bims-lifras 2023-07-23 papers

Issue of 2023‒07‒23
three papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Am J Clin Pathol. 2023 Jul 17. pii: aqad075. [Epub ahead of print]

How I diagnose myeloid neoplasms with germline predisposition.

OBJECTIVES: Pathologists play a crucial role in the initial diagnosis of germline predisposition to myeloid neoplasia and subsequent surveillance for disease progression. The diagnostic workup can be challenging, particularly if clinical history, laboratory testing, or genetic studies are incomplete or unavailable.METHODS: Through case-based examples, we illustrate common diagnostic challenges and pitfalls encountered during bone marrow examination of patients being evaluated for myeloid malignancy with potential germline predisposition to myeloid neoplasia.
RESULTS: Lack of familial disease, the absence of syndromic manifestations, and late-onset hematologic malignancy do not exclude an underlying germline predisposition syndrome. Targeted myeloid sequencing panels can help identify potential germline alterations but may not detect large deletions or insertions, noncoding, or novel variants. Confirmation of the germline nature of an alteration detected in the peripheral blood or bone marrow ideally requires genetic testing using nonhematopoietic germline DNA to definitively distinguish between germline and somatic alterations. The ideal tissue source for germline testing is cultured skin fibroblasts. Certain germline predisposition syndromes can contain characteristic baseline bone marrow dysplastic-appearing features associated with cytopenias without constituting myelodysplastic syndrome.
CONCLUSION: Recognizing germline predisposition to myeloid neoplasia is critical for proper disease management. This recognition is particularly important for patients who will undergo hematopoietic stem cell transplantation to screen potential related donors. Integration of the clinical history, bone marrow findings, cytogenetic studies, and specialized laboratory and molecular genetic testing is often essential for accurate diagnosis and subsequent disease monitoring.

Keywords: ADA2 ; GATA2 ; RUNX1 ; SAMD9L ; DBA; acute myeloid leukemia; familial leukemia; genetic testing; germline predisposition; myelodysplastic syndrome

DOI: https://doi.org/10.1093/ajcp/aqad075

Mutat Res. 2023 Jul 04. pii: S0027-5107(23)00018-0. [Epub ahead of print]827 111831

Uncommon variants detected via hereditary cancer panel and suggestions for genetic counseling.

Zeynep Özdemir, Ezgi Çevik, Ömür Berna Çakmak Öksüzoğlu, Mutlu Doğan, Öztürk Ateş, Ece Esin, İrem Bilgetekin, Umut Demirci, Çağlar Köseoğlu, Alper Topal, Nuri Karadurmuş, Haktan Bağış Erdem, Taha Bahsi.

OBJECTIVE: Hereditary cancer syndromes constitute 5-10% of all cancers. The development of next-generation sequencing technologies has made it possible to examine many hereditary cancer syndrome-causing genes in a single panel. This study's goal was to describe the prevalence and the variant spectrum using NGS in individuals who were thought to have a hereditary predisposition for cancer.MATERIAL AND METHOD: Analysis was performed for 1254 who were thought to have a familial predisposition for cancer. We excluded 46 patients who were carrying BRCA1/2 variants in this study, for focusing on the rare gene mutations. Sequencing was performed using the Sophia Hereditary Cancer Solution v1.1 Panel and the Qiagen Large Hereditary Cancer Panel. The Illumina MiSeq system was used for the sequencing procedure. The software used for the data analyses was Sophia DDM and QIAGEN Clinical Insight (QCITM) Analyze. The resulting genomic changes were classified according to the current guidelines of ACMG/AMP.
RESULTS: Pathogenic/likely pathogenic variants were detected in 172 (13.7%) of 1254 patients. After excluding the 46 BRCA1/2-positive patients, among the remaining 126 patients; there were 60 (4.8%) breast cancer, 33 (2.6%) colorectal cancer, 9 (0.7%) ovarian cancer, 5 (0.4%) endometrium cancer, 5 (0.4%) stomach cancer, 3 (0.2%) prostate cancer patients. The most altered genes were MUTYH in 27 (2.1%) patients, MMR genes (MLH1, MSH6, MSH, MSH2, PMS2 and EPCAM) in 26 (2%) patients, and ATM in 25 (2%) patients. We also examined the genotype-phenotype correlation in rare variants. Additionally, we identified 11 novel variations.
CONCLUSION: This study provided significant information regarding rare variants observed in the Turkish population because it was carried out with a large patient group. Personalized treatment options and genetic counseling for the patients are therefore made facilitated.

Keywords: Hereditary cancer syndromes; Multigene panel testing; Next generation sequencing

DOI: https://doi.org/10.1016/j.mrfmmm.2023.111831

J Ovarian Res. 2023 Jul 17. 16(1): 141

Genomic analyses of germline and somatic variation in high-grade serous ovarian cancer.

A W Adamson, Y C Ding, L Steele, L A Leong, R Morgan, M T Wakabayashi, E S Han, T H Dellinger, P S Lin, A A Hakim, S Wilczynski, C D Warden, S Tao, V Bedell, M C Cristea, S L Neuhausen.

BACKGROUND: High-grade serous ovarian cancers (HGSCs) display a high degree of complex genetic alterations. In this study, we identified germline and somatic genetic alterations in HGSC and their association with relapse-free and overall survival. Using a targeted capture of 557 genes involved in DNA damage response and PI3K/AKT/mTOR pathways, we conducted next-generation sequencing of DNA from matched blood and tumor tissue from 71 HGSC participants. In addition, we performed the OncoScan assay on tumor DNA from 61 participants to examine somatic copy number alterations (SCNA).RESULTS: Approximately one-third of tumors had loss-of-function (LOF) germline (18/71, 25.4%) or somatic (7/71, 9.9%) variants in the DNA homologous recombination repair pathway genes BRCA1, BRCA2, CHEK2, MRE11A, BLM, and PALB2. LOF germline variants also were identified in other Fanconi anemia genes and in MAPK and PI3K/AKT/mTOR pathway genes. Most tumors harbored somatic TP53 variants (65/71, 91.5%). Using the OncoScan assay on tumor DNA from 61 participants, we identified focal homozygous deletions in BRCA1, BRCA2, MAP2K4, PTEN, RB1, SLX4, STK11, CREBBP, and NF1. In total, 38% (27/71) of HGSC patients harbored pathogenic variants in DNA homologous recombination repair genes. For patients with multiple tissues from the primary debulking or from multiple surgeries, the somatic mutations were maintained with few newly acquired point mutations suggesting that tumor evolution was not through somatic mutations. There was a significant association of LOF variants in homologous recombination repair pathway genes and high-amplitude somatic copy number alterations. Using GISTIC analysis, we identified NOTCH3, ZNF536, and PIK3R2 in these regions that were significantly associated with an increase in cancer recurrence and a reduction in overall survival.
CONCLUSIONS: From 71 patients with HGCS, we performed targeted germline and tumor sequencing and provided a comprehensive analysis of these 557 genes. We identified germline and somatic genetic alterations including somatic copy number alterations and analyzed their associations with relapse-free and overall survival. This single-site long-term follow-up study provides additional information on genetic alterations related to occurrence and outcome of HGSC. Our findings suggest that targeted treatments based on both variant and SCNA profile potentially could improve relapse-free and overall survival.

Keywords: Germline mutations; High-grade serous ovarian cancer; Homologous recombination repair; Somatic mutations; Somatic copy number alterations

DOI: https://doi.org/10.1186/s13048-023-01234-x