bims-lifras 2024-02-25 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2024–02–25
seven papers selected by
Joanna Zawacka, Karolinska Institutet

Points to consider regarding prophylactic total gastrectomy in germline CDH1 variant carriers.
Characterization of a germline variant TNS1 c.2999-1G > C in a hereditary cancer syndrome family.
Hereditary Renal Cancer Syndromes.
Genetic testing for hereditary cancer syndromes in Tunisian patients: Impact on health system.
Research on Rare Diseases in Germany - The cancer predisposition syndrome registry.
Genetic Basis of Breast and Ovarian Cancer: Approaches and Lessons Learnt from Three Decades of Inherited Predisposition Testing.
Pan-Cancer Interrogation of MUTYH Variants Reveals Biallelic Inactivation and Defective Base Excision Repair Across a Spectrum of Solid Tumors.

J Surg Oncol. 2024 Feb 22.

Points to consider regarding prophylactic total gastrectomy in germline CDH1 variant carriers.

Giovanni Corso, Jeremy L Davis, Vivian E Strong.

  Pathogenic germline CDH1 mutation confers high risk for developing diffuse gastric and lobular breast cancers in asymptomatic carriers. In these individuals, the estimated gastric cancer risk at 80 years of age is up to 70% for males and 56% for females. Due to this high-risk predisposition, prophylactic total gastrectomy is considered a unique life-saving approach in germline CDH1 carriers, as endoscopy often fails to detect early stage diffuse gastric carcinoma. However, surgical indication is controversial in some clinical contexts, with possible contraindications. This review discusses points against and in favor of a more aggressive surgical approach for consideration during the decision-making process.

Keywords:  CDH1 germline mutation; gastric cancer; prophylactic total gastrectomy

DOI:  https://doi.org/10.1002/jso.27603
Gene. 2024 Feb 20. pii: S0378-1119(24)00185-9. [Epub ahead of print] 148304

Characterization of a germline variant TNS1 c.2999-1G > C in a hereditary cancer syndrome family.

Xiaotang Di, Ding Wang, Jinzheng Wu, Xiaofang Zhu, Yang Wang, Jinhua Yan, Liang Wen, Hao Jiang, Doudou Wen, Bo Shu, Shubing Zhang.

  Hereditary cancer syndromes result from the presence of inherited pathogenic variants within susceptibility genes. However, the susceptibility genes associated with hereditary cancer syndrome remain predominantly unidentified. Here, we reported a case of hereditary cancer syndrome observed in a Chinese family harboring a germline mutation in Tensin1 (TNS1). We described a 59-year-old female patient presented with Multiple myeloma and Thyroid carcinoma. The proband and her family members exhibited suspected tumor syndrome due to occurrences of other cancer cases. After oncogenetic counseling, whole-exome sequencing and Sanger sequencing were conducted and a primary driver mutation of TNS1 (NM_022648.7:c.2999-1G > C) was detected. Gene Expression Profiling Interactive Analysis revealed that TNS1 was expressed lower in different tumors when compared to normal, including Pancreatic adenocarcinoma, Breast invasive carcinoma, Thyroid carcinoma andColon adenocarcinoma cells. Despite the well-established role of TNS1 as a tumor suppressor in breast cancer and colorectal cancer, its potential utility as a marker gene for diagnosis and treatment of pancreatic cancer remains uncertain. Here, our data demonstrated that knockdown of TNS1 could promote cell proliferation and migration in Pancreatic adenocarcinoma (PDAC) cells. In addition, TNS1 regulated migration through EMT signaling pathway in PDAC cells. Our findings proposed that this variant was likely involved in cancer predisposition by disrupting the normal splicing process. In summary, we presented a genetic disease by linking an intronic mutation inTNS1. We aim to provide early detection of cancers by identifying germline variants in susceptibility genes.

Keywords:  Germline mutation; Hereditary cancer Syndromes; Susceptibility gene; Tensin1; Whole-exome sequencing

DOI:  https://doi.org/10.1016/j.gene.2024.148304
Med Sci (Basel). 2024 Feb 18. pii: 12. [Epub ahead of print]12(1):

Hereditary Renal Cancer Syndromes.

Grigory A Yanus, Ekaterina Sh Kuligina, Evgeny N Imyanitov.

  Familial kidney tumors represent a rare variety of hereditary cancer syndromes, although systematic gene sequencing studies revealed that as many as 5% of renal cell carcinomas (RCCs) are associated with germline pathogenic variants (PVs). Most instances of RCC predisposition are attributed to the loss-of-function mutations in tumor suppressor genes, which drive the malignant progression via somatic inactivation of the remaining allele. These syndromes almost always have extrarenal manifestations, for example, von Hippel-Lindau (VHL) disease, fumarate hydratase tumor predisposition syndrome (FHTPS), Birt-Hogg-Dubé (BHD) syndrome, tuberous sclerosis (TS), etc. In contrast to the above conditions, hereditary papillary renal cell carcinoma syndrome (HPRCC) is caused by activating mutations in the MET oncogene and affects only the kidneys. Recent years have been characterized by remarkable progress in the development of targeted therapies for hereditary RCCs. The HIF2aplha inhibitor belzutifan demonstrated high clinical efficacy towards VHL-associated RCCs. mTOR downregulation provides significant benefits to patients with tuberous sclerosis. MET inhibitors hold promise for the treatment of HPRCC. Systematic gene sequencing studies have the potential to identify novel RCC-predisposing genes, especially when applied to yet unstudied populations.

Keywords:  Birt–Hogg–Dubé syndrome; belzutifan; familial papillary renal cell carcinoma; hereditary cancer syndromes; hereditary leiomyomatosis and renal cell cancer; kidney cancer; next-generation sequencing; targeted therapy; tuberous sclerosis; von Hippel–Lindau disease

DOI:  https://doi.org/10.3390/medsci12010012
Transl Oncol. 2024 Feb 21. pii: S1936-5233(24)00037-8. [Epub ahead of print]43 101912

Genetic testing for hereditary cancer syndromes in Tunisian patients: Impact on health system.

Nouha Jandoubi, Maroua Boujemaa, Najah Mighri, Nesrine Mejri, Sonia Ben Nasr, Hanen Bouaziz, Yosra Berrazega, Haifa Rachdi, Nouha Daoud, Aref Zribi, Jihene Ayari, Houda El Benna, Soumaya Labidi, Abderazzek Haddaoui, Ridha Mrad, Slim Ben Ahmed, Hamouda Boussen, Sonia Abdelhak, Samir Boubaker, Yosr Hamdi.

   INTRODUCTION: Cancer management in Africa faces diverse challenges due to limited resources, health system challenges, and other matters. Identifying hereditary cancer syndromic cases is crucial to improve clinical management and preventive care in these settings. This study aims to explore the clinicopathological features and genetic factors associated with hereditary cancer in Tunisia, a North African country with a rising cancer burden MATERIALS AND METHODS: Clinicopathological features and personal/family history of cancer were explored in 521 patients. Genetic analysis using Sanger and next-generation sequencing was performed for a set of patients RESULTS: Hereditary breast and ovarian cancer syndrome was the most frequent cluster in which 36 BRCA mutations were identified. We described a subgroup of patients with likely ''breast cancer-only syndrome'' among this cluster. Two cases of Li-Fraumeni syndrome with distinct TP53 mutations namely c.638G>A and c.733G>A have been identified. Genetic investigation also allowed the identification of a new BLM homozygous mutation (c.3254dupT) in one patient with multiple primary cancers. Phenotype-genotype correlation suggests the diagnosis of Bloom syndrome. A recurrent MUTYH mutation (c.1143_1144dup) was identified in three patients with different phenotypes CONCLUSION: Our study calls for comprehensive genetic education and the implementation of genetic screening in Tunisia and other African countries health systems, to reduce the burden of hereditary diseases and improve cancer outcomes in resource-stratified settings.

Keywords:  Cancer syndromes; Clinical-phenotypic expression; Genetic testing; Health system

DOI:  https://doi.org/10.1016/j.tranon.2024.101912
J Health Monit. 2023 Dec;8(4): 17-23

Research on Rare Diseases in Germany - The cancer predisposition syndrome registry.

Christina M Dutzmann, Nathalie E Palmaers, Lucas J Müntnich, Farina J Strüwe, Judith Penkert, Birte Sänger, Beatrice Hoffmann, Anja Karow, Christina Reimer, Tanja Gerasimov, Marena R Niewisch, Christian P Kratz.

   Background: Cancer predisposition syndromes (CPS) are rare diseases that are associated with an increased risk of cancer due to genetic alterations. At least 8 % of all cases of childhood cancer are attributable to CPS [1, 2]. The CPS registry was launched in 2017 to learn more about CPS and to improve the care to those afflicted by these diseases.
Methods: This is an internationally networked registry with associated accompanying studies that investigate cancer risks and spectra, the possibilities of cancer prevention, early detection and therapy.
Results: For several of these syndromes, new insights into the cancer risks and cancer types as well as factors modifying cancer risk have been gained. In addition, experimental, psycho-oncological, preclinical and clinical studies were initiated.
Conclusions: The CPS registry is an example of how progress can be made within a short period of time to the benefit of individuals with rare diseases through systematic data collection and research.

Keywords:  CANCER PREDISPOSITION; CHILDREN; LI-FRAUMENI SYNDROME; PREVENTION; RARE DISEASES; SURVEILLANCE

DOI:  https://doi.org/10.25646/11828
Genes (Basel). 2024 Feb 08. pii: 219. [Epub ahead of print]15(2):

Genetic Basis of Breast and Ovarian Cancer: Approaches and Lessons Learnt from Three Decades of Inherited Predisposition Testing.

Valeria Barili, Enrico Ambrosini, Beatrice Bortesi, Roberta Minari, Erika De Sensi, Ilenia Rita Cannizzaro, Antonietta Taiani, Maria Michiara, Angelica Sikokis, Daniela Boggiani, Chiara Tommasi, Olga Serra, Francesco Bonatti, Alessia Adorni, Anita Luberto, Patrizia Caggiati, Davide Martorana, Vera Uliana, Antonio Percesepe, Antonino Musolino, Benedetta Pellegrino.

  Germline variants occurring in BRCA1 and BRCA2 give rise to hereditary breast and ovarian cancer (HBOC) syndrome, predisposing to breast, ovarian, fallopian tube, and peritoneal cancers marked by elevated incidences of genomic aberrations that correspond to poor prognoses. These genes are in fact involved in genetic integrity, particularly in the process of homologous recombination (HR) DNA repair, a high-fidelity repair system for mending DNA double-strand breaks. In addition to its implication in HBOC pathogenesis, the impairment of HR has become a prime target for therapeutic intervention utilizing poly (ADP-ribose) polymerase (PARP) inhibitors. In the present review, we introduce the molecular roles of HR orchestrated by BRCA1 and BRCA2 within the framework of sensitivity to PARP inhibitors. We examine the genetic architecture underneath breast and ovarian cancer ranging from high- and mid- to low-penetrant predisposing genes and taking into account both germline and somatic variations. Finally, we consider higher levels of complexity of the genomic landscape such as polygenic risk scores and other approaches aiming to optimize therapeutic and preventive strategies for breast and ovarian cancer.

Keywords:  BRCA1 and BRCA2; hereditary breast and ovarian cancer (HBOC) syndrome; homologous recombination deficiency (HRD); poly (ADP-ribose) polymerase (PARP) inhibitors

DOI:  https://doi.org/10.3390/genes15020219
JCO Precis Oncol. 2024 Feb;8 e2300251

Pan-Cancer Interrogation of MUTYH Variants Reveals Biallelic Inactivation and Defective Base Excision Repair Across a Spectrum of Solid Tumors.

Channing J Paller, Hanna Tukachinsky, Alexandra Maertens, Brennan Decker, Julian R Sampson, Jeremy P Cheadle, Emmanuel S Antonarakis.

PURPOSE: Biallelic germline pathogenic variants of the base excision repair (BER) pathway gene MUTYH predispose to colorectal cancer (CRC) and other cancers. The possible association of heterozygous variants with broader cancer susceptibility remains uncertain. This study investigated the prevalence and consequences of pathogenic MUTYH variants and MUTYH loss of heterozygosity (LOH) in a large pan-cancer analysis.
MATERIALS AND METHODS: Data from 354,366 solid tumor biopsies that were sequenced as part of routine clinical care were analyzed using a validated algorithm to distinguish germline from somatic MUTYH variants.
RESULTS: Biallelic germline pathogenic MUTYH variants were identified in 119 tissue biopsies. Most were CRCs and showed increased tumor mutational burden (TMB) and a mutational signature consistent with defective BER (COSMIC Signature SBS18). Germline heterozygous pathogenic variants were identified in 5,991 biopsies and their prevalence was modestly elevated in some cancer types. About 12% of these cancers (738 samples: including adrenal gland cancers, pancreatic islet cell tumors, nonglioma CNS tumors, GI stromal tumors, and thyroid cancers) showed somatic LOH for MUTYH, higher rates of chromosome 1p loss (where MUTYH is located), elevated genomic LOH, and higher COSMIC SBS18 signature scores, consistent with BER deficiency.
CONCLUSION: This analysis of MUTYH alterations in a large set of solid cancers suggests that in addition to the established role of biallelic pathogenic MUTYH variants in cancer predisposition, a broader range of cancers may possibly arise in MUTYH heterozygotes via a mechanism involving somatic LOH at the MUTYH locus and defective BER. However, the effect is modest and requires confirmation in additional studies before being clinically actionable.

DOI: https://doi.org/10.1200/PO.23.00251