bims-lifras 2021-06-13 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–06–13
eight papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Pathogenic Germline Variants in Cancer Susceptibility Genes in Children and Young Adults With Rhabdomyosarcoma.
Hereditary Leiomyomatosis and Renal Cell Cancer: Recent Insights Into Mechanisms and Systemic Treatment.
MLH1 Exon 12 Gene Deletion Leading to Lynch Syndrome: A Case Report.
Prevalence of BRCA1 and BRCA2 Mutations Among Patients With Ovarian, Primary Peritoneal, and Fallopian Tube Cancer in India: A Multicenter Cross-Sectional Study.
Gene polymorphism-related differences in the outcomes of abiraterone for prostate cancer: a systematic overview.
Hereditary inflammatory fibroid polyps caused by germline pathogenic variants in PDGFRA: Refining PDGFRA-mutation syndrome.
Germline predisposition to haematopoietic malignancies.
Hereditary cancer syndrome-associated pathogenic variants are common in patients with hematologic malignancies subsequent to primary solid cancer.

JCO Precis Oncol. 2021 ;pii: PO.20.00218. [Epub ahead of print]5

Pathogenic Germline Variants in Cancer Susceptibility Genes in Children and Young Adults With Rhabdomyosarcoma.

Jung Kim, Nicholas Light, Vallijah Subasri, Erin L Young, Talia Wegman-Ostrosky, Donald A Barkauskas, David Hall, Philip J Lupo, Rajesh Patidar, Luke D Maese, Kristine Jones, Mingyi Wang, Sean V Tavtigian, Dongjing Wu, Adam Shlien, Frank Telfer, Anna Goldenberg, Stephen X Skapek, Jun S Wei, Xinyu Wen, Daniel Catchpoole, Douglas S Hawkins, Joshua D Schiffman, Javed Khan, David Malkin, Douglas R Stewart.

Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and accounts for 3% of all pediatric cancer. In this study, we investigated germline sequence and structural variation in a broad set of genes in two large, independent RMS cohorts.
MATERIALS AND METHODS: Genome sequencing of the discovery cohort (n = 273) and exome sequencing of the secondary cohort (n = 121) were conducted on germline DNA. Analyses were performed on 130 cancer susceptibility genes (CSG). Pathogenic or likely pathogenic (P/LP) variants were predicted using the American College of Medical Genetics and Genomics (ACMG) criteria. Structural variation and survival analyses were performed on the discovery cohort.
RESULTS: We found that 6.6%-7.7% of patients with RMS harbored P/LP variants in dominant-acting CSG. An additional approximately 1% have structural variants (ATM, CDKN1C) in CSGs. CSG variants did not influence survival, although there was a significant correlation with an earlier age of tumor onset. There was a nonsignificant excess of P/LP variants in dominant inheritance genes in the patients with FOXO1 fusion-negative RMS patients versus the patients with FOXO1 fusion-positive RMS. We identified pathogenic germline variants in CSGs previously (TP53, NF1, DICER1, mismatch repair genes), rarely (BRCA2, CBL, CHEK2, SMARCA4), or never (FGFR4) reported in RMS. Numerous genes (TP53, BRCA2, mismatch repair) were on the ACMG Secondary Findings 2.0 list.
CONCLUSION: In two cohorts of patients with RMS, we identified pathogenic germline variants for which gene-specific therapies and surveillance guidelines may be beneficial. In families with a proband with an RMS-risk P/LP variant, genetic counseling and cascade testing should be considered, especially for ACMG Secondary Findings genes and/or with gene-specific surveillance guidelines.

DOI: https://doi.org/10.1200/PO.20.00218
Front Oncol. 2021 ;11 686556

Hereditary Leiomyomatosis and Renal Cell Cancer: Recent Insights Into Mechanisms and Systemic Treatment.

Congwang Zhang, Lijun Li, Yipeng Zhang, Changchun Zeng.

  Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare autosomal dominant hereditary cancer syndrome characterized by a predisposition to cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma (RCC). It is known to be caused by germline mutations of the fumarate hydratase (FH) gene, which encodes an enzyme component of the citric acid cycle and catalyzes the conversion of fumarate to L-malate. Currently, there is no standardized treatment for HLRCC, which may be due in part to a lack of understanding of the underlying mechanisms. Here, the underlying molecular mechanisms by which the inactivation of FH causes HLRCC are discussed. Additionally, potential therapeutic pharmacological strategies are also summarized to provide new perspectives for the prevention and treatment of HLRCC.

Keywords:  fumarate hydratase; hereditary leiomyomatosis and renal cell carcinoma; mechanism; pathogenesis; treatment

DOI:  https://doi.org/10.3389/fonc.2021.686556
Oncol Res Treat. 2021 Jun 04. 1-7

MLH1 Exon 12 Gene Deletion Leading to Lynch Syndrome: A Case Report.

Shiyun Cui, Xiao Zhang, Ruihan Zou, Fan Ye, Yutong Wang, Jing Sun.

   INTRODUCTION: Deleterious heterozygous mutation of the MLH1 gene is an important cause of Lynch syndrome (LS), an autosomal dominant cancer caused by functional defects in the DNA mismatch repair (MMR) complex.
CASE REPORT: The proband was a 35-year-old patient with confirmed colorectal cancer (CRC). Immunohistochemical (IHC) staining revealed the absence of MLH1 and PMS2 expression in the colorectal tissue specimens of the patient. Genetic counselling and tumor gene testing were performed using next-generation sequencing technology. The genetic tumor verification report showed the deletion of 4 bases in exon 12 of the tested MLH1 gene and a transcoding mutation. To our knowledge, this germline splice site mutation of MLH1 has not been reported before. The proband accepted several therapeutic regimens including PD-1 inhibitor and ultimately died of multiple organ failure.
CONCLUSION: Nonsense mutations and frameshift mutations of MMR genes are the most common causes of LS. Common mutations include those in MSH2, MLH1, MSH6, and PMS2. We report a mutation of MLH1 that has never been reported before. We recommend that patients with a history of colon or rectal cancer receive universal MMR or MSI testing and checkpoint inhibitor therapy for the first-line treatment of deficient MMR CRC.

Keywords:  Colorectal cancer; Germline mutation; Lynch syndrome; Mismatch repair; PD-1 inhibitors

DOI:  https://doi.org/10.1159/000516659
JCO Glob Oncol. 2021 Jun;7 849-861

Prevalence of BRCA1 and BRCA2 Mutations Among Patients With Ovarian, Primary Peritoneal, and Fallopian Tube Cancer in India: A Multicenter Cross-Sectional Study.

Sudeep Gupta, Senthil Rajappa, Suresh Advani, Amit Agarwal, Shyam Aggarwal, Chanchal Goswami, Satya Dattatreya Palanki, Devavrat Arya, Shekhar Patil, Rohit Kodagali.

PURPOSE: There are deficient data on prevalence of germline mutations in breast cancer susceptibility genes 1 and 2 (BRCA1/BRCA2) in Indian patients with ovarian cancer who are not selected by clinical features.
METHODS: This prospective, cross-sectional, noninterventional study in nine Indian centers included patients with newly diagnosed or relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer. The primary objective was to assess the prevalence of BRCA1/BRCA2 mutations, and the secondary objective was to correlate BRCA1/BRCA2 status with clinicopathologic characteristics. Mutation testing was performed by a standard next-generation sequencing assay.
RESULTS: Between March 2018 and December 2018, 239 patients with a median age of 53.0 (range, 23.0-86.0 years) years were included, of whom 203 (84.9%) had newly diagnosed disease, 36 (15.1%) had family history of ovarian or breast cancer, and 159 (66.5%) had serous subtype of epithelial ovarian cancer. Germline pathogenic or likely pathogenic mutations in BRCA1 and BRCA2 were detected in 37 (15.5%; 95% CI, 11.1 to 20.7) and 14 (5.9%; 95% CI, 3.2 to 9.6) patients, respectively, whereas variants of uncertain significance in these genes were seen in four (1.7%; 95% CI, 0.5 to 4.2) and six (2.5%; 95% CI, 0.9 to 5.4) patients, respectively. The prevalence of pathogenic or likely pathogenic BRCA mutations in patients with serous versus nonserous tumors, with versus without relevant family history, and ≤ 50 years versus > 50 years, were 40 of 159 (25.2%; 95% CI, 18.6 to 32.6) versus 11 of 80 (13.8%; 95% CI, 7.1 to 23.3; P = .0636), 20 of 36 (55.6%; 95% CI, 38.1 to 72.1) versus 41 of 203 (20.2%; 95% CI, 14.9 to 26.4; P < .0001), and 20 of 90 (22.2%; 95% CI, 14.1 to 32.2) versus 31 of 149 (20.8%; 95% CI, 14.6 to 28.2; P = .7956), respectively.
CONCLUSION: There is a high prevalence of pathogenic or likely pathogenic germline BRCA mutations in Indian patients with ovarian cancer.

DOI: https://doi.org/10.1200/GO.21.00051
Am J Cancer Res. 2021 ;11(5): 1873-1894

Gene polymorphism-related differences in the outcomes of abiraterone for prostate cancer: a systematic overview.

Min Liu, Hongzhe Shi, Jiaqing Yan, Yuan Zhang, Yinglin Ma, Kaidi Le, Zhongdong Li, Nianzeng Xing, Guohui Li.

Numerous prostate cancer (PC) associated genes have been reported in previous genome-wide association studies. Elucidation of prostate cancer pharmacogenomics have enhanced studies into the impact of germline genetic changes on treatment, in addition to evaluating related genomic alterations and biomarkers in prostate tumor tissues. Currently, Abiraterone (Abi) is used as one of the therapeutic options for PC. In this article, germline variants that have been associated with responses to Abi in patients with advanced PC are summarized. These include biomarker genes such as CYP17A1, AR-V7, HSD3B1, SLCO2B1, SULT1E1, and SRD5A2 that are involved in homologous recombination, as well as in gene expression mutations in important signaling pathways, such as WNT and Abi metabolic pathways.

Keywords: Genetic polymorphisms; abiraterone; androgen receptor; prognostic; prostate cancer
Cancer Genet. 2021 May 24. pii: S2210-7762(21)00109-5. [Epub ahead of print]256-257 106-109

Hereditary inflammatory fibroid polyps caused by germline pathogenic variants in PDGFRA: Refining PDGFRA-mutation syndrome.

Rachel Hodan, Gregory W Charville, Uri Ladabaum.

  A 35-year-old Filipino woman presented with epigastric pain and was found to have two large jejunal and ileal inflammatory fibroid polyps (IFPs) and dozens of subcentimeter small bowel submucosal nodules. Targeted exon sequencing of PDGFRA on the resected jejunum IFP identified a variant c.1664A>G that was subsequently confirmed in the germline. Family history was striking for three relatives with confirmed IFPs, including one with small bowel intussusception on five occasions. All relatives with IFPs were confirmed to have the same PDGFRA germline likely pathogenic variant, all were female, and all had IFPs by age 50 years that necessitated surgery. Two obligate carriers were reported to have had a similar phenotype while at least one obligate male carrier had no reported history of IFPs. This is the sixth reported family with a germline PDGFRA pathogenic variant and history of IFPs or gastrointestinal stromal tumor (GIST). This is the second report of the c.1664A>G likely pathogenic variant in a family that is unrelated to, and of different ethnic origin than, the first family. This second family exhibited a striking history of multiple IFPs without any reported GISTs, suggesting a possible genotype/phenotype association for this variant, and a possible female gender penetrance bias.

Keywords:  Germline mutation; Hereditary gastrointestinal cancer; Inflammatory polyps; Small bowel polyps

DOI:  https://doi.org/10.1016/j.cancergen.2021.05.003
Hum Mol Genet. 2021 Jun 07. pii: ddab141. [Epub ahead of print]

Germline predisposition to haematopoietic malignancies.

Simone Feurstein, Michael Drazer, Lucy A Godley.

Once thought to be exceedingly rare, the advent of next-generation sequencing has revealed a plethora of germline predisposition disorders that confer risk for haematopoietic malignancies (HMs). These syndromes are now recognized to be much more common than previously thought. The recognition of a germline susceptibility risk allele in an individual impacts the clinical management and health surveillance strategies in the index patient and relatives who share the causative DNA variant. Challenges to accurate clinical testing include a lack of familiarity in many health care providers, the requirement for DNA samples that reasonably approximate the germline state, and a lack of standardization among diagnostic platforms as to which genes are sequenced and their capabilities in detecting the full range of variant types that confer risk. Current knowledge gaps include a comprehensive understanding of all predisposition genes; whether scenarios exist in which an allogeneic stem cell transplant using donor haematopoietic stem cells with deleterious variants is permissive; and effective means of delivering genetic counseling and results disclosure for these conditions. We are hopeful that comprehensive germline genetic testing, universal germline testing for all patients with an HM, universal germline testing for allogeneic haematopoietic stem cell donors, and the development of preventive strategies to delay or even prevent malignancies will be available in the near future. These factors will likely contribute to improved health outcomes for at-risk individuals and their family members.

DOI: https://doi.org/10.1093/hmg/ddab141
J Cancer. 2021 ;12(14): 4288-4294

Hereditary cancer syndrome-associated pathogenic variants are common in patients with hematologic malignancies subsequent to primary solid cancer.

Joowon Oh, Yu Ri Kim, Yoonjung Kim, Boyeon Kim, Kyung Sun Park, Seong-Hyeuk Nam, Kyung-A Lee.

  Background: As the number of long-term survivors of solid cancers keeps increasing, risk assessment of secondary hematologic malignancies is important for the prognosis of the patient. Germline genetic predisposition to secondary hematologic malignancy has been studied widely in myeloid neoplasms and rarely in lymphoid neoplasms. This study aimed to profile the mutational spectrums of patients with subsequent lymphoid tissue neoplasm to shed some light on the understudied area. Methods: In total, 39 patients who had primary solid cancer and subsequent hematologic malignancies were enrolled. We performed two next-generation sequencing (NGS) panel tests encompassing hereditary cancer predisposition genes and genes related to clonal hematopoiesis of indeterminate potential (CHIP). All statistical analyses were performed using R 3.5.1. Results: We found 8 of 39 patients with germline mutations in cancer predisposition genes; 4 of 18 patients had therapy-related myeloid neoplasms (22.2%); and 4 of 15 patients had secondary lymphoid malignancies (26.7%). Notably, of 14 patients who initially suffered from thyroid cancer, 5 patients (35.7%) had germline mutations. Malignancy of lymphoid tissue showed no association with radioactive iodine therapy but was observed to a greater extent in germline mutation-positive thyroid cancer patients regardless of their history of treatment. We observed that 24 of 39 patients (61.5%) were CHIP carriers. Patients who had secondary lymphoid malignancy were less likely to have CHIP than those who had myeloid malignancy. Conclusions: In patients with primary solid cancer who are planning to undergo cytotoxic chemotherapy, radiotherapy, or radioactive iodine therapy, an initial assessment with germline mutation testing using an expanded NGS panel, including low, moderate, and high-risk cancer-associated genes, and somatic CHIP mutation testing can screen the patients who are at risk of developing therapy-related myeloid and lymphoid malignancies. Through careful screening and monitoring throughout the treatment process, patients can benefit from the early detection of secondary malignancies and receive proper treatment.

Keywords:  clonal hematopoiesis of indeterminate potential; germline predisposition to cancer; hematologic malignancy; next-generation sequencing; therapy-related myeloid neoplasms

DOI:  https://doi.org/10.7150/jca.54169