bims-lifras 2024-03-17 papers

Issue of 2024–03–17
seven papers selected by
Joanna Zawacka, Karolinska Institutet

Clin Genitourin Cancer. 2024 Feb 12. pii: S1558-7673(24)00024-7. [Epub ahead of print] 102052

Mainstream Model of Genetic Testing for Prostate Cancer at a Large Tertiary Cancer Centre.

Xin Wang, Larissa Waldman, Yael Silberman, Michael Wang, Caleb Tackey, Lilian Hanna, Danny Vesprini, Urban Emmenegger, Andrea Eisen, Martin Smoragiewicz.

BACKGROUND: An estimated 20% to 30% of men with advanced prostate cancer carry a mutation in DNA damage repair genes, of which half are estimated to be germline. Eligibility criteria for germline genetic testing expanded significantly for Ontario patients in May 2021 and many centers adopted a "mainstream" model, defined as oncologist-initiated genetic testing.
METHODS: We conducted a retrospective chart review to report on the first-year mainstream experience of a large tertiary oncologic center, the Sunnybrook Odette Cancer Centre. All patients who underwent mainstream at the discretion of their treating physician were included. A subset underwent somatic profiling as part of clinical trial screening. Descriptive statistics were used to report baseline clinicopathologic characteristics and treatments received.
RESULTS: Between May 1, 2021, and May 30, 2022, 174 patients with prostate cancer underwent mainstream germline genetic testing with a 19-gene panel. Median age was 75 (IQR 68-80), and 82% of patients were diagnosed with either de novo metastatic or high-risk localized prostate adenocarcinoma. Fourteen patients (8%; 95% CI 4%-12%) were found to have a deleterious germline mutation, including pathogenic or likely pathogenic variants in BRCA1/2, ATM, CHEK2, PMS2, RAD51C, HOXB13, and BRIP1. Forty-nine patients (28%; 95% CI 21%-35%) were found to have a variant of uncertain significance. Thirty-four patients also had next-generation sequencing (NGS) of their somatic tissue. Among this subset, 8 of 34 (23%) had an alteration in homologous recombination repair (HRR) genes. Of the 14 patients with a germline mutation, none had a prior personal history of malignancy and 6 (43%) did not have any first- or second-degree relatives with history of prostate, pancreatic, breast, or ovarian cancer.
CONCLUSION: We report on the real-world characteristics of prostate cancer patients who underwent mainstream germline genetic testing. Personal history and family history of cancer cannot reliably stratify patients for the presence of pathogenic germline variants.

Keywords: Germline testing; Homologous recombination repair; Mainstream testing; Personalized medicine; Prostate cancer

DOI: https://doi.org/10.1016/j.clgc.2024.02.003

Blood Res. 2024 Mar 08. 59(1): 12

Genomic testing for germline predisposition to hematologic malignancies.

Sang Mee Hwang.

Germline predisposition (GPD) to hematological malignancies has gained interest because of the increased use of genetic testing in this field. Recent studies have suggested that GPD is underrecognized and requires appropriate genomic testing for an accurate diagnosis. Identification of GPD significantly affects patient management and has diverse implications for family members. This review discusses the reasons for testing GPD in hematologic malignancies and explores the considerations necessary for appropriate genomic testing. The aim is to provide insights into how these genetic insights can inform treatment strategies and genetic counseling, ultimately enhancing patient care.

Keywords: Genomic testing; Germline predisposition; Hematologic malignancies; Myeloid neoplasms; Next-generation sequencing

DOI: https://doi.org/10.1007/s44313-024-00012-y

Cancers (Basel). 2024 Feb 26. pii: 947. [Epub ahead of print]16(5):

Advancing Precision Oncology in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Integrated Interpretation and Data Sharing of the Germline and Tumor Genomes.

Huma Q Rana, Diane R Koeller, McKenzie Walker, Busra Unal, Alison Schwartz Levine, Anu Chittenden, Raymond A Isidro, Connor P Hayes, Monica D Manam, Ryan M Buehler, Danielle K Manning, Justine A Barletta, Jason L Hornick, Judy E Garber, Arezou A Ghazani, Int Grate Oncology Consortium.

Standard methods of variant assessment in hereditary cancer susceptibility genes are limited by the lack of availability of key supporting evidence. In cancer, information derived from tumors can serve as a useful source in delineating the tumor behavior and the role of germline variants in tumor progression. We have previously demonstrated the value of integrating tumor and germline findings to comprehensively assess germline variants in hereditary cancer syndromes. Building on this work, herein, we present the development and application of the INT2GRATE|HPPGL platform. INT2GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) is a multi-institution oncology consortium that aims to advance the integrated application of constitutional and tumor data and share the integrated variant information in publicly accessible repositories. The INT2GRATE|HPPGL platform enables automated parsing and integrated assessment of germline, tumor, and genetic findings in hereditary paraganglioma-pheochromocytoma syndromes (HPPGLs). Using INT2GRATE|HPPGL, we analyzed 8600 variants in succinate dehydrogenase (SDHx) genes and their associated clinical evidence. The integrated evidence includes germline variants in SDHx genes; clinical genetics evidence: personal and family history of HPPGL-related tumors; tumor-derived evidence: somatic inactivation of SDHx alleles, KIT and PDGFRA status in gastrointestinal stromal tumors (GISTs), multifocal or extra-adrenal tumors, and metastasis status; and immunohistochemistry staining status for SDHA and SDHB genes. After processing, 8600 variants were submitted programmatically from the INT2GRATE|HPPGL platform to ClinVar via a custom-made INT2GRATE|HPPGL variant submission schema and an application programming interface (API). This novel integrated variant assessment and data sharing in hereditary cancers aims to improve the clinical assessment of genomic variants and advance precision oncology.

Keywords: INT2GRATE; INT2GRATE Oncology Consortium; PCC; PGL; germline VUS; hereditary paraganglioma–pheochromocytoma syndromes (HPPGLs); somatic and germline integration; tumor signature profile

DOI: https://doi.org/10.3390/cancers16050947

Hum Genome Var. 2024 Mar 15. 11(1): 11

BARD1 deletion in a patient with suspected hereditary colorectal cancer.

Nobue Takaiso, Issei Imoto, Akiyo Yoshimura, Akira Ouchi, Koji Komori, Hiroji Iwata, Yasuhiro Shimizu.

Deleterious germline variants in the BRCA1-associated ring domain (BARD1) gene moderately elevate breast cancer risk; however, their potential association with other neoplasms remains unclear. Here, we present the case of a 43-year-old female patient diagnosed with sigmoid colon adenocarcinoma whose maternal family members met the Amsterdam Criteria II for Lynch syndrome. Comprehensive multigene panel testing revealed a heterozygous BARD1 exon 3 deletion.

DOI: https://doi.org/10.1038/s41439-024-00267-y

J Endocr Soc. 2024 Mar 12. 8(5): bvae038

Patient Sex and Origin Influence Distribution of Driver Genes and Clinical Presentation of Paraganglioma.

Susan Richter, Nicole Bechmann.

Context: Sexual and ancestral differences in driver gene prevalence have been described in many cancers but have not yet been investigated in pheochromocytoma and paraganglioma (PPGL).
Objective: This study aims to assess whether sex and ancestry influence prevalence of PPGL driver genes and clinical presentation.
Methods: We conducted a retrospective analysis of patients with PPGL considering studies from 2010 onwards that included minimal data of type of disease, sex, mutated gene, and country of origin. Additional features were recorded when available (age, tumor location, bilateral or multifocal, somatic or germline, and metastatic disease).
Results: We included 2162 patients: 877 in Europe and 757 in Asia. Males presented more often with germline pathogenic variants (PVs) in genes activating hypoxia pathways (P = .0006) and had more often sympathetic paragangliomas (P = .0005) and metastasis (P = .0039). On the other hand, females with PPGLs due to MAX PVs were diagnosed later than males (P = .0378) and more often developed metastasis (P = .0497). European but not Asian females presented more often with PPGLs due to PVs in genes related to kinase signaling (P = .0052), particularly RET and TMEM127. Contrary to experiences from Europe, Asian patients with PPGL due to PVs in kinase signaling genes NF1, HRAS, and FGFR1 showed a high proportion of sympathetic tumors, while European patients almost exclusively had adrenal tumors (P < .005).
Conclusion: Personalized management of patients with PPGL might benefit from considering sexual and ancestral differences. Further studies with better clinically aligned cohorts from various origins are required to better dissect ancestral influences on PPGL development.

Keywords: Asian; European; germline; pheochromocytoma; somatic pathogenic variants

DOI: https://doi.org/10.1210/jendso/bvae038

Fam Cancer. 2024 Mar 13.

Cascade screening in HBOC and Lynch syndrome: guidelines and procedures in a UK centre.

D Gareth Evans, Kate Green, George J Burghel, Claire Forde, Fiona Lalloo, Helene Schlecht, Emma R Woodward.

In the 33 years since the first diagnostic cancer predisposition gene (CPG) tests in the Manchester Centre for Genomic Medicine, there has been substantial changes in the identification of index cases and cascade testing for at-risk family members. National guidelines in England and Wales are usually determined from the National Institute of healthcare Evidence and these have impacted on the thresholds for testing BRCA1/2 in Hereditary Breast Ovarian Cancer (HBOC) and in determining that all cases of colorectal and endometrial cancer should undergo screening for Lynch syndrome. Gaps for testing other CPGs relevant to HBOC have been filled by the UK Cancer Genetics Group and CanGene-CanVar project (web ref. https://www.cangene-canvaruk.org/ ). We present time trends (1990-2020) of identification of index cases with germline CPG variants and numbers of subsequent cascade tests, for BRCA1, BRCA2, and the Lynch genes (MLH1, MSH2, MSH6 and PMS2). For BRCA1/2 there was a definite increase in the proportion of index cases with ovarian cancer only and pre-symptomatic index tests both doubling from 16 to 32% and 3.2 to > 8% respectively. A mean of 1.73-1.74 additional family tests were generated for each BRCA1/2 index case within 2 years. Overall close to one positive cascade test was generated per index case resulting in > 1000 risk reducing surgery operations. In Lynch syndrome slightly more cascade tests were performed in the first two years potentially reflecting the increased actionability in males with 42.2% of pre-symptomatic tests in males compared to 25.8% in BRCA1/2 (p < 0.0001).

Keywords: BRCA1/2; Cancer predisposition gene (CPG); Genetic testing; Lynch syndrome

DOI: https://doi.org/10.1007/s10689-024-00360-9