bims-lifras 2023-11-26 papers

JCO Precis Oncol. 2023 Sep;7 e2300190

Rate of Pathogenic Germline Variants in Patients With Lung Cancer.

Steven Sorscher, Jaclyn LoPiccolo, Brandie Heald, Elaine Chen, Sara L Bristow, Scott T Michalski, Sarah M Nielsen, Alix Lacoste, Emil Keyder, Hayan Lee, Robert L Nussbaum, Renato Martins, Edward D Esplin.

PURPOSE: Germline genetic testing (GGT) is now recommended for all patients diagnosed with ovarian or pancreatic cancer and for a large proportion of patients based solely on a diagnosis of colorectal or breast cancer. However, GGT is not yet recommended for all patients diagnosed with lung cancer (LC), primarily because of a lack of evidence that supports a significant frequency of identifying pathogenic germline variants (PGVs) in these patients. This study characterizes GGT results in a cohort of patients with LC.
METHODS: We reviewed deidentified data for 7,788 patients with GGT (2015-2022). PGV frequencies were compared to a control cohort of unaffected individuals. GGT results were stratified by genomic ancestry, history of cancer, and PGV clinical actionability per current guidelines.
RESULTS: Of all patients with LC, 14.9% (1,161/7,788) had PGVs. The rate was similar when restricted to patients with no cancer family history (FH) or personal history (PH) of other cancers (14.3%). PGVs were significantly enriched in BRCA2, ATM, CHEK2, BRCA1, and mismatch repair genes compared with controls. Patients of European (EUR) genomic ancestry had the highest PGV rate (18%) and variants of uncertain significance were significantly higher in patients of non-EUR genomic ancestry. Of the PGVs identified, 61.3% were in DNA damage repair (DDR) genes and 95% were clinically actionable.
CONCLUSION: This retrospective study shows a LC diagnosis identifies patients with a significant likelihood of having a cancer-predisposing PGV across genomic ancestries. Enrichment of PGVs in DDR genes suggests that these PGVs may contribute to LC cancer predisposition. The frequency of PGVs among patients with LC did not differ significantly according to FH or PH of other cancers.

DOI: https://doi.org/10.1200/PO.23.00190

Hum Pathol. 2023 Nov 22. pii: S0046-8177(23)00232-0. [Epub ahead of print]

Spectrum of histopathologic findings in risk-reducing bilateral prophylactic mastectomy in patients with and without BRCA mutations.

Baris Boyraz, Amy Ly.

Many germline mutations have been implicated in breast cancer pathogenesis and despite several studies on occult atypical lesions in prophylactic mastectomy specimens from patients with BRCA1/2 mutations, there are very limited data on other genes associated with increased breast cancer risk and the distribution of lesions in patients with hereditary breast cancer. We identified 207 patients who underwent bilateral prophylactic mastectomy due to germline mutations in BRCA1/2, PALB2, CHEK2, ATM, CDH1, PTEN, BARD1, or strong family history between 2015 and 2023. Patients with biopsy-proven past or current invasive breast carcinoma or carcinoma in-situ preoperatively were excluded. In addition to multiple benign lesions, the following atypical lesions were identified: flat epithelial atypia (16.9%), atypical ductal hyperplasia (14.0%), lobular neoplasia (14.0%), ductal carcinoma in-situ (4.3%), invasive ductal carcinoma (0.4%). Both low-grade and high-grade pathway lesions were identified in this cohort, and in a subset of patients, they co-occurred. The frequency of atypical lesions identified in patients with strong family history were comparable to those with proven germline mutation. PTEN immunohistochemistry showed loss of expression in ductal carcinoma in-situ and tubular adenomas in PTEN-mutant patients. Overall, findings from this cohort support the benefit of prophylactic mastectomy in patients with germline mutations and/or strong family history. Additionally, this is the first demonstration that PTEN immunohistochemistry may be helpful in identifying germline mutations in patients with atypical or neoplastic proliferations.

Keywords: BRCA mutation; Hereditary/familial breast cancer; PTEN mutation; Prophylactic mastectomy; Risk-reducing mastectomy

DOI: https://doi.org/10.1016/j.humpath.2023.11.010

Blood Rev. 2023 Nov 20. pii: S0268-960X(23)00104-2. [Epub ahead of print] 101143

Unraveling germline predisposition in hematological neoplasms: Navigating complexity in the genomic era.

Joaquín Jerez, Marta Santiago.

Genomic advancements have yielded pivotal insights into hematological neoplasms, particularly concerning germline predisposition mutations. Following the WHO 2016 revisions, dedicated segments were proposed to address these aspects. Current WHO 2022, ICC 2022, and ELN 2022 classifications recognize their significance, introducing more mutations and prompting integration into clinical practice. Approximately 5-10% of hematological neoplasm patients show germline predisposition gene mutations, rising with risk factors such as personal cancer history and familial antecedents, even in older adults. Nevertheless, technical challenges persist. Optimal DNA samples are skin fibroblast-extracted, although not universally applicable. Alternatives such as hair follicle use are explored. Moreover, the scrutiny of germline genomics mandates judicious test selection to ensure precise and accurate interpretation. Given the significant influence of genetic counseling on patient care and post-assessment procedures, there arises a demand for dedicated centers offering specialized services.

Keywords: Genetic counseling; Germline predisposition; Technical challenges

DOI: https://doi.org/10.1016/j.blre.2023.101143

Cancers (Basel). 2023 Nov 16. pii: 5439. [Epub ahead of print]15(22):

Ring Chromosomes in Hematological Malignancies Are Associated with TP53 Gene Mutations and Characteristic Copy Number Variants.

Rachel J Boyd, Jaclyn B Murry, Laura A Morsberger, Melanie Klausner, Suping Chen, Christopher D Gocke, Andrew S McCallion, Ying S Zou.

Ring chromosomes (RC) are present in <10% of patients with hematological malignancies and are associated with poor prognosis. Until now, only small cohorts of patients with hematological neoplasms and concomitant RCs have been cytogenetically characterized. Here, we performed a conventional chromosome analysis on metaphase spreads from >13,000 patients diagnosed with hematological malignancies at the Johns Hopkins University Hospital and identified 98 patients with RCs-90 with myeloid malignancies and 8 with lymphoid malignancies. We also performed a targeted Next-Generation Sequencing (NGS) assay, using a panel of 642 cancer genes, to identify whether these patients harbor relevant pathogenic variants. Cytogenetic analyses revealed that RCs and marker chromosomes of unknown origin are concurrently present in most patients by karyotyping, and 93% of patients with NGS data have complex karyotypes. A total of 72% of these individuals have pathogenic mutations in TP53, most of whom also possess cytogenetic abnormalities resulting in the loss of 17p, including the loss of TP53. All patients with a detected RC and without complex karyotypes also lack TP53 mutations but have pathogenic mutations in TET2. Further, 70% of RCs that map to a known chromosome are detected in individuals without TP53 mutations. Our data suggest that RCs in hematological malignancies may arise through different mechanisms, but ultimately promote widespread chromosomal instability.

Keywords: complex karyotype; copy number variants; gene mutation; myeloid malignancies; ring chromosomes

DOI: https://doi.org/10.3390/cancers15225439

Children (Basel). 2023 Nov 07. pii: 1793. [Epub ahead of print]10(11):

An Asymptomatic, Ectopic Mass as a Presentation of Adrenocortical Carcinoma Due to a Novel Germline TP53 p.Phe338Leu Tetramerisation Domain Variant.

Justyna Walenciak, Zuzanna Urbanska, Agata Pastorczak, Katarzyna Babol-Pokora, Kamila Wypyszczak, Ewa Bien, Aleksandra Gawlowska-Marciniak, Jozef Kobos, Wieslawa Grajkowska, Joanna Smyczynska, Wojciech Mlynarski, Szymon Janczar.

Adrenocortical carcinoma (ACC) is a rare cancer in childhood. ACC is frequently associated with germline TP53 variants, with founder effects especially due to the p.Arg337His mutation. ACC leads to the secretion of adrenocortical hormones, resulting in endocrine syndromes, which is the usual trigger for establishing the diagnosis. We present a surprising ACC pathology in a non-secreting, ectopic retroperitoneal tumour in a 4-year-old boy, successfully controlled with chemotherapy and mitotane after microscopically incomplete tumour resection with spillage. Genomic analysis (gene panel sequencing and copy-number microarray) demonstrated a novel p.Phe338Leu tetramerisation domain (TD) TP53 variant in the proband and his cancer-free mother and a monoallelic deletion encompassing the TP53 locus in cancer tissue, consistent with cancer-predisposition syndrome. While the recurrent p.Arg337His variant translates into high ACC risk, residue 338 and, in general, TD domain variants drive heterogeneous clinical scenarios, despite generally being considered less disruptive than TP53 DNA-binding domain mutations.

Keywords: Li–Fraumeni syndrome; TP53; adrenocortical carcinoma; cancer predisposition

DOI: https://doi.org/10.3390/children10111793