bims-lifras 2023-05-28 papers

Blood. 2023 May 22. pii: blood.2022019304. [Epub ahead of print]

Prevalence and clinical expression of germline predisposition to myeloid neoplasms in adults with marrow hypocellularity.

Elisabetta Molteni, Elisa Bono, Anna Galli, Chiara Elena, Jacqueline Ferrari, Nicolas Fiorelli, Sara Pozzi, Virginia Valeria Ferretti, Martina Sarchi, Ettore Rizzo, Virginia Camilotto, Emanuela Boveri, Mario Cazzola, Luca Malcovati.

Systematic studies of germline genetic predisposition to myeloid neoplasms are still limited in adult patients. In this work, we performed germline and somatic targeted sequencing in a large cohort of adult patients with cytopenia and hypoplastic bone marrow to study germline predisposition variants and their clinical correlates. The study population included 402 consecutive adult patients investigated for unexplained cytopenia and reduced age-adjusted bone marrow cellularity. Germline mutation analysis was performed using a panel of 60 genes, and variants were interpreted according to the ACMG/AMP guidelines; somatic mutation analysis was performed using a panel of 54 genes. Twenty-seven out of 402 (6.7%) subjects carried germline variants causative of a predisposition syndrome/disorder. The most frequent predisposition disorders were DDX41-associated predisposition, Fanconi anemia, GATA2-deficiency syndrome, severe congenital neutropenia, RASopathy and Diamond-Blackfan anemia. Eighteen of 27 patients (67%) with causative germline genotype were diagnosed with myeloid neoplasm, whereas the remaining with cytopenia of undetermined significance. Subjects with predisposition syndrome/disorder were younger than the remaining ones (P=.03) and had higher risk of severe or multiple cytopenias and advanced myeloid malignancy (OR ranging from 2.51 to 5.58). In patients with myeloid neoplasm, causative germline mutations were associated with increased risk of progression into acute myeloid leukemia (HR=3.92, P=.008). Family history of cancer or personal history of multiple tumors, did not show significant association with a predisposition syndrome/disorder. The findings of this study unveil the spectrum, clinical expressivity and prevalence of germline predisposition mutations in an unselected cohort of adult patients with cytopenia and hypoplastic bone marrow.

DOI: https://doi.org/10.1182/blood.2022019304

Front Oncol. 2023 ;13 1177942

Case Report: Lung adenocarcinoma associated with germline ERCC2 frameshift mutation.

Lili Liu, Jia Cui, Siye Liu, Evenki Pan, Limin Sun.

Family history is an established risk factor for lung cancer. Previous studies have found that germline genetic alterations, such as those in EGFR, BRCA1, BRCA2, CHEK2, CDKN2A, HER2, MET, NBN, PARK2, RET, TERT, TP53, and YAP1, are associated with an increased risk of developing lung cancer. The study reports the first of a lung adenocarcinoma proband with germline ERCC2 frameshift mutation c.1849dup (p. A617Gfs*32). Her family cancer history review demonstrated that her two healthy sisters, a brother with lung cancer, and three healthy cousins were positive for ERCC2 frameshift mutation, which might contribute to increased cancer risk. Our study highlights the necessity of performing comprehensive genomic profiling in discovering rare genetic alterations, early cancer screening, and monitoring for patients with family cancer history.

Keywords: ERCC2 frameshift mutation; family history; germline mutation; lung adenocarcinoma; next-generation sequencing

DOI: https://doi.org/10.3389/fonc.2023.1177942

Front Genet. 2023 ;14 1172365

Diagnostic rate of germline pathogenic variants in pancreatic ductal adenocarcinoma patients using whole genome sequencing.

An-Ko Chung, Ro-Ting Lin, Chun-Chieh Yeh, Chi-Ying Yang, Chang-Jiun Wu, Pei-Lung Chen, Jaw-Town Lin.

Identification of germline pathogenic variants in cancer patients is critical for treatment planning, genetic counseling, and health policymaking. However, previous estimates of the prevalence of germline etiology of pancreatic ductal adenocarcinoma (PDAC) were biased because they were based only on sequencing data of protein-coding regions of known PDAC candidate genes. To determine the percentage of patients with PDAC carrying germline pathogenic variants, we enrolled the inpatients from the digestive health clinics, hematology and oncology clinics, and surgical clinics of a single tertiary medical center in Taiwan for whole genome sequencing (WGS) analysis of genomic DNA. The virtual gene panel of 750 genes comprised PDAC candidate genes and those listed in the COSMIC Cancer Gene Census. The genetic variant types under investigation included single nucleotide substitutions, small indels, structural variants, and mobile element insertions (MEIs). In 8 of 24 (33.3%) patients with PDAC, we identified pathogenic/likely pathogenic variants, including single nucleotide substitutions and small indels in ATM, BRCA1, BRCA2, POLQ, SPINK1 and CASP8, as well as structural variants in CDC25C and USP44. We identified additional patients carrying variants that could potentially affect splicing. This cohort study demonstrates that an extensive analysis of the abundant information yielded by the WGS approach can uncover many pathogenic variants that could be missed by traditional panel-based or whole exome sequencing-based approaches. The percentage of patients with PDAC carrying germline variants might be much higher than previously expected.

Keywords: cancer genetic; germline genetic testing; pancreatic ductal adenocarcinoma (PADC); structural variant (SV); whole genome sequencing (WGS)

DOI: https://doi.org/10.3389/fgene.2023.1172365

Lung Cancer. 2023 May 13. pii: S0169-5002(23)00785-7. [Epub ahead of print]181 107247

Germline EGFR c.2527G > A (p.V843I) variant and familial lung cancer.

Saba Alsaddah, Andreas I Papadakis, Nora Wong, Laura Palma, David Szlachtycz, Tania Cruz Marino, Pierre-Olivier Fiset, William D Foulkes.

BACKGROUND: Somatic epidermal growth factor receptor (EGFR) pathogenic variants have been identified and are routinely tested in the molecular diagnosis of non-small cell lung cancer (NSCLC) as they represent a target for EGFR tyrosine kinase inhibitor (TKI) therapy. However, germline variants in EGFR are much less frequently reported.
CASE PRESENTATION: Herein, we report the case of a 46-year-old woman diagnosed with lung adenocarcinoma who was found to harbor a rare germline missense variant in exon 21 of EGFR: NM_005228.5(EGFR):c.2527G>A (p.V843I). In the tumor, this variant (Cosmic ID COSV51767379) was accompanied by a secondary, known pathogenic EGFR variant in cis, also occurring in exon 21, c.2573T>G (p.L858R) (Cosmic ID 6224). Her mother was previously diagnosed with poorly differentiated lung carcinoma and her tumor was also found to harbour the p.V843I variant but no other pathogenic variants. Notably, the proband's sister, diagnosed with a lung carcinoma with sarcomatous features at age 44, did not carry this variant or any other somatic or germline EGFR variants.
CONCLUSION: This is the second report of familial lung adenocarcinoma associated with the germline p.V843I variant, which remains classified as a variant of uncertain significance. The lack of segregation of this variant in the proband's affected sister illustrates the complexity with evaluating lung cancer predisposition factors. Currently, there is a paucity of data regarding the therapeutic outcomes of patients with tumors expressing this rare germline variant, therefore we propose an algorithm for the identification of at-risk individuals and families as the first step for their personalized management.

Keywords: EGFR germline variants; EGFR rare pathogenic variants; EGFR somatic variants; Lung cancer

DOI: https://doi.org/10.1016/j.lungcan.2023.107247

Genes (Basel). 2023 Apr 30. pii: 1025. [Epub ahead of print]14(5):

Hereditary Cancer Syndromes: A Comprehensive Review with a Visual Tool.

Mattia Garutti, Lorenzo Foffano, Roberta Mazzeo, Anna Michelotti, Lucia Da Ros, Alessandra Viel, Gianmaria Miolo, Alberto Zambelli, Fabio Puglisi.

Hereditary cancer syndromes account for nearly 10% of cancers even though they are often underdiagnosed. Finding a pathogenic gene variant could have dramatic implications in terms of pharmacologic treatments, tailored preventive programs, and familiar cascade testing. However, diagnosing a hereditary cancer syndrome could be challenging because of a lack of validated testing criteria or because of their suboptimal performance. In addition, many clinicians are not sufficiently well trained to identify and select patients that could benefit from a genetic test. Herein, we searched the available literature to comprehensively review and categorize hereditary cancer syndromes affecting adults with the aim of helping clinicians in their daily clinical practice through a visual tool.

Keywords: BRCA; Li–Fraumeni; breast cancer; cancer genetics; cancer predisposition syndromes; colon cancer; hereditary cancer syndromes; lynch syndrome; melanoma

DOI: https://doi.org/10.3390/genes14051025