bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022‒08‒07
ten papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. Challenges in the interpretation of a germline TERT variant in a patient with juvenile myelomonocytic leukemia.
  2. Spectrum of Germline Mutations Within Fanconi Anemia-Associated Genes Across Populations of Varying Ancestry.
  3. Variable Clinical Features in a Large Family With Diamond Blackfan Anemia Caused by a Pathogenic Missense Mutation in RPS19.
  4. Two Cases of Thymic Cancer in Patients with Lynch Syndrome.
  5. Breast cancer in East Africa: Prevalence and spectrum of germline SNV/indel and CNVs in BRCA1 and BRCA2 genes among breast cancer patients in Tanzania.
  6. Fibroblast testing can inform medical management in individuals with mosaic variants detected on hereditary cancer panels.
  7. Management Strategies of Breast Cancer Patients with BRCA1 and BRCA2 Pathogenic Germline Variants.
  8. Clinical and pathological characteristics of familial melanoma with germline TERT promoter variants.
  9. Exome sequencing reveals a distinct somatic genomic landscape in breast cancer from women with germline PTEN variants.
  10. Germline variants profiling of BRCA1 and BRCA2 in Chinese Hakka breast and ovarian cancer patients.
  1. Pediatr Blood Cancer. 2022 Aug 04. e29909
    Challenges in the interpretation of a germline TERT variant in a patient with juvenile myelomonocytic leukemia.
    Szymon Janczar, Martin Kirschner, Fabian Beier, Tim H Brümmendorf, Marek Ussowicz, Katarzyna Babol-Pokora, Aleksandra Oszer, Ayami Yoshimi, Krzysztof Kalwak, Wojciech Mlynarski.
      Dyskeratosis congenita (DC) is a bone marrow failure syndrome with extrahematopoietic abnormalities. DC is a paradigmatic telomere biology disorder (TBD) caused by germline mutations in genes responsible for telomere maintenance including TERT. Cryptic TBD is a bone marrow failure syndrome due to premature telomere shortening but without additional symptoms, frequently clinically indistinguishable from severe aplastic anemia (SAA) or hypoplastic myelodysplastic syndrome. We present the complex diagnostic pathway in a boy with a rare germline p.Thr726Met TERT variant with previous reports of SAA association and compromised enzymatic function who presented with juvenile myelomonocytic leukemia, which is a rare myelodysplastic/myeloproliferative neoplasm of childhood.
    Keywords:  dyskeratosis congenita; juvenile myelomonocytic leukemia; severe aplastic anemia; telomerase; telomeropathy
    DOI:  https://doi.org/10.1002/pbc.29909
  2. JNCI Cancer Spectr. 2021 Jan 05. pii: pkaa117. [Epub ahead of print]5(1):
    Spectrum of Germline Mutations Within Fanconi Anemia-Associated Genes Across Populations of Varying Ancestry.
    Sock Hoai Chan, Ying Ni, Shao-Tzu Li, Jing Xian Teo, Nur Diana Binte Ishak, Weng Khong Lim, Joanne Ngeow.
      BACKGROUND: Fanconi anemia (FA) is a rare genetic disorder associated with hematological disorders and solid tumor predisposition. Owing to phenotypic heterogeneity, some patients remain undetected until adulthood, usually following cancer diagnoses. The uneven prevalence of FA cases with different underlying FA gene mutations worldwide suggests variable genetic distribution across populations. Here, we aim to assess the genetic spectrum of FA-associated genes across populations of varying ancestries and explore potential genotype-phenotype associations in cancer.METHODS: Carrier frequency and variant spectrum of potentially pathogenic germline variants in 17 FA genes (excluding BRCA1/FANCS, BRCA2/FANCD1, BRIP1/FANCJ, PALB2/FANCN, RAD51C/FANCO) were evaluated in 3523 Singaporeans and 7 populations encompassing Asian, European, African, and admixed ancestries from the Genome Aggregation Database. Germline and somatic variants of 17 FA genes in 7 cancer cohorts from The Cancer Genome Atlas were assessed to explore genotype-phenotype associations.
    RESULTS: Germline variants in FANCA were consistently more frequent in all populations. Similar trends in carrier frequency and variant spectrum were detected in Singaporeans and East Asians, both distinct from other ancestry groups, particularly in the lack of recurrent variants. Our exploration of The Cancer Genome Atlas dataset suggested higher germline and somatic mutation burden between FANCA and FANCC with head and neck and lung squamous cell carcinomas as well as FANCI and SLX4/FANCP with uterine cancer, but the analysis was insufficiently powered to detect any statistical significance.
    CONCLUSION: Our findings highlight the diverse genetic spectrum of FA-associated genes across populations of varying ancestries, emphasizing the need to include all known FA-related genes for accurate molecular diagnosis of FA.
    DOI:  https://doi.org/10.1093/jncics/pkaa117
  3. Front Genet. 2022 ;13 914141
    Variable Clinical Features in a Large Family With Diamond Blackfan Anemia Caused by a Pathogenic Missense Mutation in RPS19.
    Sarah Cole, Neelam Giri, Blanche P Alter, D Matthew Gianferante.
      Introduction: Diamond Blackfan anemia (DBA) is an autosomal dominant ribosomopathy caused predominantly by pathogenic germline variants in ribosomal protein genes. It is characterized by failure of red blood cell production, and common features include congenital malformations and cancer predisposition. Mainstays of treatment are corticosteroids, red blood cell transfusions, and hematologic stem cell transplantation (HSCT). Despite a better understanding of the genotype of DBA, the biological mechanism resulting in the clinical phenotype remains poorly understood, and wide heterogeneity can be seen even within a single family as depicted here. Case Description: Thirty family members enrolled in the National Cancer Institute inherited bone marrow failure syndromes study were evaluated with detailed medical questionnaires and physical examinations, including 22 in the family bloodline and eight unrelated partners. Eight participants had been previously told they had DBA by clinical criteria. Targeted germline RPS19 testing was done on all family members. A pathogenic heterozygous missense mutation in RPS19 (p.R62Q, c.185G > A) was detected in ten family members, including one person previously presumed unaffected. Eight family members presented with macrocytic anemia in infancy; all of whom were responsive to prednisone. Four family members became treatment independent; however, one individual became transfusion-dependent 36 years later following an episode of pneumonia. One prednisone responsive individual electively discontinued steroid treatment, and lives with severe anemia. One prednisone responsive individual died at age 28 from a stroke. Two family members developed colorectal cancer in their fifties; one had never required treatment for anemia. None had major congenital anomalies. Discussion: This large family with DBA demonstrates the heterogeneity of phenotypes that can be seen within the same genotype. Most family members presented with steroid-responsive anemia in infancy and subtle congenital malformations, findings consistent with recent genotype-phenotype studies of RPS DBA. However, two family members were relatively unaffected, underscoring the importance of further studies to assess modifier genes, and epigenetic and/or environmental factors which may result in normal erythropoiesis despite underlying ribosome dysfunction. This large, multigenerational family highlights the need for individualized treatment, the importance of early cancer surveillance even in individuals with clinically mild phenotypes, and the benefit of long-term follow-up to identify late complications.
    Keywords:  DBA; genotype; inherited bone marrow failure syndrome; phenotype; ribosomopathy
    DOI:  https://doi.org/10.3389/fgene.2022.914141
  4. Intern Med. 2022 Jul 29.
    Two Cases of Thymic Cancer in Patients with Lynch Syndrome.
    Mototsugu Watanabe, Kohji Tanakaya, Shinichi Furukawa, Toshio Shiotani, Yumiko Sato, Fumitaka Taniguchi, Nobuhiko Kanaya, Hideki Aoki, Koukichi Sugano, Hideyuki Ishida, Kiwamu Akagi, Kazuhiko Kataoka.
      We herein report two cases of thymic cancer with Lynch syndrome showing a high frequency of microsatellite instability and loss of mismatch repair protein expression without MLH1 promoter hyper-methylation. In Case 1, a 71-year-old man had a pathogenic germline variant in MLH1 and underwent tumor resection. No relapse has been reported thus far. In Case 2, a 43-year-old man underwent genetic testing that also showed a pathogenic germline variant in MLH1. Since these two cases had MLH variants, we suspect a possible association between thymic cancer with Lynch syndrome and germline pathogenic variants in MLH1.
    Keywords:  Lynch syndrome; high frequency of microsatellite instability (MSI-H); thymic cancer
    DOI:  https://doi.org/10.2169/internalmedicine.9729-22
  5. Cancer Med. 2022 Jul 31.
    Breast cancer in East Africa: Prevalence and spectrum of germline SNV/indel and CNVs in BRCA1 and BRCA2 genes among breast cancer patients in Tanzania.
    Linus P Rweyemamu, Büşra K Gültaşlar, Gokce Akan, Nazima Dharsee, Lucy A Namkinga, Sylvester L Lyantagaye, Hülya Yazıcı, Fatmahan Atalar.
      BACKGROUND: Growing prevalence and aggressiveness of breast cancer (BC) among East African women strongly indicate that the genetic risk factor implicated in the etiology of the disease may have a key role. Germline pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) are known to increase the lifetime risk of BC. This study investigated the prevalence and spectrum of germline single nucleotide variant/insertion and deletion (SNV/indel), and copy number variations (CNVs) in BRCA1/2 among Tanzanian BC patients, and evaluated the associations of identified variants with patient's socio-demographic and histopathological characteristics.METHODS: One hundred BC patients were examined for BRCA1/2 variants using next-generation sequencing (NGS). Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) assay were performed for the confirmation of SNV/indel and CNVs, respectively.
    RESULTS: Six germline SNV/indel pathogenic variants were detected from six unrelated patients. Five of these variants were identified in BRCA1, and one in BRCA2. We also identified, in one patient, one variant of uncertain clinical significance (VUS). CNV was not detected in any of the BC patients. Furthermore, we found that in our cohort, BRCA1/2 variant carriers were triple-negative BC patients (p = 0.019).
    CONCLUSIONS: Our study provides first insight into BC genetic landscape by the use of NGS in the under-represented East African Tanzanian populations. Our findings support the importance of genetic risk factors in BC etiology in Tanzania and showed a relatively high overall prevalence (6%) of germline BRCA1/2 pathogenic variants in BC patients. Therefore, our results indicate that BRCA1/2 pathogenic variants may well contribute to BC incidence in Tanzania. Thus, the identification of frequent variants in BRCA1/2 genes will enable implementation of rapid, inexpensive population-specific BRCA1/2 genetic testing, particularly for triple-negative BC patients known for their high prevalence in Tanzania. This will, in turn, greatly contributes to provide effective therapeutic strategies.
    Keywords:   BRCA1/2 ; Tanzania; breast cancer; germline mutations; next-generation sequencing
    DOI:  https://doi.org/10.1002/cam4.5091
  6. Cancer Genet. 2022 Jul 28. pii: S2210-7762(22)00106-5. [Epub ahead of print]266-267 86-89
    Fibroblast testing can inform medical management in individuals with mosaic variants detected on hereditary cancer panels.
    Erin G Sutcliffe, Jessica L Mester, Lisa R Susswein, Maegan E Roberts, Megan L Marshall, Kathleen S Hruska.
      Mosaic variants are regularly detected on hereditary cancer genetic tests. While some of these variants may be constitutional, the majority are likely limited to blood lineages. In the present study, we correlate clinical histories from individuals with mosaic findings identified on hereditary cancer testing and the outcomes of follow-up fibroblast (FB) testing. We observed 620 mosaic variants, including 339 pathogenic or likely pathogenic variants (PVs) occurring most often in TP53, CHEK2, ATM, and NF1. About half of individuals with NF1 mosaic PVs did not report any clinical features of NF1 and were older at testing (p<0.0001) compared to those with an NF1-related phenotype. Among 42 mosaic PVs evaluated by FB testing, 17 (40.5%) were confirmed in FB and were mostly identified in individuals with phenotypes consistent with the gene disease spectrum. Our data show that FB testing is helpful for identifying those with likely constitutional mosaicism benefitting from increased screening and follow-up vs. those with blood-limited variants potentially not requiring intense surveillance but warranting further hematologic work-up.
    Keywords:  Fibroblast testing; Hereditary cancer; Mosaicism
    DOI:  https://doi.org/10.1016/j.cancergen.2022.07.004
  7. Onco Targets Ther. 2022 ;15 815-826
    Management Strategies of Breast Cancer Patients with BRCA1 and BRCA2 Pathogenic Germline Variants.
    Sarah Edaily, Hikmat Abdel-Razeq.
      Most of breast cancer cases are sporadic; however, 15-20% are associated with family history, and some are inherited. Among those, deleterious mutations in BRCA1 and BRCA2 tumor suppressor genes are the most commonly encountered pathogenic germline variants (PGVs). Given the availability and affordability of multi-gene panel sequencing technologies, testing for PGVs is commonly practiced. With our enhanced understanding of cancer genetics and specific molecular alterations, the better acceptance of risk-directed screening and prevention, and the recent introduction of novel targeted therapies, management of BRCA-positive breast cancers is taking a new direction, focusing more on risk-reducing interventions, including mastectomy and salpingo-oophorectomy, and incorporating special treatment regimens, including platinum-based chemotherapy, and the recently-introduced PARP (poly (ADP)-ribose polymerase) inhibitors. Given the recent advances in reproductive technology and molecular medicine, younger women with PGVs may have the option of embryo selection through preimplantation genetic testing and diagnosis, thus preventing the potential transmission of the implicated genes to the next generations. In this review, we cover the clinical implications of identifying a pathogenic germline mutation in BRCA1 and BRCA2 genes in breast cancer patients, and their relatives, across the continuum of care - from cancer prevention and early detection, through active treatment and up to survivorship issues.
    Keywords:  BRCA1; BRCA2; breast cancer; germline mutation; risk-reducing surgery
    DOI:  https://doi.org/10.2147/OTT.S369844
  8. Pigment Cell Melanoma Res. 2022 Aug 01.
    Clinical and pathological characteristics of familial melanoma with germline TERT promoter variants.
    Anne Zaremba, Friedegund Meier, Christian Schlein, Philipp Jansen, Georg Lodde, Mingxia Song, Julia Kretz, Inga Möller, Nadine Stadtler, Elisabeth Livingstone, Lisa Zimmer, Eva Hadaschik, Antje Sucker, Dirk Schadendorf, Klaus Griewank.
      Around 10% of melanoma occur in patients with a suspected familial predisposition. TERT promoter mutations are the most common somatic hotspot mutations in human cancers. However, only two families with germline mutations have been identified to date. We present detailed histological, clinical and molecular pathologic analyses of affected patients and details of newly identified individuals in one of these previously reported families. TERT (NM_198253.3) Chr.5:1,295,161T>C (c.-57 T>C) promoter variants were detected in all melanoma-affected (n=18) and one non-diseased family member. Median age at diagnosis was 30 years (n=18, range 16-46 years, 2 unknown). While most primary melanoma arose on the upper extremities (n=7, 21%) and were superficial spreading melanoma (SSM, n=8, 24%), many primary melanoma also originated from non UV-exposed mucosal (n=2, 6%) and acral (n=4, 12%) locations. One SSM sample harboured a Chr.5:1,295,228C>T TERT promoter region in addition to the germline Chr.5:1,295,161T>C variant, arguing additional pathway activation can support tumor pathogenesis. Patients treated with BRAF inhibitor and/or immune checkpoint inhibition (ICI) showed responses, although of limited duration. One mucosal melanoma harboured both a KIT copy number gain and an activating c.1727 p.Leu576Pro mutation. Following modest response to ICI, subsequent KIT inhibitor (imatinib) therapy demonstrated an ongoing complete pathological response (currently 7 months).
    Keywords:  Familial melanoma; TERT promoter variant
    DOI:  https://doi.org/10.1111/pcmr.13060
  9. Am J Hum Genet. 2022 Aug 04. pii: S0002-9297(22)00309-3. [Epub ahead of print]109(8): 1520-1533
    Exome sequencing reveals a distinct somatic genomic landscape in breast cancer from women with germline PTEN variants.
    Takae Brewer, Lamis Yehia, Peter Bazeley, Charis Eng.
      Germline PTEN variants (PTEN hamartoma tumor syndrome [PHTS]) confer up to 85% lifetime risk of female breast cancer (BC). BCs arising in PHTS are clinically distinct from sporadic BCs, including younger age of onset, multifocality, and an increased risk of second primary BCs. Yet, there is no previous investigation into the underlying genomic landscape of this entity. We sought to address the hypothesis that BCs arising in PHTS have a distinct genomic landscape compared to sporadic counterparts. We performed and analyzed exome sequencing data from 44 women with germline PTEN variants who developed BCs. The control cohort comprised of 497 women with sporadic BCs from The Cancer Genome Atlas (TCGA) dataset. We demonstrate that PHTS-derived BCs have a distinct somatic mutational landscape compared to the sporadic counterparts, namely second somatic hits in PTEN, distinct mutational signatures, and increased genomic instability. The PHTS group had a significantly higher frequency of somatic PTEN variants compared to TCGA (22.7% versus 5.6%; odds ratio [OR] 4.93; 95% confidence interval [CI] 2.21 to 10.98; p < 0.001) and a lower mutational frequency in PIK3CA (22.7% versus 33.4%; OR 0.59; 95% CI 0.28 to 1.22; p = 0.15). Somatic variants in PTEN and PIK3CA were mutually exclusive in PHTS (p = 0.01) but not in TCGA. Our findings have important implications for the personalized management of PTEN-related BCs, especially in the context of more accessible genetic testing.
    Keywords:  PTEN; PTEN hamartoma tumor syndrome; breast cancer; exome seqeuncing; tumor profiling; tumor suppressor gene
    DOI:  https://doi.org/10.1016/j.ajhg.2022.07.005
  10. BMC Cancer. 2022 Aug 02. 22(1): 842
    Germline variants profiling of BRCA1 and BRCA2 in Chinese Hakka breast and ovarian cancer patients.
    Yunuo Zhang, Heming Wu, Zhikang Yu, Liang Li, Jinhong Zhang, Xinhong Liang, Qingyan Huang.
      OBJECTIVE: To investigate the prevalence and spectrum of BRCA1 and BRCA2 mutations in Chinese Hakka patients with breast and ovarian cancer.METHODS: A total of 1,664 breast or ovarian cancer patients were enrolled for genetic testing at our hospital. Germline mutations of the BRCA gene were analysed by next-generation sequencing, including the coding regions and exon intron boundary regions.
    RESULTS: The 1,664 patients included 1,415 (85.04%) breast cancer patients and 245 (14.72%) ovarian cancer patients, while four (0.24%) patients had both the breast and ovarian cancers. A total of 151 variants, including 71 BRCA1 variants and 80 BRCA2 variants, were detected in the 234 (14.06%) patients. The 151 variants included 58 pathogenic variants, 8 likely pathogenic variants, and 85 variants of unknown significance (VUS). A total of 56.25% (18/32) and 65.38% (17/26) of pathogenic variants (likely pathogenic variants are not included) were distributed in exon 14 of BRCA1 and exon 11 of BRCA2, respectively. The most common pathogenic variants among this Hakka population are c.2635G > T (p.Glu879*) (n = 7) in the BRCA1 gene and c.5164_5165del (p.Ser1722Tyrfs*4) (n = 7) in the BRCA2 gene among the Hakka population. A hotspot mutation in the Chinese population, the BRCA1 c.5470_5477del variant was not found in this Hakka population. The prevalence and spectrum of variants in the BRCA genes in the Hakka patients are different from that in other ethnic groups.
    CONCLUSIONS: The most common pathogenic variant in this population is c.2635G > T in the BRCA1 gene, and c.5164_5165delAG in the BRCA2 gene in this population. The prevalence and spectrum of variants in the BRCA1 and BRCA2 genes in the Hakka patients from southern China are different from those in other ethnic groups.
    Keywords:  BRCA gene; Breast cancer; Hakka population; Ovarian cancer; Variants
    DOI:  https://doi.org/10.1186/s12885-022-09943-0
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