bims-lifras 2022-04-03 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022–04–03
ten papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Lessons From Pediatric MDS: Approaches to Germline Predisposition to Hematologic Malignancies.
The germline p53 activation syndrome: A new patient further refines the clinical phenotype.
Identification and Management of Pathogenic Variants in BRCA1, BRCA2, and PALB2 in a Tumor-Only Genomic Testing Program.
Genetic Analysis of a Family with Multiple Incidences of Prostate Cancer.
Functional analysis of ATM variants in a high risk cohort provides insight into missing heritability.
Early age of onset and broad cancer spectrum persist in MSH6- and PMS2-associated Lynch syndrome.
DETECTION OF DISEASE-CAUSING MUTATIONS IN PROSTATE CANCER BY NGS SEQUENCING.
An inherited gain-of-function risk allele in EPOR predisposes to familial JAK2V617F myeloproliferative neoplasms.
Germline Mutation Analysis in Sporadic Breast Cancer Cases With Clinical Correlations.
BAP1 Tumor Predisposition Syndrome Presenting as a Recurrent Ovarian Sex Cord-Stromal Tumor.

Front Oncol. 2022 ;12 813149

Lessons From Pediatric MDS: Approaches to Germline Predisposition to Hematologic Malignancies.

Serine Avagyan, Akiko Shimamura.

  Pediatric myelodysplastic syndromes (MDS) often raise concern for an underlying germline predisposition to hematologic malignancies, referred to as germline predisposition herein. With the availability of genetic testing, it is now clear that syndromic features may be lacking in patients with germline predisposition. Many genetic lesions underlying germline predisposition may also be mutated somatically in de novo MDS and leukemias, making it critical to distinguish their germline origin. The verification of a suspected germline predisposition informs therapeutic considerations, guides monitoring pre- and post-treatment, and allows for family counseling. Presentation of MDS due to germline predisposition is not limited to children and spans a wide age range. In fact, the risk of MDS may increase with age in many germline predisposition conditions and can present in adults who lack classical stigmata in their childhood. Furthermore, germline predisposition associated with DDX41 mutations presents with older adult-onset MDS. Although a higher proportion of pediatric patients with MDS will have a germline predisposition, the greater number of MDS diagnoses in adult patients may result in a larger overall number of those with an underlying germline predisposition. In this review, we present a framework for the evaluation of germline predisposition to MDS across all ages. We discuss characteristics of personal and family history, clinical exam and laboratory findings, and integration of genetic sequencing results to assist in the diagnostic evaluation. We address the implications of a diagnosis of germline predisposition for the individual, for their care after MDS therapy, and for family members. Studies on MDS with germline predisposition have provided unique insights into the pathogenesis of hematologic malignancies and mechanisms of somatic genetic rescue vs. disease progression. Increasing recognition in adult patients will inform medical management and may provide potential opportunities for the prevention or interception of malignancy.

Keywords:  germline; hematologic malignancy; inherited bone marrow failure syndromes; myelodysplastic syndrome; predisposition syndromes

DOI:  https://doi.org/10.3389/fonc.2022.813149
Am J Med Genet A. 2022 Apr 01.

The germline p53 activation syndrome: A new patient further refines the clinical phenotype.

Runjun D Kumar, Mustafa Tosur, Seema R Lalani, Donald H Mahoney, Alison A Bertuch.

  The tumor suppressor p53 has well known roles in cancer development and germline cancer predisposition disorders, but increasing evidence supports the role of activation of this transcription factor in the pathogenesis of inherited bone marrow failure and chromosomal instability disorders. Here we report a patient with red cell aplasia, which was steroid responsive, as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths, who had a germline heterozygous C-terminal frameshift variant in TP53 similar to others that activate the transcription factor. This is the third reported individual with a germline p53 activation syndrome, with several unique features that refine the clinical disease associated with these variants.

Keywords:  bone marrow failure; nonsense-mediated decay; p53; red cell aplasia

DOI:  https://doi.org/10.1002/ajmg.a.62749
Clin Cancer Res. 2022 Apr 01. pii: clincanres.2861.2021. [Epub ahead of print]

Identification and Management of Pathogenic Variants in BRCA1, BRCA2, and PALB2 in a Tumor-Only Genomic Testing Program.

Brittany L Bychkovsky, Tianyu Li, Jilliane Sotelo, Nabihah Tayob, Joanna Mercado, Israel Gomy, Anu Chittenden, Sarah Kane, Samantha Stokes, Melissa E Hughes, Ji Seok Kim, Renato Umeton, Mark M Awad, Panagiotis A Konstantinopoulos, Matthew B Yurgelun, Brian M Wolpin, Mary-Ellen Taplin, Randall E Newmark, Bruce E Johnson, Neal I Lindeman, Laura E MacConaill, Judy E Garber, Nancy U Lin.

PURPOSE: Tumor-only genomic testing can uncover somatic and germline pathogenic variants (P/LPs) in cancer predisposition genes. We describe the prevalence of P/LPs in BRCA1/2 and PALB2 (B1B2P2) across malignancies and the frequency of clinical germline testing (CGT) in patients with P/LPs in B1B2P2 identified on tumor-only testing.
EXPERIMENTAL DESIGN: Among 7,575 patients tested between 2016-2018 with the OncoPanel tumor-only sequencing assay, we characterized P/LP frequencies by tumor type, receipt of CGT prior to or within 12 months (m) after OncoPanel, and factors associated with CGT.
RESULTS: 272 (3.6%) had OncoPanel-detected P/LPs in B1B2P2: 37.5% of P/LPs were in BRCA-related cancers; the remainder were in non-BRCA tumors. P/LPs were detected in {greater than or equal to}5% of breast, pancreatic, prostate, ovarian, non-melanoma skin, endometrial, small-cell lung and colorectal cancers. 37.9% of patients with P/LPs received GCT prior to OncoPanel; an additional 10.7% underwent CGT within 12m of OncoPanel. Among 132 with CGT, 88.6% had {greater than or equal to}1 clinical factor for CGT compared to 47.1% who did not undergo CGT. Patients with BRCA-tumors were more likely to have CGT compared to those without (81.4% vs. 29.0%, p<0.0001). Among patients with CGT, 70.5% (93/132) of P/LPs were germline.
CONCLUSION: Tumor-only genomic testing identified P/LPs in B1B2P2 in 3.6% of patients. 52.9% of patients with tumor-detected P/LPs and without CGT did not meet personal or family history criteria for CGT. Additionally, some patients with tumor-detected P/LPs were not referred for CGT, especially those with non-BRCA tumors. Given implications for treatment selection and familial cancer risk, processes to reliably trigger CGT from tumor-genomic findings are needed.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-2861
Case Rep Oncol. 2022 Jan-Apr;15(1):15(1): 86-90

Genetic Analysis of a Family with Multiple Incidences of Prostate Cancer.

Ninghan Feng, Fengping Liu, Xinyu Xu, Yang Wang, Qingsong Sheng, Kuichun Zhu.

  A family with multiple members diagnosed with prostate cancer was identified, and genetic variants were analyzed. Three brothers were diagnosed with prostate cancer. Germline variants in BRCA1, BRCA2, TINF2, and CD19 were found through next-generation DNA sequencing using a hereditary cancer panel. The BRCA1 G275D variant was present in patients, but absent in the healthy member. An ELAC2 variant was found in 1 patient. Several mutations were predicted to be deleterious by a set of computation programs. Multiple gene mutations might contribute to the overall predisposition to prostate cancer in the family. Even in cases with potentially deleterious variants in BRCA1 or BRCA2, there could be diverse clinical manifestations.

Keywords:  Genetic; Germline; Mutation; Predisposition; Prostate cancer

DOI:  https://doi.org/10.1159/000521122
Cancer Genet. 2022 Mar 20. pii: S2210-7762(22)00027-8. [Epub ahead of print]264-265 40-49

Functional analysis of ATM variants in a high risk cohort provides insight into missing heritability.

Scott L Baughan, Fatima Darwiche, Michael A Tainsky.

  Variants of unknown significance (VUS) remain a constant challenge in the diagnosis of hereditary cancer and the counseling of patients with pedigrees suggestive of such a syndrome. In order to assess some of this limitation, several variants in the DNA repair gene ATM were selected from a cohort of high risk individuals with negative genetic diagnoses. ATM has proven a challenge in the counseling of patients due to its nature as a moderate penetrance gene. In this study, six ATM missense mutations with a high likelihood for pathogenicity were assessed through a battery of experiments to yield high fidelity information on their biochemical effect on ATM activity. We report that several of these variants show signs of reduced ATM function indicative of likely pathogenicity. With further study, this data may be used in clinic, improving diagnosis, surveillance, and outcome for patients carrying these mutations.

Keywords:  ATM; Cancer genetics; Cancer predisposition; Inherited risk; Variants of unknown significance

DOI:  https://doi.org/10.1016/j.cancergen.2022.03.003
Genet Med. 2022 Mar 25. pii: S1098-3600(22)00674-8. [Epub ahead of print]

Early age of onset and broad cancer spectrum persist in MSH6- and PMS2-associated Lynch syndrome.

Ying L Liu, Karen A Cadoo, Anna Maio, Zalak Patel, Yelena Kemel, Erin Salo-Mullen, Amanda Catchings, Megha Ranganathan, Sarah Kane, Robert Soslow, Ozge Ceyhan-Birsoy, Diana Mandelker, Maria I Carlo, Michael F Walsh, Jinru Shia, Arnold J Markowitz, Kenneth Offit, Zsofia K Stadler, Alicia Latham.

   PURPOSE: This study aimed to characterize MSH6/PMS2-associated mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) tumors, given revised guidelines suggesting more modest phenotypes.
METHODS: Patients who consented to Institutional Review Board-approved protocols of tumor/germline sequencing or Lynch syndrome registry at a single institution from February 2005 to January 2021 with germline, heterozygous MSH6/PMS2 pathogenic/likely pathogenic variants were identified. Clinical data were abstracted and correlated with MMR/microsatellite instability status using nonparametric tests.
RESULTS: We identified 243 patients (133 sequencing, 110 registry) with germline MSH6/PMS2 pathogenic/likely pathogenic variants; 186 (77%) had >1 cancer. Of 261 pooled tumors, colorectal cancer (CRC) and endometrial cancer (EC) comprised 55% and 43% of cancers in MSH6 and PMS2, respectively; 192 tumors underwent molecular assessments and 122 (64%) were MMR-D/MSI-H (77 in MSH6, 45 in PMS2). MMR-D/MSI-H cancers included CRC (n = 56), EC (n = 35), small bowel cancer (n = 6), ovarian cancer (n = 6), urothelial cancer (n = 5), pancreas/biliary cancer (n = 4), gastric/esophageal cancer (n = 3), nonmelanoma skin tumors (n = 3), prostate cancer (n = 2), breast cancer (n = 1), and central nervous system/brain cancer (n = 1). Among MMR-D/MSI-H CRC and EC, median age of diagnosis was 51.5 (range = 27-80) and 55 (range = 39-74) years, respectively; 9 of 56 (16%) MMR-D/MSI-H CRCs were diagnosed at age <35 years.
CONCLUSION: MSH6/PMS2 heterozygotes remain at risk for a broad spectrum of cancers, with 16% of MMR-D/MSI-H CRCs presenting before upper threshold of initiation of colonoscopy per guidelines.

Keywords:  Early-onset colorectal cancer; Lynch syndrome; MSH6 and PMS2; Microsatellite instability; Mismatch repair deficiency

DOI:  https://doi.org/10.1016/j.gim.2022.02.016
Cell Biol Int. 2022 Mar 29.

DETECTION OF DISEASE-CAUSING MUTATIONS IN PROSTATE CANCER BY NGS SEQUENCING.

Alessandra Mangolini, Christian Rocca, Cristian Bassi, Carmelo Ippolito, Massimo Negrini, Lucio Dell'Atti, Giovanni Lanza, Roberta Gafà, Nicoletta Bianchi, Paolo Pinton, Gianluca Aguiari.

   BACKGROUND: gene mutations may affect the fate of many tumors including prostate cancer (PCa); therefore, the research of specific mutation associated with tumor outcome might help the urologist to identify the best therapy for PCa patients such as surgical resection, adjuvant therapy or active surveillance.
METHODS: Genomic DNA (gDNA) was extracted from 48 paraffin-embedded PCa samples and normal paired tissues. Next, gDNA was amplified and analyzed by NGS using a specific gene panel for PCa. Raw data were refined to exclude false-positive mutations; thus, variants with coverage and frequency lower than 100x and 5%, respectively were removed. Mutation significance was processed by Genomic Evolutionary Rate Profiling, ClinVar and Varsome tools.
RESULTS: most of 3000 mutations (80%) were single nucleotide variants (SNVs) and the remaining 20% indels. After raw data elaboration, 312 variants were selected. Most mutated genes were KMT2D (26.45%), FOXA1 (16.13%), ATM (15.81%), ZFHX3 (9.35%), TP53 (8.06%) and APC (5.48%). Hot spot mutations in FOXA1, ATM, ZFHX3, SPOP and MED12 were also found. Truncating mutations of ATM, lesions lying in hot spot regions of SPOP and FOXA1 as well as mutations of TP53 correlated with poor prognosis. Importantly, we have also found some germline mutations associated with hereditary cancer-predisposing syndrome.
CONCLUSIONS: gDNA sequencing of 48 cancer tissues by NGS allowed to detect new tumor variants as well as confirmed lesions in genes linked to prostate cancer. Overall, somatic and germline mutations linked to good/poor prognosis could represent new prognostic tools to improve the management of PCa patients. This article is protected by copyright. All rights reserved.

Keywords:  Gene Mutations; Hereditary Cancer-Predisposing Syndrome; NGS; Prostate Cancer; Signaling Pathways; prognosis

DOI:  https://doi.org/10.1002/cbin.11803
Br J Haematol. 2022 Mar 30.

An inherited gain-of-function risk allele in EPOR predisposes to familial JAK2V617F myeloproliferative neoplasms.

Graciela Rabadan Moraes, Florence Pasquier, Christophe Marzac, Eric Deconinck, Carlotta Caterina Damanti, Gwendoline Leroy, Mira El-Khoury, Wassim El Nemer, Jean-Jacques Kiladjian, Hana Raslova, Albert Najman, William Vainchenker, Caroline Marty, Christine Bellanné-Chantelot, Isabelle Plo.

  Myeloproliferative neoplasms (MPN) are mainly sporadic but inherited variants have been associated with higher risk development. Here, we identified an EPOR variant (EPORP488S ) in a large family diagnosed with JAK2V617F -positive polycythaemia vera (PV) or essential thrombocytosis (ET). We investigated its functional impact on JAK2V617F clonal amplification in patients and found that the variant allele fraction (VAF) was low in PV progenitors but increase strongly in mature cells. Moreover, we observed that EPORP488S alone induced a constitutive phosphorylation of STAT5 in cell lines or primary cells. Overall, this study points for searching inherited-risk alleles affecting the JAK2/STAT pathway in MPN.

Keywords:   EPOR P488S ; JAK2 V617F ; familial myeloproliferative neoplasms; germline factor; predisposition

DOI:  https://doi.org/10.1111/bjh.18165
Front Genet. 2022 ;13 820610

Germline Mutation Analysis in Sporadic Breast Cancer Cases With Clinical Correlations.

Sadia Ajaz, Sani-E-Zehra Zaidi, Saleema Ali, Aisha Siddiqa, Muhammad Ali Memon.

  Demographics for breast cancers vary widely among nations. The frequency of germline mutations in breast cancers, which reflects the hereditary cases, has not been investigated adequately and accurately in highly-consanguineous Pakistani population. In the present discovery case series, germ-line mutations in twenty-seven breast cancer candidate genes were investigated in eighty-four sporadic breast cancer patients along with the clinical correlations. The germ-line variants were also assessed in two healthy gender-matched controls. The clinico-pathological features were evaluated by descriptive analysis and Pearson χ2 test (with significant p-value <0.05). The most frequent parameters associated with hereditary cancer cases are age and ethnicity. Therefore, the analyses were stratified on the basis of age (≤40 years vs. >40 years) and ethnicity. The breast cancer gene panel assay was carried out by BROCA, which is a genomic capture, massively parallel next generation sequencing assay on Illumina Hiseq2000 with 100bp read lengths. Copy number variations were determined by partially-mapped read algorithm. Once the mutation was identified, it was validated by Sanger sequencing. The ethnic analysis stratified on the basis of age showed that the frequency of breast cancer at young age (≤40 years) was higher in Sindhis (n = 12/19; 64%) in contrast to patients in other ethnic groups. Majority of the patients had stage III (38.1%), grade III (50%), tumor size 2-5 cm (54.8%), and invasive ductal carcinoma (81%). Overall, the analysis revealed germ-line mutations in 11.9% of the patients, which was not significantly associated with younger age or any particular ethnicity. The mutational spectrum was restricted to three genes: BRCA1, BRCA2, and TP53. The identified mutations consist of seven novel germ-line mutations, while three mutations have been reported previously. All the mutations are predicted to result in protein truncation. No mutations were identified in the remaining twenty-four candidate breast cancer genes. The present study provides the framework for the development of hereditary-based preventive and treatment strategies against breast cancers in Pakistani population.

Keywords:  Pakistani population; breast cancer; candidate genes; genomics; next-generating sequencing; susceptibility

DOI:  https://doi.org/10.3389/fgene.2022.820610
Int J Gynecol Pathol. 2022 Mar 29.

BAP1 Tumor Predisposition Syndrome Presenting as a Recurrent Ovarian Sex Cord-Stromal Tumor.

Benjamin B Albright, Elizabeth Wignall, Rex C Bentley, Laura J Havrilesky, Rebecca A Previs, Kyle C Strickland.

The BRCA1-associated protein 1 (BAP1) gene encodes a tumor suppressor that functions as a ubiquitin hydrolase involved in DNA damage repair. BAP1 germline mutations are associated with increased risk of multiple solid malignancies, including mesothelioma, uveal melanoma, renal cell carcinoma, and high-grade rhabdoid meningiomas. Here, we describe the case of a 52-yr-old woman who experienced multiple abdominal recurrences of an ovarian sex cord-stromal tumor that was originally diagnosed at age 25 and who was found to have a germline mutation in BAP1 and a family history consistent with BAP1 tumor predisposition syndrome. Recurrence of the sex cord-stromal tumor demonstrated loss of BAP1 expression by immunohistochemistry. Although ovarian sex cord-stromal tumors have been described in mouse models of BAP1 tumor predisposition syndrome, this relationship has not been previously described in humans and warrants further investigation. The case presentation, tumor morphology, and immunohistochemical findings have overlapping characteristics with peritoneal mesotheliomas, and this case represents a potential pitfall for surgical pathologists.

DOI: https://doi.org/10.1097/PGP.0000000000000855