bims-lifras 2024-08-25 papers

Issue of 2024–08–25
five papers selected by
Joanna Zawacka, Karolinska Institutet

Front Oncol. 2024 ;14 1419739

Case report: Germline POT1 mutation in a patient with GIST and lung adenocarcinoma.

Stefania Martino, Simona De Summa, Brunella Pilato, Maria Digennaro, Letizia Laera, Stefania Tommasi, Margherita Patruno.

The gene protection of telomere 1 (POT1) is involved in telomere maintenance and stability and plays a crucial role in the preservation of genomic stability. POT1 is considered a high-penetrance melanoma susceptibility gene; however, the number of cancer types associated with the pathogenic germline variants of POT1 is gradually increasing, including chronic lymphocytic leukemia (CLL), angiosarcomas, and gliomas, even though many associations are still elusive. Here, we reported a case of a 60-year-old man who showed early-onset multiple neoplasms, including multiple melanomas, gastrointestinal stromal tumor (GIST), and lung adenocarcinoma. Next-generation sequencing (NGS) analyses revealed a germline heterozygous pathogenic variant in the POT1 gene. Notably, GIST and lung adenocarcinoma were not previously reported in association with the POT1 germline variant. Lung cancer susceptibility syndrome is very rare and the actual knowledge is limited to a few genes although major genetic factors are unidentified. Recently, genome-wide association studies (GWAS) have pointed out an association between POT1 variants and lung cancer. This case report highlights the clinical relevance of POT1 alterations, particularly their potential involvement in lung cancer. It also suggests that POT1 testing may be warranted in patients with familial cancer syndrome, particularly those with a history of melanoma and other solid tumors.

Keywords: GIST; POT1; case report; lung adenocarcinoma; tumor predisposition syndrome

DOI: https://doi.org/10.3389/fonc.2024.1419739

J Med Genet. 2024 Aug 17. pii: jmg-2024-110109. [Epub ahead of print]

Shared germline genomic variants in two patients with double primary gastrointestinal stromal tumours (GISTs).

David S Moura, Daniel López López, Davide di Lernia, Marta Martin-Ruiz, Maria Lopez-Alvarez, Rafael Ramos, Jose Merino, Joaquin Dopazo, Jose Lopez-Guerrero, Jose L Mondaza-Hernandez, Pablo Romero, Nadia Hindi, Jesus Garcia-Foncillas, Javier Martin-Broto.

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are prevalent mesenchymal tumours of the gastrointestinal tract, commonly exhibiting structural variations in KIT and PDGFRA genes. While the mutational profiling of somatic tumours is well described, the genes behind the susceptibility to develop GIST are not yet fully discovered. This study explores the genomic landscape of two primary GIST cases, aiming to identify shared germline pathogenic variants and shed light on potential key players in tumourigenesis.
METHODS: Two patients with distinct genotypically and phenotypically GISTs underwent germline whole genome sequencing. CNV and single nucleotide variant (SNV) analyses were performed.
RESULTS: Both patients harbouring low-risk GISTs with different mutations (PDGFRA and KIT) shared homozygous germline pathogenic deletions in both CFHR1 and CFHR3 genes. CNV analysis revealed additional shared pathogenic deletions in other genes such as SLC25A24. No particular pathogenic SNV shared by both patients was detected.
CONCLUSION: Our study provides new insights into germline variants that can be associated with the development of GISTs, namely, CFHR1 and CFHR3 deep deletions. Further functional validation is warranted to elucidate the precise contributions of identified germline mutations in GIST development.

Keywords: Genotype; Germ-Line Mutation; Human Genetics; Sequence Analysis, DNA

DOI: https://doi.org/10.1136/jmg-2024-110109

Hered Cancer Clin Pract. 2024 Aug 19. 22(1): 13

Benefits of osimertinib treat a lung adenocarcinoma patient with germline EGFR T790M, somatic EGFR 19-Del, TP53 and PIK3CA mutations.

Yingxue Li, Guangqi Li, Zheng Zheng, Wenjuan Wen, Haihui Zhao, Xia Liu, Jiaping Xie, Lin Han.

BACKGROUND: Somatic mutations in the EGFR gene occur in about 50% of non-small cell lung cancers, with the T790M mutation significantly contributing to secondary resistance against EGFR-TKI drugs. However, EGFR T790M germline mutations rarely occur.
CASE PRESENTATION: In this study, we report a case of a lung adenocarcinoma family lineage linked to a germline EGFR T790M mutation. The main subject was diagnosed with stage IV lung adenocarcinoma and experienced a 19-month period without disease progression while treated with Osimertinib. We collected both clinicopathological and familial data from a patient with lung adenocarcinoma. Next-generation sequencing of 40 key genes was performed on the proband's tumor tissue. To detect EGFR germline mutations, Sanger sequencing was conducted on peripheral blood mononuclear cells from the proband and his two daughters. Mutations such as EGFR T790M, EGFR 19-Del, TP53, and PIK3CA were identified in the proband's lung cancer tissue. Additionally, germline EGFR T790M mutations were confirmed in the proband and his daughters through sequencing of their peripheral blood samples. CT scans revealed multiple pulmonary nodules in both daughters.
CONCLUSIONS: These observations suggest that germline mutations in EGFR T790M could be strongly linked to a familial predisposition to lung cancer.

Keywords: PIK3CA mutation; Germline T790M mutation; Lung adenocarcinoma; Osimertinib; Somatic EGFR 19-Del mutations

DOI: https://doi.org/10.1186/s13053-024-00286-4

Klin Onkol. 2024 ;38(4): 292-299

The guidelines for clinical practice for carriers of germline mutations in hereditary breast, ovarian, prostate, and pancreatic cancer predisposition genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 (4.2024).

The Guidelines for Clinical Practice for carriers of pathogenic variants in clinically relevant cancer predisposition genes define the steps of primary and secondary prevention that should be provided to these individuals at high risk of developing hereditary cancer in the Czech Republic. The drafting of the guidelines was organized by the Oncogenetics Working Group of the Society for Medical Genetics and Genomics of J. E. Purkyně Czech Medical Society (SLG ČLS JEP) in cooperation with the representatives of oncology and oncogynecology. The guidelines are based on the current recommendations of the National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO) and take into account the capacity of the Czech healthcare system.

Keywords: ATM; BRCA1; BRCA2; CHEK2; PALB2; consensus; germline mutation carriers; guidelines for clinical practice

DOI: https://doi.org/10.48095/ccko2024292

J Cancer Allied Spec. 2024 ;10(2): 617

Marginal Contribution of Pathogenic RAD51D Germline Variants to Pakistani Early-Onset and Familial Breast/Ovarian Cancer Patients.

Noor Muhammad, Muhammad Sohail Afzal, Ute Hamann, Muhammad Usman Rashid.

Introduction: RAD51D has been reported as a breast cancer (BC) and ovarian cancer (OC) predisposition gene, particularly among Caucasian populations. We studied the prevalence of RAD51D variants in Pakistani BC/OC patients.
Materials and Methods: In total, 371 young or familial BC/OC patients were thoroughly analyzed for RAD51D sequence variants using denaturing high-performance liquid chromatography pursued by DNA sequencing of differentially eluted amplicons. We also assessed the pathogenic effects of novel variants using in-silico algorithms. All detected RAD51D variants were investigated in 400 unaffected controls.
Results: No pathogenic RAD51D variant was detected. However, we identified nine unique heterozygous variants. Of these, two missense variants (p.Pro10Leu and p.Ile311Asn) and one intronic variant (c.481-26_23delGTTC) were classified as in silico-predicted variants of uncertain significance, with a frequency of 0.8% (3/371). The p.Pro10Leu variant was detected in a 28-year-old female BC patient of Punjabi ethnic background, whose mother and maternal cousin had BCs at ages 53 and 40, respectively. This variant was also detected in 1/400 (0.25%) healthy controls, where the control subject's daughter had acute lymphoblastic leukemia. The p.Ile311Asn variant was identified in a female BC patient at age 29 of Punjabi ethnicity and in 1/400 (0.25%) healthy controls, where the control subject's daughter had Hodgkin's disease at age 14. A novel intronic variant, c.481-26_-23delGTTC, was found in a 30-year-old Punjabi female BC patient but not in 400 healthy controls.
Conclusion: No pathogenic RAD51D variant was identified in the current study. Our study data suggested a negligible association of RAD51D variants with BC/OC risk in Pakistani women.

Keywords: Breast cancer; Pakistan; RAD51D; germline variants; ovarian cancer

DOI: https://doi.org/10.37029/jcas.v10i2.617