-penetrance gPVs, 63% (47/75) of ECs had biallelic alterations, primarily affecting mismatch repair (MMR) and homologous recombination (HR) genes, including BRCA1/2, RAD51D, and PALB2. Biallelic inactivation varied across molecular subtypes with highest rates in microsatellite instability-high (MSI-H) or copy-number (CN)-high subtypes [3/12 (25%) POLE, 30/77 (39%) MSI-H, 27/60 (45%) CN-H, 9/57 (16%) CN-L, P<.001].
CONCLUSIONS: Thirteen percent of unselected patients with EC had gPVs, with 63% of gPVs in high-penetrance genes (MMR and HR) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention.

Keywords:  biallelic inactivation; endometrial cancer; germline assessment; germline pathogenic variant; high-penetrance genes; homologous recombination; loss of heterozygosity; mismatch repair deficiency; monoallelic inactivation

DOI:  https://doi.org/10.1093/jnci/djad016
Front Endocrinol (Lausanne). 2022 ;13 1070074

Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma.

Sara Mellid, Eduardo Gil, Rocío Letón, Eduardo Caleiras, Emiliano Honrado, Susan Richter, Nuria Palacios, Marcos Lahera, Juan C Galofré, Adriá López-Fernández, Maria Calatayud, Aura D Herrera-Martínez, María A Galvez, Xavier Matias-Guiu, Milagros Balbín, Esther Korpershoek, Eugénie S Lim, Francesca Maletta, Sofia Lider, Stephanie M J Fliedner, Nicole Bechmann, Graeme Eisenhofer, Letizia Canu, Elena Rapizzi, Irina Bancos, Mercedes Robledo, Alberto Cascón.

   Introduction: The percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPGL patients. Moreover, the application of NGS to the diagnosis of PPGL detects unexpected co-occurrences of pathogenic allelic variants in different susceptibility genes.
Methods: Herein we uncover several cases with dual mutations in NF1 and other PPGL genes by targeted sequencing. We studied the molecular characteristics of the tumours with co-occurrent mutations, using omic tools to gain insight into the role of these events in tumour development.
Results: Amongst 23 patients carrying germline NF1 mutations, targeted sequencing revealed additional pathogenic germline variants in DLST (n=1) and MDH2 (n=2), and two somatic mutations in H3-3A and PRKAR1A. Three additional patients, with somatic mutations in NF1 were found carrying germline pathogenic mutations in SDHB or DLST, and a somatic truncating mutation in ATRX. Two of the cases with dual germline mutations showed multiple pheochromocytomas or extra-adrenal paragangliomas - an extremely rare clinical finding in NF1 patients. Transcriptional and methylation profiling and metabolite assessment showed an "intermediate signature" to suggest that both variants had a pathological role in tumour development.
Discussion: In conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients.

Keywords:  DLST; MDH2; NF1; co-occurrent mutations; germline mutation; pheochromocytoma

DOI:  https://doi.org/10.3389/fendo.2022.1070074