bims-lifras 2024-08-11 papers

Issue of 2024–08–11
five papers selected by
Joanna Zawacka, Karolinska Institutet

Cancer Rep (Hoboken). 2024 Aug;7(8): e2141

Identification of Novel Potential Predisposing Variants in Familial Acute Myeloid Leukemia.

Chiara Ronchini, Federica Gigli, Martina Fontanini, Raffaella Furgi, Viviana Amato, Fabio Giglio, Giuliana Gregato, Francesco Bertolini, Michela Rondoni, Francesco Lanza, Atto Billio, Enrico Derenzini, Corrado Tarella, Pier Giuseppe Pelicci, Myriam Alcalay, Elisabetta Todisco.

BACKGROUND: Myeloid neoplasms, including acute myeloid leukemia, have been traditionally among the less investigated cancer types concerning germline predisposition. Indeed, myeloid neoplasms with germline predisposition are challenging to identify because often display similar clinical and morphological characteristics of sporadic cases and have similar age at diagnosis. However, a misidentifications of familiarity in myeloid neoplasms have a critical impact on clinical management both for the carriers and their relatives.
AIMS: We conducted a family segregation study, in order to identify novel cancer predisposing genes in myeloid neoplasms and classify novel identified variants.
METHODS AND RESULTS: We performed a thorough genomic analysis using a large custom gene panel (256 genes), the Myelo-Panel, targeted on cancer predisposing genes. In particular, we assessed both germline and somatic variants in four families, each with two siblings, who developed hematological neoplasms: seven acute myeloid leukemia and one Philadelphia-positive chronic myeloid leukemia. In each family, we identified at least one novel potentially predisposing variant, affecting also genes not included in the current European LeukemiaNet guidelines for AML management. Moreover, we suggest reclassification of two germline variants as pathogenic: likely pathogenic p.S21Tfs*139 in CEPBA and VUS p.K392Afs*66 in DDX41.
CONCLUSION: We believe that predisposition to hematological neoplasms is still underestimated and particularly difficult to diagnosed. Considering that misidentification of familiarity in myeloid neoplasms have a critical impact on the clinical management both for the carriers and their relatives, our study highlights the importance of revision, in this clinical context, of clinical practices that should include thorough reconstruction of family history and in-depth genetic testing.

Keywords: AML; cancer genetics; cancer predisposition; germline variants

DOI: https://doi.org/10.1002/cnr2.2141

J Urol. 2024 Aug 09. 101097JU0000000000004190

Clinician-Reported Management Recommendations in Response to Universal Germline Genetic Testing in Patients With Prostate Cancer.

PURPOSE: Identification of pathogenic germline variants in patients with prostate cancer can help inform treatment selection, screening for secondary malignancies, and cascade testing. Limited real-world data are available on clinician recommendations following germline genetic testing in patients with prostate cancer.
MATERIALS AND METHODS: Patient data and clinician recommendations were collected from unselected patients with prostate cancer who underwent germline testing through the PROCLAIM trial. Differences among groups of patients were determined by 2-tailed Fisher's exact test with significance set at P < .05. Logistic regression was performed to assess the influence of test results in clinical decision-making while controlling for time of diagnosis (newly vs previously diagnosed).
RESULTS: Among 982 patients, 100 (10%) were positive (>1 pathogenic germline variant), 482 (49%) had uncertain results (>1 variant of uncertain significance) and 400 (41%) were negative. Patients with positive results were significantly more likely than those with negative or uncertain results to receive recommendations for treatment changes (18% vs 1.4%, P < .001), follow-up changes (64% vs 11%, P < .001), and cascade testing (71% vs 5.4%, P < .001). Logistic regression demonstrated that positive and uncertain results were significantly associated with both changes to treatment and follow-up (P < .001) when controlling for new or previous diagnosis.
CONCLUSIONS: Germline genetic testing results informed clinical recommendations for patients with prostate cancer, especially in patients with positive results. Higher than anticipated rates of clinical management changes in patients with uncertain results highlight the need for increased genetic education of clinicians treating patients with prostate cancer.

Keywords: clinical recommendations; genetic testing; germline variants; precision medicine; prostate cancer

DOI: https://doi.org/10.1097/JU.0000000000004190

AACE Clin Case Rep. 2024 Jul-Aug;10(4):10(4): 127-131

Papillary Thyroid Carcinoma, Cushing Disease, and Adrenocortical Carcinoma in a Patient with Li-Fraumeni Syndrome.

Jared G Friedman, Ioannis G Papagiannis.

Background/Objective: Li-Fraumeni syndrome (LFS) is an inherited sequence variant in TP53 characterized by the early onset of various core malignancies including adrenocortical carcinoma (ACC), sarcomas, breast cancer, leukemias, and central nervous system tumors. We present a case of a patient with LFS who developed endocrine neoplasms not classically seen in LFS in addition to developing ACC.
Case Report: A 26-year-old nonbinary individual assigned female at birth with a history of LFS complicated by osteosarcoma of the jaw was incidentally found to have thyroid and sellar masses on surveillance magnetic resonance imaging. Fine-needle aspiration of thyroid mass confirmed papillary thyroid carcinoma, and the patient underwent total thyroidectomy. Pituitary workup was notable for laboratory test results consistent with adrenocorticotropic hormone-dependent hypercortisolism; the patient underwent resection of the pituitary lesion. The patient was subsequently noted on abdominal imaging to have a new left adrenal mass; they underwent left adrenalectomy with pathology consistent with ACC.
Discussion: There is limited literature on the relationship between LFS and thyroid and pituitary neoplasms. Genetic testing has suggested that TP53 sequence variants may play a role in tumorigenesis in thyroid and pituitary neoplasms; however, most of the current literature is based on evidence of somatic rather than germline sequence variants.
Conclusion: This case highlights a patient with LFS with neoplasia of multiple endocrine organs including ACC, which is a classic finding, as well as papillary thyroid carcinoma and Cushing disease. Further investigation may be necessary to assess if patients with LFS are at a higher risk of various endocrine neoplasms in addition to the core malignancies classically described because this could affect future screening protocols.

Keywords: Li-Fraumeni syndrome; adrenocortical carcinoma; endocrine neoplasia; p53

DOI: https://doi.org/10.1016/j.aace.2024.03.007

J Obstet Gynaecol Res. 2024 Aug 08.

Four cancer cases with pathological germline variant RAD51D c.270_271dup.

Eiko Ishihara, Hiroyuki Matsubayashi, Seiichiro Nishimura, Mitsuhiro Isaka, Hayato Konno, Seiya Goto, Ken Yamaguchi, Kenichi Urakami.

Pathological germline variants (PGVs) of RAD51D increase the risk of breast and ovarian cancer. In East Asia, c.270_271dup is the most frequently detected PGV of RAD51D; however, only a few cases have been reported in Japan. We report four cancer cases with a germline RAD51D c.270_271dup PGV. Three of them (lung cancer: 2, oral cancer: 1) were incidentally identified by whole genome sequencing in patients negative for the associated cancer histories, homologous recombination (HR) deficiency, or a second hit of RAD51D in the cancer DNA. For genetic counseling, we provided information on surveillance and cascade testing based on Western guidelines. The PGVs of moderate-risk HR-related genes are difficult to detect based on phenotype, especially in male-predominant pedigrees. The current spread of cancer genomic analysis will increase opportunities for incidental variant identification. The establishment of Japanese guidelines is expected to aid in the management of PGV carriers of moderate-risk genes.

Keywords: RAD51D 270_271dup; cancer risk; germline; moderate‐risk cancer gene

DOI: https://doi.org/10.1111/jog.16045

Genes Chromosomes Cancer. 2024 Aug;63(8): e23263

Hereditary Colorectal Cancer and Polyposis Syndromes Caused by Variants in Uncommon Genes.

Ahmed Bouras, Aurélie Fabre, Hélène Zattara, Sandrine Handallou, Françoise Desseigne, Caroline Kientz, Fabienne Prieur, Magalie Peysselon, Clémentine Legrand, Laura Calavas, Jean-Christophe Saurin, Qing Wang.

A substantial number of hereditary colorectal cancer (CRC) and colonic polyposis cannot be explained by alteration in confirmed predisposition genes, such as mismatch repair (MMR) genes, APC and MUTYH. Recently, a certain number of potential predisposition genes have been suggested, involving each a small number of cases reported so far. Here, we describe the detection of rare variants in the NTLH1, AXIN2, RNF43, BUB1, and TP53 genes in nine unrelated patients who were suspected for inherited CRC and/or colonic polyposis. Seven of them were classified as pathogenic or likely pathogenic variants (PV/LPV). Clinical manifestations of carriers were largely consistent with reported cases with, nevertheless, distinct characteristics. PV/LPV in these uncommon gene can be responsible for up to 2.7% of inherited CRC or colonic polyposis syndromes. Our findings provide supporting evidence for the role of these genes in cancer predisposition, and contribute to the determination of related cancer spectrum and cancer risk for carriers, allowing for the establishment of appropriate screening strategy and genetic counseling in affected families.

Keywords: cancer predisposition genes; colorectal cancer; polyposis

DOI: https://doi.org/10.1002/gcc.23263