bims-lifras 2022-10-16 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022–10–16
twelve papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Breast Cancer after Radiation Therapy in a Patient with Li-Fraumeni Syndrome: A Case Report.
A novel germline mutation of TP53 with breast cancer diagnosed as Li-Fraumeni syndrome.
Mutation Patterns in Portuguese Families with Hereditary Breast and Ovarian Cancer Syndrome.
Landscape of germline cancer predisposition mutations testing and management in pediatrics: Implications for research and clinical care.
Germline Variants in 32 Cancer-Related Genes among 700 Chinese Breast Cancer Patients by Next-Generation Sequencing: A Clinic-Based, Observational Study.
Moderate-Risk Genes for Hereditary Ovarian Cancers Involved in the Homologous Recombination Repair Pathway.
Increased Co-Occurrence of Pathogenic Variants in Hereditary Breast and Ovarian Cancer and Lynch Syndromes: A Consequence of Multigene Panel Genetic Testing?
Management of ovarian and breast cancer risk in non-BRCA HBOC pathogenic variant carriers in a large California health care system.
A Germline Variant Deregulates MYC Expression in IDH1-Mutant Glioma.
A need to tailor surveillance based on family history: describing a highly penetrant familial paraganglioma kindred with an SDHD pathogenic variant.
A novel germline HAVCR2 (TIM-3) compound heterozygous mutation is related to hemophagocytic lymphohistiocytic syndrome in EBV-positive peripheral T-cell lymphoma (NOS) with down-regulated TIM-3 signaling.
ASSESSING PATIENT ATTITUDES TOWARD GENETIC TESTING FOR HEREDITARY HEMATOLOGIC MALIGNANCY.

Taehan Yongsang Uihakhoe Chi. 2022 Jan;83(1): 246-251

Breast Cancer after Radiation Therapy in a Patient with Li-Fraumeni Syndrome: A Case Report.

In Na Yoon, Eun Suk Cha, Jeoung Hyun Kim, Jee Eun Lee, Jin Chung.

  Li-Fraumeni syndrome (LFS) is an inherited autosomal-dominant tumor-predisposition disorder caused by germline mutations in the TP53 tumor suppressor gene. Since patients with LFS are likely to develop therapy-related cancers, radiation therapy should be avoided if breast cancer is found in these individuals. Herein, we present a case of secondary breast cancer in an LFS patient after radiation and chemotherapy for the first diagnosed breast sarcoma.

Keywords:  Breast Neoplasms; Li-Fraumeni Syndrome; Sarcoma; Second Primary

DOI:  https://doi.org/10.3348/jksr.2021.0045
Surg Case Rep. 2022 Oct 11. 8(1): 197

A novel germline mutation of TP53 with breast cancer diagnosed as Li-Fraumeni syndrome.

Masaya Kai, Makoto Kubo, Sawako Shikada, Saori Hayashi, Takafumi Morisaki, Mai Yamada, Yuka Takao, Akiko Shimazaki, Yurina Harada, Kazuhisa Kaneshiro, Yusuke Mizuuchi, Koji Shindo, Masafumi Nakamura.

  TP53 is a tumor suppressor gene and, when dysfunctional, it is known to be involved in the development of cancers. Li-Fraumeni syndrome (LFS) is a hereditary tumor with autosomal dominant inheritance that develops in people with germline pathogenic variants of TP53. LFS frequently develops in parallel to tumors, including breast cancer. We describe a novel germline mutation in TP53 identified by performing a multi-gene panel assay in a breast cancer patient with bilateral breast cancer.

Keywords:  Breast cancer; Genetic medicine; Genetic testing; Hereditary cancer; Li–Fraumeni syndrome; Multi-gene panel assay; TP53 pathogenic variant

DOI:  https://doi.org/10.1186/s40792-022-01546-y
Cancers (Basel). 2022 Sep 28. pii: 4717. [Epub ahead of print]14(19):

Mutation Patterns in Portuguese Families with Hereditary Breast and Ovarian Cancer Syndrome.

Rodrigo Vicente, Diogo Alpuim Costa, Marina Vitorino, Ana Duarte Mendes, Catarina Santos, Mário Fontes-Sousa.

  Germline pathogenic variants in the Breast Cancer Genes 1 (BRCA1) and 2 (BRCA2) are responsible for Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Genetic susceptibility to breast cancer accounts for 5-10% of all cases, phenotypically presenting with characteristics such as an autosomal dominant inheritance pattern, earlier age of onset, bilateral tumours, male breast cancer, and ovarian tumours, among others. BRCA2 pathogenic variant is usually associated with other cancers such as melanoma, prostate, and pancreatic cancers. Many rearrangements of different mutations were found in both genes, with some ethnic groups having higher frequencies of specific mutations due to founder effects. Despite the heterogeneity of germline BRCA1/BRCA2 mutations in Portuguese breast or/and ovarian cancer families, the first described founder mutation in the BRCA2 gene (c.156_157insAlu) and two other variants in the BRCA1 gene (c.3331_3334del and c.2037delinsCC) contribute to about 50% of all pathogenic mutations. Furthermore, the families with the BRCA1 c.3331_3334del or the c.2037delinsCC mutations share a common haplotype, suggesting that these may also be founder mutations in the Portuguese population. Identifying specific and recurrent/founder mutations plays an important role in increasing the efficiency of genetic testing since it allows the use of more specific, cheaper and faster strategies to screen HBOC families. Therefore, this review aims to describe the mutational rearrangements of founder mutations and evaluate their impact on the genetic testing criteria for HBOC families of Portuguese ancestry.

Keywords:  Portuguese families; breast cancer; founder mutations; genetic testing; hereditary breast and ovarian cancer syndrome; ovarian cancer

DOI:  https://doi.org/10.3390/cancers14194717
Front Pediatr. 2022 ;10 1011873

Landscape of germline cancer predisposition mutations testing and management in pediatrics: Implications for research and clinical care.

Shilpa A Shahani, Erin L Marcotte.

  As germline genetic testing capacities have improved over the last two decades, increasingly more people are newly diagnosed with germline cancer susceptibility mutations. In the wake of this growth, there remain limitations in both testing strategies and translation of these results into morbidity- and mortality-reducing practices, with pediatric populations remaining especially vulnerable. To face the challenges evoked by an expanding diversity of germline cancer mutations, we can draw upon a model cancer-associated genetic condition for which we have developed a breadth of expertise in managing, Trisomy 21. We can additionally apply advances in other disciplines, such as oncofertility and pharmacogenomics, to enhance care delivery. Herein, we describe the history of germline mutation testing, epidemiology of known germline cancer mutations and their associations with childhood cancer, testing limitations, and future directions for research and clinical care.

Keywords:  cancer predisposition; cancer syndrome; childhood cancer; genetic testing; germline predisposition

DOI:  https://doi.org/10.3389/fped.2022.1011873
Int J Mol Sci. 2022 Sep 24. pii: 11266. [Epub ahead of print]23(19):

Germline Variants in 32 Cancer-Related Genes among 700 Chinese Breast Cancer Patients by Next-Generation Sequencing: A Clinic-Based, Observational Study.

Liu Yang, Fei Xie, Chang Liu, Jin Zhao, Taobo Hu, Jinbo Wu, Xiaotao Zhao, Shu Wang.

  Breast cancer (BC) is associated with hereditary components, and some deleterious germline variants have been regarded as effective therapeutic targets. We conducted a clinic-based, observational study to better understand the distribution of deleterious germline variants and assess any clinicopathological predictors related to the variants among Chinese BC patients using a 32 cancer-related genes next-generation sequencing panel. Between November 2020 and February 2022, a total of 700 BC patients were recruited, and 13.1% (92/700) of them carried deleterious germline variants in 15 cancer-related genes, including 37 (37/700, 5.3%) in BRCA2, 29 (29/700, 4.1%) in BRCA1, 8 (8/700, 1.1%) in PALB2, 4 (4/700, 0.6%) in NBN, 3 (3/700, 0.4%) in MRE11A, 3 (3/700, 0.4%) in TP53 and 12 (12/700, 1.7%) in other genes. There were 28 novel variants detected: 5 in BRCA1, 14 in BRCA2, and 9 in non-BRCA1/2 genes. The variants in panel genes, HRR (homologous recombination repair)-related genes, and BRCA1/2 were significantly associated with the following clinicopathological factors: age at the initial diagnosis of BC, family history of any cancer, molecular subtype, Ki-67 index, and hereditary risk. In conclusion, we further expanded the spectrum of germline deleterious variants in Chinese BC patients, and the clinicopathological predictors of variants were identified to facilitate clinical genetic testing and counseling for appropriate individuals.

Keywords:  BRCA1/2; Chinese population; breast cancer; germline mutations; next-generation sequencing

DOI:  https://doi.org/10.3390/ijms231911266
Int J Mol Sci. 2022 Oct 04. pii: 11790. [Epub ahead of print]23(19):

Moderate-Risk Genes for Hereditary Ovarian Cancers Involved in the Homologous Recombination Repair Pathway.

Akiko Abe, Issei Imoto, Arisa Ueki, Hidetaka Nomura, Hiroyuki Kanao.

  Approximately 20% of cases of epithelial ovarian cancer (EOC) are hereditary, sharing many causative genes with breast cancer. The lower frequency of EOC compared to breast cancer makes it challenging to estimate absolute or relative risk and verify the efficacy of risk-reducing surgery in individuals harboring germline pathogenic variants (GPV) in EOC predisposition genes, particularly those with relatively low penetrance. Here, we review the molecular features and hereditary tumor risk associated with several moderate-penetrance genes in EOC that are involved in the homologous recombination repair pathway, i.e., ATM, BRIP1, NBN, PALB2, and RAD51C/D. Understanding the molecular mechanisms underlying the expression and function of these genes may elucidate trends in the development and progression of hereditary tumors, including EOC. A fundamental understanding of the genes driving EOC can help us accurately estimate the genetic risk of developing EOC and select appropriate prevention and treatment strategies for hereditary EOC. Therefore, we summarize the functions of the candidate predisposition genes for EOC and discuss the clinical management of individuals carrying GPV in these genes.

Keywords:  epithelial ovarian cancer; germline pathogenic variant; hereditary tumor; homologous recombination repair pathway; moderate risk

DOI:  https://doi.org/10.3390/ijms231911790
Int J Mol Sci. 2022 Sep 29. pii: 11499. [Epub ahead of print]23(19):

Increased Co-Occurrence of Pathogenic Variants in Hereditary Breast and Ovarian Cancer and Lynch Syndromes: A Consequence of Multigene Panel Genetic Testing?

Mar Infante, Mónica Arranz-Ledo, Enrique Lastra, Luis Enrique Abella, Raquel Ferreira, Marta Orozco, Lara Hernández, Noemí Martínez, Mercedes Durán.

  The probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes for hereditary breast and ovarian cancer and lynch syndromes in the same patient is uncommon, except in populations where founder effects exist. Two breast cancer women that are double heterozygotes (DH) for both BRCA1/BRCA2, one ovarian cancer case DH for BRCA1/RAD51C, and another breast and colorectal cancer who is DH for BRCA2/PMS2 were identified in our cohort. Ages at diagnosis and severity of disease in BRCA1/BRCA2 DH resembled BRCA1 single-carrier features. Similarly, the co-existence of the BRCA2 and PMS2 mutations prompted the development of breast and colorectal cancer in the same patient. The first BRCA1/BRCA2 DH was identified by HA-based and Sanger sequencing (1 of 623 families with BRCA PVs). However, this ratio has increased up to 2.9% (1 DH carrier vs. 103 single PV carriers) since using a custom 35-cancer gene on-demand panel. The type of cancer developed in each DH patient was consistent with the independently inherited condition, and the clinical outcome was no worse than in patients with single BRCA1 mutations. Therefore, the clinical impact, especially in patients with two hereditary syndromes, lies in genetic counseling tailor-made for each family based on the clinical guidelines for each syndrome. The number of DH is expected to be increased in the future as a result of next generation sequencing routines.

Keywords:  Hereditary Breast and Ovarian Cancer Syndrome (HBOC); Lynch Syndrome (LS); double heterozygotes; genetic counseling; multi-gene panel testing

DOI:  https://doi.org/10.3390/ijms231911499
Gynecol Oncol. 2022 Oct 08. pii: S0090-8258(22)01857-1. [Epub ahead of print]

Management of ovarian and breast cancer risk in non-BRCA HBOC pathogenic variant carriers in a large California health care system.

C Bethan Powell, Cecile Laurent, Christine Garcia, Elizabeth Hoodfar, Audrey Karlea, Christine Kobelka, Jaimie Lee, Janise Roh, Lawrence H Kushi.

   PURPOSE: To describe breast and ovarian cancer risk reduction strategies in the clinical management of women who test positive for non-BRCA hereditary breast and ovarian cancer (HBOC) pathogenic variants compared to those who test positive for pathogenic BRCA variants or have negative germline panel testing.
METHODS: Examination of imaging and preventive surgeries in women undergoing HBOC genetic testing from 1/1/2015 to 12/31/2018, with follow up to 03/31/2020 in Kaiser Permanente Northern California.
RESULTS: A total of 13,271 tests which included HBOC genes were identified. Rate of bilateral salpingo-oophorectomy after genetic testing were similar for BRCA and the non-BRCA moderate risk ovarian pathogenic variants (PVs) (47.4% vs 54%, p = 0.25). Rates were lower for low risk or unknownrisk non-BRCA PVs (12.8%, p < 0.001, 5.3% (p < 0.001). Rates of surveillance for ovarian cancer with ultrasound and CA 125 in the first year was 63.3% and 64.7% for BRCA PV, 37.5% and 27.1%, for non-BRCA moderate risk PVs and 13.7% and 4.6%, for low-risk PVs. Bilateral mastectomy rates were 19.7% for BRCA PV, 10.1% (p = 0.028) for non-BRCA breast high risk PVs, for moderate risk PVs 7.7% (p < 0.001) and for unknown risk 0.4% (p < 0.001). MRI surveillance rates in the first year similarly were 47.4% for non-BRCA BRCA PV, 43% for breast high risk PV, 39.4% for moderate risk and 4.9% for unknown risk PV.
CONCLUSION: Surgical and surveillance strategies are underutilized for HBOC PV, however there is concordance of uptake of preventive strategies with specific risk associated with non-BRCA PVs.

Keywords:  Breast neoplasms; Cancer panel testing; Genetics; Hereditary; Ovarian neoplasms

DOI:  https://doi.org/10.1016/j.ygyno.2022.10.001
Cancer Discov. 2022 Oct 14. OF1

A Germline Variant Deregulates MYC Expression in IDH1-Mutant Glioma.

The germline polymorphism rs55705857-G was identified as the causal variant in IDH-mutant glioma.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-181
Fam Cancer. 2022 Oct 12.

A need to tailor surveillance based on family history: describing a highly penetrant familial paraganglioma kindred with an SDHD pathogenic variant.

Madeline Foley, Anu Sharma, Kinley Garfield, Luke Maese, Luke Buchmann, Julie Boyle, Wendy Kohlmann, Joanne Jeter, Samantha Greenberg.

  Pathogenic variants (PVs) in the SDHD gene increase risk for paragangliomas (PGL)/pheochromocytomas, renal cell carcinomas, and gastrointestinal stromal tumors. Penetrance in individuals with SDHD PVs varies in reported research from 40-70%, and there is limited evidence of specific genotype risks. This study aims to characterize a multi-generational family with SDHD p.Trp43* PVs and potential genotype-phenotype considerations for surveillance. Individuals with a paternally inherited SDHD p.Trp43*(c.129G > A) PV were identified. Genetic, medical and family histories were abstracted, including clinical characteristics, tumor histories, and treatment approaches. Eleven individuals with the SDHD PV in the same kindred were diagnosed with 41 SDHx-related tumors across all family members. Eight individuals developed 27 head and neck PGL of varying origins, and seven individuals developed tumors outside of the head and neck region. Many individuals had multiple tumors, and age of first tumor diagnosis ranged from age 10 to age 45 years old. Individuals with SDHD p.Trp43* variants may have higher risks for SDHx related tumors than other SDHD variants. Prioritizing identification of at-risk individuals and initiating surveillance tailored to family history is recommended given the rate of multiple tumors found in one familial branch of individuals under 18 years old. Individuals with strong family histories of PGL at young ages with this PV will benefit from tailored surveillance recommendations.

Keywords:  Genetics; Germline mutation; Pheochromocytoma; SDHx; Succinate dehydrogenase; Tumor predisposition

DOI:  https://doi.org/10.1007/s10689-022-00318-9
Front Oncol. 2022 ;12 870676

A novel germline HAVCR2 (TIM-3) compound heterozygous mutation is related to hemophagocytic lymphohistiocytic syndrome in EBV-positive peripheral T-cell lymphoma (NOS) with down-regulated TIM-3 signaling.

Yang Zhang, Zhihua Wang, Guoyu Hu, Jieping Li, Yongheng Chen, Yi Jiang, Haiying Zhong, Xianling Liu, Chunhong Hu, Honglin Peng, Yunxiao Xu, Zhao Cheng, Guangsen Zhang.

  Recently, it have been reported that Hepatitis A Virus-Cellular Receptor 2(HAVCR2,encoding T-cell immunoglobulin and Mucin-Containing Protein 3[TIM3]) mutations are associated with severe hemophagocytic syndrome(HLH) in subcutaneous panniculitis-like T-cell lymphoma(SPTCL),and there are also frequent mutations in sporadic SPTCL, suggesting the individuals harboring HAVCR2(TIM-3) germline mutations are highly susceptible to familial or sporadic SPTCL. Here, we identify a novel germline compound heterozygous mutation of TIM-3 gene,c.245A>G (p.Tyr82Cys) and c.265C>T(p.Arg89Cys) variations in a single familial case with EBV-positive peripheral T-cell lymphoma(NOS),accompanied HLH;we also detected Tyr82Cys germline mutation in TIM-3 gene in one sporadic patient with cutaneous T cell lymphoma. We screened the distributive frequencies for TIM-3 mutations in healthy controls(n=87), B-(n=79) or T-cell lymphoma(n=25) not SPTCL, and the results showed that the mutation was found in two out of 25 patients with T-cell lymphoma but was not detected in 79 patients with B-cell lymphoma nor in a group of 87 controls. The mRNA expression of TIM-3 on primary cells and transfected HEK293 cells reduced significantly, indicating Tyr82Cys and Arg89Cys mutations is a loss-of function mutations on TIM-3,resulting in a weakened TIM-3 signaling. Our results suggest Tyr82Cys TIM-3 germline mutations are not only limited in SPTCL, and also occurred in other types of T-cell lymphoma, especially complicated HLH. TIM-3 mutations may be an predisposing factor for T-cell lymphoma and molecular marker for auxiliary diagnosis in T cell lymphoma,especially complicated with HLH.

Keywords:  EBV-positive; HAVCR2 (TIM-3); hemophagocytic lymphohistiocytic syndrome; mutation; peripheral T-cell lymphoma

DOI:  https://doi.org/10.3389/fonc.2022.870676
Eur J Haematol. 2022 Oct 09.

ASSESSING PATIENT ATTITUDES TOWARD GENETIC TESTING FOR HEREDITARY HEMATOLOGIC MALIGNANCY.

Addison Q Johnson, Sarah A Bannon, Laura S Farach, Samuel M Hyde, S Shahrukh Hashmi, Chelsea Wagner, Courtney D DiNardo.

  Since 2003, more than 15 genes have been identified to predispose to hereditary hematologic malignancy (HHM). Although the yield of germline analysis for leukemia appears like that of solid tumors, genetic referrals in adults with leukemia remains underperformed. We assessed leukemia patients' attitudes toward genetic testing and leukemia-related distress through a survey of 1093 patients diagnosed with acute or chronic leukemia, myelodysplastic syndrome, or aplastic anemia. Principal component analysis (PCA) was used to analyze patient attitudes. Distress was measured through the Impact of Event Scale-Revised (IES-R). 19.8% of eligible respondents completed the survey. The majority reported interest in (77%) or choosing to have (78%) genetic testing for HHM. Slightly over half identified worry about cost of genetic testing (58%) or health insurance coverage (61%) as possible barriers. PCA identified relevant themes of interest in genetic testing, impact on leukemia treatment, discrimination and confidentiality, psychosocial and familial impacts, and cost of testing. The majority reported low distress. Leukemia patients report high interest in genetic testing, few barriers, and relatively low distress. This article is protected by copyright. All rights reserved.

Keywords:  Genetic counseling; attitudes; distress; genetic testing; hematologic malignancy; leukemia

DOI:  https://doi.org/10.1111/ejh.13880