bims-lifras 2022-10-02 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022‒10‒02
nine papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

A case report: invasive ductal carcinoma in mosaic Li-Fraumeni syndrome.
Detection of BRCA1 Pathogenic Variant in a 24-Year-Old Endometrial Cancer Patient: Risks of Several Hereditary Tumor Syndromes Assessed Using Germline Multigene Panel Testing.
Germline BRCA mutation carriers are more likely to undergo cytoreductive surgery for relapsed, platinum sensitive, ovarian cancer.
Targeted molecular profiling of epithelial ovarian cancer from Italian BRCA wild-type patients with a BRCA and PARP pathways gene panel.
MDS-287 Genetic Landscape of Somatic Myeloid Mutations in the Presence of Rare TERT Variants and Their Relation to Myeloid Neoplasia.
Characterization of lung cancers in patients with BRCA germline variants: A multicenter series.
Genetic testing for patients at risk of hereditary breast and ovarian cancer.
Familial Pancreatic Cancer.
Germline RB1 Mutation in Retinoblastoma Patients: Detection Methods and Implication in Tumor Focality.

J Surg Case Rep. 2022 Sep;2022(9): rjac408

A case report: invasive ductal carcinoma in mosaic Li-Fraumeni syndrome.

Danielle Wenger, Sasha Kurumety, Zeynep B Aydi.

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant condition caused by pathogenic variants in the TP53 tumor suppressor gene and characterized by a high lifetime risk of various cancers with a very early age of onset. We are presenting a 41-year-old woman with right invasive ductal cancer and no family history of cancers, diagnosed with mosaic LFS confirmed with blood and skin punch biopsy samples. She was treated with neoadjuvant chemotherapy, mastectomy and sentinel node biopsy with completion axillary dissection. Adjuvant radiation was not recommended due to increased risk of secondary cancers. She also elected to undergo risk reducing contralateral mastectomy. Further research is warranted to determine the appropriate clinical management and surveillance strategies in patients with mosaic LFS as whether individuals with mosaic LFS have differing cancer risks in comparison to classic germline LFS is unknown.

DOI: https://doi.org/10.1093/jscr/rjac408
Case Rep Oncol. 2022 May-Aug;15(2):15(2): 792-797

Detection of BRCA1 Pathogenic Variant in a 24-Year-Old Endometrial Cancer Patient: Risks of Several Hereditary Tumor Syndromes Assessed Using Germline Multigene Panel Testing.

Xiaofei Wang, Keika Kaneko, Hiromi Arakawa, Eri Habano, Makiko Omi, Eri Nakashima, Hiroshi Kawachi, Akiko Tonooka, Kohei Omatsu, Hidetaka Nomura, Mayu Yunokawa, Hiroyuki Kanao, Shunji Takahashi, Takeshi Nakajima, Arisa Ueki.

  A 24-year-old woman suspected of Lynch syndrome was found to carry a BRCA1 pathogenic variant, based on germline multigene panel testing (MGPT). The patient was diagnosed with endometrial carcinoma and underwent modified radical hysterectomy, bilateral salpingo-oophorectomy, pelvic lymphadenectomy, and omentectomy at the age of 23. Based on her father's history of colorectal cancer and her history of early onset endometrial cancer, mismatch repair protein immunohistochemistry analysis was performed. However, no loss of expression for mismatch repair proteins was found. Given her family history of ovarian and breast cancers, MGPT was recommended to identify the presence of any hereditary tumor syndromes. This testing revealed a BRCA1 pathogenic variant (exon13: c.1016delA, p.Lys339ArgfsX2) and diagnosed as hereditary breast and ovarian cancer syndrome (HBOC). Subsequently, the patient's mother also underwent single-site analysis for this variant, and the same pathogenic variant was detected. The patient and her mother are at high risk of developing BRCA1-associated HBOC-related cancers. Based on family history, clinical surveillance is currently underway for this patient and her mother. Currently, MGPT offers the potential for comprehensive genetic cancer risk assessment and may provide a more rational approach for the genetic assessment of those individuals whose personal and family cancer histories do not fit neatly into a single syndrome. This case suggests that if a patient is at high risk for hereditary tumor syndromes, MGPT should be considered to improve disease management strategies in clinical settings.

Keywords:  BRCA1; Endometrial cancer; Hereditary breast and ovarian; Lynch syndrome; Multigene panel testing; cancer syndrome

DOI:  https://doi.org/10.1159/000525941
Gynecol Oncol. 2022 Sep 22. pii: S0090-8258(22)00574-1. [Epub ahead of print]

Germline BRCA mutation carriers are more likely to undergo cytoreductive surgery for relapsed, platinum sensitive, ovarian cancer.

Kadan Yfat, Kotait Mariam, Beiner Mario, Hirte Hal, Josephy Dana, Salman Lina, Bruchim Ilan, Pond Gregory, Helpman Limor.

  OBJECTIVE: BRCA mutations have been associated with improved outcomes in ovarian cancer patients. This study's objective was to compare the secondary cytoreduction surgery (SCS) rates among ovarian cancer patients by BRCA mutation status.METHODS: The study was retrospective and included platinum sensitive recurrent high grade serous ovarian cancer patients from one Canadian center and two Israeli centers from January 1999 to December 2018. Demographic and genetic data, tumor characteristics, patterns of recurrence and surgical and medical treatments were obtained from electronic charts. Patients were grouped according to BRCA mutation status. Logistic regression analyses were used to explore potential prognostic factors of secondary cytoreduction.
RESULTS: 147 patients were enrolled, including 97 from Canada and 50 from Israel. Forty-seven patients (32%) had a BRCA mutation, including 39 (26.5%) germline mutations and 8 (5.5%) somatic mutations. Thirty-one patients (21.1%) underwent SCS. The rate of SCS was 33.3% among the germline BRCA mutation carriers and 15.7% among patients without germline BRCA mutation (p = 0.026). Predictors of secondary cytoreduction included germline BRCA mutation (OR = 2.5, p = 0.03), time to recurrence (OR = 1.004 per month, p < 0.001), absence of lymphatic recurrence (OR = 3.08, p = 0.013), three or fewer lesions at recurrence (OR = 36.74, p < 0.001) and absence of ascites (OR = 9.1, p = 0.034). After adjusting for the number of lesions at recurrence, no other variable remained a significant predictor.
CONCLUSION: Germline BRCA mutation carriers are more likely to undergo secondary cytoreduction. This may be mediated in part by lower volume disease at recurrence. This observation should be considered when planning surveillance for these patients after first-line treatment.

Keywords:  BRCA mutation; Ovarian cancer; Secondary cytoreduction surgery

DOI:  https://doi.org/10.1016/j.ygyno.2022.08.020
Exp Mol Pathol. 2022 Sep 20. pii: S0014-4800(22)00096-X. [Epub ahead of print]128 104833

Targeted molecular profiling of epithelial ovarian cancer from Italian BRCA wild-type patients with a BRCA and PARP pathways gene panel.

Annamaria Salvati, Ileana Carnevali, Elena Alexandrova, Sofia Facchi, Susanna Ronchi, Laura Libera, Nora Sahnane, Domenico Memoli, Jessica Lamberti, Sonia Amabile, Stefano Pepe, Roberta Tarallo, Fausto Sessa, Alessandro Weisz, Maria Grazia Tibiletti, Francesca Rizzo.

  Ovarian cancer (OC) is the fifth most common type of cancer in women and the fourth most common cause of cancer death in women. Identification of pathogenic variants in OC tissues has an important clinical significance for therapeutic and prevention purposes. This study aims to evaluate the mutational profile of a patient cohort, negative for BRCA1/2 germinal variants and Mismatch Repair defects, using next-generation sequencing (NGS) approach on DNA from formalin-fixed paraffin-embedded samples. We used a custom NGS panel, targeting 34 cancer-related genes, mainly of the BRCA and PARP pathways, and analyzed NGS data to identify somatic and germline variants in Italian patients affected by primary epithelial ovarian cancer. We analyzed 75 epithelial ovarian cancer tissues and identified 54 pathogenic variants and 56 variants of unknown significance. TP53 was characterized by the highest mutational rate, occurring in 55% of tested epithelial ovarian cancers (EOCs). Interestingly, a subset of 8 EOCs showed pathogenic variants of homologous recombination pathway, which could be sensitive to PARP-inhibitor therapies. Germline analysis of actionable genes revealed 4 patients carrier of pathogenic germline variants respectively of RAD51C (2 patients), RAD51D, and PALB2. Molecular profiling of EOCs using our custom NGS panel has enabled the detection of both somatic and germline variants, allowing the selection of patients suitable for targeted therapies, and the identification of high-risk OC families that can benefit from genetic counseling and testing.

Keywords:  Epithelial ovarian cancer; Next-generation sequencing; PARP inhibitors; Pathogenic variant; Risk assessment

DOI:  https://doi.org/10.1016/j.yexmp.2022.104833
Clin Lymphoma Myeloma Leuk. 2022 Oct;pii: S2152-2650(22)01404-5. [Epub ahead of print]22 Suppl 2 S309

MDS-287 Genetic Landscape of Somatic Myeloid Mutations in the Presence of Rare TERT Variants and Their Relation to Myeloid Neoplasia.

Alejandro Ferrer, Abhishek M Mangaonkar, Terra L Lasho, Mark E Wylam, Christy M Finke, Jenna A Fernandez, Rong He, David S Viswanatha, Mrinal M Patnaik.

  CONTEXT: Germline variants in the TERT gene may lead to impaired telomere maintenance implicated in the pathogenesis of myelodysplastic syndromes (MDS) by unknown mechanisms.OBJECTIVE: To explore the clinical and genetic associations of germline TERT variants in patients with suspicion of myeloid neoplasm.
DESIGN: We selected patients tested through our institutional amplicon-based sequencing panel (42 myeloid genes, including exons 2 to 16 of TERT, read depth >250X) that carried a TERT variant with allele frequency between 35% and 65%. Variants were classified into those with CADD score >20 and <20 to identify the top 1% according to predicted deleteriousness. Results were correlated with MDS diagnosis and clinical and survival information.
SETTING: Division of Hematology (Mayo Clinic). Research protocol approved by Institutional Review Board.
PATIENTS: Unselected cohort of patients screened with a myeloid mutation gene panel due to clinical suspicion of myeloid neoplasia.
RESULTS: 55 different TERT variants (46 missense, 3 splice sites, 4 synonymous, and 2 in-frame deletions) were identified in 148 individuals from April 2016 to November 2021. None of these patients were diagnosed with a telomere biology disorder and no telomere length measurement was available. All variants were clinically classified as uncertain significance. 17 (12%) patients carried CADD>20 TERT variants of which, 59% (10 patients) were diagnosed with MDS. [5 with <5% bone marrow blasts (4 with normal karyotype) and 5 with 5-19% blasts (all with complex karyotype)] This percentage was higher compared to CADD<20 TERT carriers (34%, 49 patients, p=0.048 by Chi-square test). No major differences were found in age at diagnosis (median 70 vs 73-year-old, p=0.2305), AML-free survival (median 10 vs 15.5 months since diagnosis, p=0.4674), or percentage of carriers of additional variants in myeloid-related genes (60% vs 64%). The most frequently mutated genes in CADD>20 carriers were TP53 (22%), TET2 (18%) and RUNX1 (9%) while in CADD<20 carriers were TET2 (14%), ASXL1 (11%), and SRSF2 (9%). TP53 variants were significantly enriched in CADD>20 TERT carriers. (22.7% vs 7.4%, p=0.0169) Conclusions: CADD>20 TERT variant carriers were more likely to be associated with a diagnosis of MDS and with somatic TP53 mutations than CADD<20 carriers.

Keywords:  MDS; TERT; TP53; Telomere; next-generation sequencing

DOI:  https://doi.org/10.1016/S2152-2650(22)01404-5
Lung Cancer. 2022 Sep 06. pii: S0169-5002(22)00616-X. [Epub ahead of print]173 67-70

Characterization of lung cancers in patients with BRCA germline variants: A multicenter series.

Mateo Sanchis-Borja, Vincent Fallet, Elisabeth Fabre, Marie Wislez, Stéphane Culine, Gérard Zalcman, Jean-Philippe Spano, Nathalie Chabbert Buffet, Florence Coulet, Patrick R Benusiglio, Jacques Cadranel.

  INTRODUCTION: BRCA1 and BRCA2 (BReast CAncer susceptibility genes) are two tumor-suppressor genes associated with the hereditary breast and ovarian cancer susceptibility syndrome. Recent studies also suggest an increased lung adenocarcinoma risk in carriers.METHODS: We conducted a multi-center retrospective study in 18 different French pulmonology and/or oncology departments on medico-administrative and clinical data prospectively collected in the Clinical Data Warehouse (CDW) of Greater Paris University Hospitals (Assistance Publique-Hôpitaux de Paris, AP-HP). Clinical characteristics and outcomes of patients with LC and a previously known BRCA1/2gl variant were retrospectively evaluated.
RESULTS: 17 patients with LC and known BRCA1/2gl variant were included. Patients were most women, former smokers with localized disease and BRCA2 variants. All LC were adenocarcinoma. For patients with medical history of cancer, median time from the first cancer in the BRCA spectrum and the LC occurrence was 20 years. Median disease-free survival (DFS) and overall survival (OS) in localized tumor (Stage I and II) was not reached and 78.6 months, respectively. In advanced cancer (Stade III and IV) median progression free survival was 9.7 months and median OS was 17.8 months. Univariate OS and DFS/PFS analyses by BRCA status did not find significant differences.
CONCLUSION: Results seem to show particular LC features in carriers of BRCA2 variants: adenocarcinoma subtype, woman, former or non-smoker.

Keywords:  BRCA1; BRCA2; Genetic susceptibility to cancer; Germline variants; Lung cancer

DOI:  https://doi.org/10.1016/j.lungcan.2022.09.002
JAAPA. 2022 Oct 01. 35(10): 48-52

Genetic testing for patients at risk of hereditary breast and ovarian cancer.

Alisha DeTroye, Kayla Gabbett, Cheryl Yi, Melanie Judice, Victor Luu, Brittany Nelson, Tanya Gregory.

ABSTRACT: The field of cancer genetic testing has made great advances in correctly identifying patients at risk for hereditary cancer syndromes. These tests, used during a genetic consultation, promote earlier detection of cancer and potentially increase survival. Despite these advancements, a large number of persons at risk for BRCA1/2 mutations remain untested due to a shortage of genetic counselors and lack of clinician knowledge on how to properly screen, identify, and refer patients to genetic counseling. We suggest team-based practices that physician associates/assistants (PAs) and NPs can use in collaboration with genetic counselors. We also explore how PAs and NPs can alleviate the burden on genetic counselors by taking a comprehensive family history, providing elements of counseling, and ordering appropriate genetic tests. This approach maximizes the amount of time the patient spends receiving actual genetic counseling. By creating this collaborative relationship, PAs and NPs can help increase the number of qualifying patients who receive genetic testing and counseling for hereditary breast and ovarian cancer syndromes.

DOI: https://doi.org/10.1097/01.JAA.0000873796.81961.da
Gastroenterol Clin North Am. 2022 Sep;pii: S0889-8553(22)00032-2. [Epub ahead of print]51(3): 561-575

Familial Pancreatic Cancer.

Helena Saba, Michael Goggins.

  Individuals at increased risk of developing pancreatic cancer, including those with a significant family history of the disease and those with pancreatic cancer susceptibility gene variants, can benefit from pancreas surveillance. Most pancreatic cancers diagnosed during surveillance are early-stage and such patients can achieve long-term survival. Determining who should undergo pancreas surveillance is still a work-in-progress, but the main tools clinicians use to estimate an individual's risk of pancreatic cancer are patient's age, the extent of their family history of pancreatic cancer, and whether or not they have a pancreatic cancer susceptibility gene mutation.

Keywords:  Familial; Hereditary; Pancreas surveillance; Pancreatic cancer; Screening

DOI:  https://doi.org/10.1016/j.gtc.2022.06.006
Transl Vis Sci Technol. 2022 Sep 01. 11(9): 30

Germline RB1 Mutation in Retinoblastoma Patients: Detection Methods and Implication in Tumor Focality.

Duangnate Rojanaporn, Sermsiri Chitphuk, Nareenart Iemwimangsa, Takol Chareonsirisuthigul, Duangporn Saengwimol, Rangsima Aroonroch, Usanarat Anurathathapan, Suradej Hongeng, Rossukon Kaewkhaw.

Purpose: The study aimed to generate a stepwise method to reduce the workload of full-scale RB1 sequencing for germline mutation screening in retinoblastoma (RB) patients. The implication of germline mutation in tumor focality was also determined in this study.Methods: A stepwise method was created on the basis of "hotspot" exons analyzed using data on germline RB1 mutation in the RB1-Leiden Open Variation Database and then tested for mutation screening in the blood DNA of 42 patients with RB. The method was compared with the clinical next-generation sequencing (NGS) panel in terms of sequencing outcomes. The germline RB1 mutation was examined in association with multifocality in RB.
Results: Germline RB1 mutation was identified in 61% of all bilateral cases in the first step of the 3 stepwise method and in 78% and 89% for the two and three steps combined, respectively. NGS detected a mosaic variant of RB1 that was not detected by the first two steps and increased the sensitivity from 78% to 83%. Analysis of the relationship between mutation status and tumor focality indicated that multifocality in RB was dependent on germline RB1 mutation, confirming a higher tendency to have a germline RB1 mutation in patients with multifocal RB.
Conclusions: A 3 stepwise method reduces the workload needed for sequencing of the RB1 for bilateral cases. NGS outweighs conventional sequencing in terms of the identification of germline mosaic variants. Multifocal tumors in RB may be used to presume germline mutation.
Translational Relevance: The presence of "hotspot" exons of germline RB1 mutation in bilateral cases facilitates a mutation screening. However, when genetic testing is not available, multifocality in RB regardless of tumor laterality is predictive of germline RB1 mutation.

DOI: https://doi.org/10.1167/tvst.11.9.30