bims-lifras 2022-01-09 papers

JCO Precis Oncol. 2021 Nov;5 1677-1686

Evaluation of TP53 Variants Detected on Peripheral Blood or Saliva Testing: Discerning Germline From Somatic TP53 Variants.

Alison N Schwartz, Sophie R Hyman, Samantha M Stokes, Danielle Castillo, Nadine M Tung, Jeffrey N Weitzel, Huma Q Rana, Judy E Garber.

PURPOSE: Multigene panel testing (MGPT) identifies TP53 pathogenic or likely pathogenic (P/LP) variants in patients with diverse phenotypes, of which only one is classic Li-Fraumeni syndrome. Low variant allelic fraction (VAF) in TP53 found on germline testing may suggest aberrant clonal expansion or constitutional mosaicism. We evaluated TP53-positive probands seen in a cancer genetics program to determine germline versus somatic status.
METHODS: We reviewed TP53-positive probands from 2012 to 2019 identified by MGPT on blood or saliva (N = 84). Available VAFs were collected. Probands with a familial variant, who met Li-Fraumeni syndrome testing criteria or who carried a founder variant, were considered germline. For those with uncertain germline status, TP53 variants were further examined using ancillary data of family members and somatic tissue.
RESULTS: Of the 84 probands, 54.7% had germline variants with 33.3% meeting criteria for germline status and 21.4% confirmed through ancillary testing. Aberrant clonal expansion comprised 13.1% with clonal hematopoiesis of indeterminate potential and 2.4% with a hematologic malignancy. Constitutional mosaicism was confirmed in 8.3% probands. Definitive status could not be determined in 3.6% despite ancillary assessment, and 17.9% did not have ancillary testing.
CONCLUSION: A TP53 P/LP variant found on peripheral blood or saliva MGPT does not always originate in the germline. In a clinical cancer genetics cohort, approximately half of the patients had TP53 P/LP germline variants; these patients plus those with constitutional mosaicism require intensified surveillance. A framework of multiple strategies enables discernment of germline from constitutional mosaic and acquired variants, which is essential for appropriate management.

DOI: https://doi.org/10.1200/PO.21.00278

JCO Precis Oncol. 2021 Nov;5 808-816

Clinical Implications of Pathogenic Germline Variants in Small Intestine Neuroendocrine Tumors (SI-NETs).

Kimberly Perez, Matthew H Kulke, Anu Chittenden, Chinedu Ukaegbu, Kristina Astone, Holly Alexander, Lauren Brais, Jinming Zhang, John Garcia, Edward D Esplin, Shan Yang, Annacarolina Da Silva, Jonathan A Nowak, Matthew B Yurgelun, Judy Garber, Sapna Syngal, Jennifer Chan.

PURPOSE: An inherited basis for presumed sporadic neuroendocrine tumor (NET) has been suggested by evidence of familial clustering of NET and a higher incidence of second malignancies in patients and families with NET. To further investigate a potential heritable basis for sporadic neuroendocrine tumors, we performed multigene platform germline analysis to determine the frequency of hereditary susceptibility gene variants in a cohort of patients with sporadic small intestine NET (SI-NET).
METHODS: We performed a multigene platform germline analysis with Invitae's 83-gene, next-generation sequencing panel using DNA from 88 individuals with SI-NET from a clinically annotated database of patients with NET evaluated at Dana-Farber Cancer Institute (DFCI) who are considered high risk for inherited variants. Additionally, we evaluated the prevalence of pathogenic variants in an unselected cohort of patients with SI-NET who underwent testing with Invitae.
RESULTS: Of the 88 patients in the DFCI cohort, a pathogenic germline variant was identified in eight (9%) patients. In an independent cohort of 120 patients with SI-NET, a pathogenic germline variant was identified in 13 (11%) patients. Pathogenic variants were identified in more than one patient in the following genes: ATM, RAD51C, MUTYH, and BLM. Somatic testing of tumors from the DFCI cohort was suboptimal because of insufficient coverage of all targeted exons, and therefore, analysis was limited.
CONCLUSION: We demonstrate a 9%-11% incidence of pathogenic germline variants in genes associated with inherited susceptibility for malignancy not previously described in association with SI-NET. The association of these germline variants with neuroendocrine carcinogenesis and risk is uncertain but warrants further characterization.

DOI: https://doi.org/10.1200/PO.21.00047

Hum Hered. 2022 Jan 06.

Identification of CHEK2 germline mutations in BRCA1/2 and PALB2 negative breast and ovarian cancer patients.

Fuat Aksoy, Havva Tezcan Unlu, Gulsah Cecener, Gamze Guney Eskiler, Unal Egeli, Berrin Tunca, Ecem Efendi Erdem, Kazım Senol, Mustafa Sehsuvar Gokgoz.

INTRODUCTION: The CHEK2 gene is known to be an important signal transducer involved in DNA repair, apoptosis, or cell cycle arrest in response to DNA damage. The mutations in this gene have been associated with a wide range of cancers, both sporadic and hereditary. Germline CHEK2 mutations are linked to an increased risk of breast cancer. Therefore, the aim of this study was to identify the prevalence of CHEK2 variants in BRCA1/2 and PALB2 negative early-onset patients with breast cancer and/or ovarian cancer in a Turkish population for the first time.
METHODS: The study included 95 patients with BRCA1/2 and PALB2 negative early-onset breast cancer and/or ovarian cancer and also 60 unaffected women. All the intron/exon boundaries and coding exons of CHEK2 were subjected to mutational analysis by heteroduplex analysis and DNA sequencing.
RESULTS: A total of 16 CHEK2 variants were found in breast cancer patients within the Turkish population. CHEK2 c.1100delC mutation studied in the CHEK2 gene most frequently was not detected in our study. The prevalence of variants of uncertain significance in CHEK2 was found to be 7.3% (n= 7) in BRCA1/2 and PALB2 mutation negative Turkish patients with early-onset breast and/or ovarian cancer.
DISCUSSION/CONCLUSION: The present study may shed light on alternative variations that could be significant for understanding the prevalence and clinical suitability of the CHEK2 gene.

DOI: https://doi.org/10.1159/000521369

Fam Cancer. 2022 Jan 04.

BRCA1 Norway: comparison of classification for BRCA1 germline variants detected in families with suspected hereditary breast and ovarian cancer between different laboratories.

Henrikke N Hovland, Rafal Al-Adhami, Sarah Louise Ariansen, Marijke Van Ghelue, Wenche Sjursen, Sigrid Lima, Marte Bolstad, Amund H Berger, Hildegunn Høberg-Vetti, Per Knappskog, Bjørn Ivar Haukanes, Ingvild Aukrust, Elisabet Ognedal.

Pathogenic germline variants in Breast cancer susceptibility gene 1 (BRCA1) predispose carriers to hereditary breast and ovarian cancer (HBOC). Through genetic testing of patients with suspected HBOC an increasing number of novel BRCA1 variants are discovered. This creates a growing need to determine the clinical significance of these variants through correct classification (class 1-5) according to established guidelines. Here we present a joint collection of all BRCA1 variants of class 2-5 detected in the four diagnostic genetic laboratories in Norway. The overall objective of the study was to generate an overview of all BRCA1 variants in Norway and unveil potential discrepancies in variant interpretation between the hospitals, serving as a quality control at the national level. For a subset of variants, we also assessed the change in classification over a ten-year period with increasing information available. In total, 463 unique BRCA1 variants were detected. Of the 126 variants found in more than one hospital, 70% were interpreted identically, while 30% were not. The differences in interpretation were mainly by one class (class 2/3 or 4/5), except for one larger discrepancy (class 3/5) which could affect the clinical management of patients. After a series of digital meetings between the participating laboratories to disclose the cause of disagreement for all conflicting variants, the discrepancy rate was reduced to 10%. This illustrates that variant interpretation needs to be updated regularly, and that data sharing and improved national inter-laboratory collaboration greatly improves the variant classification and hence increases the accuracy of cancer risk assessment.

Keywords: BRCA1; Breast and ovarian cancer; Variant classification; Variants of uncertain significance

DOI: https://doi.org/10.1007/s10689-021-00286-6

JCO Precis Oncol. 2021 Nov;5 107-122

Inherited Susceptibility to Hematopoietic Malignancies in the Era of Precision Oncology.

Gregory W Roloff, Michael W Drazer, Lucy A Godley.

As germline predisposition to hematopoietic malignancies has gained increased recognition and attention in the field of oncology, it is important for clinicians to use a systematic framework for the identification, management, and surveillance of patients with hereditary hematopoietic malignancies (HHMs). In this article, we discuss strategies for identifying individuals who warrant diagnostic evaluation and describe considerations pertaining to molecular testing. Although a paucity of prospective data is available to guide clinical monitoring of individuals harboring pathogenic variants, we provide recommendations for clinical surveillance based on consensus opinion and highlight current advances regarding the risk of progression to overt malignancy in HHM variant carriers. We also discuss the prognosis of HHMs and considerations surrounding the utility of allogeneic stem-cell transplantation in these individuals. We close with an overview of contemporary issues at the intersection of HHMs and precision oncology.

DOI: https://doi.org/10.1200/PO.20.00387