bims-lifras 2024-06-09 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2024–06–09
ten papers selected by
Joanna Zawacka, Karolinska Institutet

Prevalence of Potentially Pathogenic Germline Variants Among Adult Patients in the Philippines With Solid Malignancies Who Underwent Tumor Genomic Profiling.
Myeloid neoplasms in individuals with breast and ovarian cancer and the association with deleterious germline variants.
Therapeutic applications of germline testing for cancer predisposition genes in Asia in the real world.
Comprehensive next-generation sequencing identifies novel putative pathogenic or likely pathogenic germline variants in patients with concurrent tubo-ovarian and endometrial serous and endometrioid carcinomas or precursors.
Population-Level Identification of Patients With Lynch Syndrome for Clinical Care, Quality Improvement, and Research.
Implementation of and Systems-Level Barriers to Guideline-Driven Germline Genetic Evaluation in the Care of Patients With Myelodysplastic Syndrome and Acute Myeloid Leukemia.
Genetic counseling and genetic testing for pathogenic germline mutations among high-risk patients previously diagnosed with breast cancer: a traceback approach.
High frequency of germline variants in CFTR identified in PDAC patients enrolled in an expanded panel multi-gene panel testing program.
Retrospective study of germline variants in patients with hereditary melanoma study criteria in a real clinical practice setting.
Implementation of Universal Pan-Cancer Germline Genetic Testing in an Arab Population: The Jordanian Exploratory Cancer Genetics Study.

JCO Glob Oncol. 2024 Jun;10 e2400019

Prevalence of Potentially Pathogenic Germline Variants Among Adult Patients in the Philippines With Solid Malignancies Who Underwent Tumor Genomic Profiling.

Paula Isabel Franco, Jose Jasper Andal, Daphne Chua Ang, Frances Victoria Que.

PURPOSE: In high-income countries, 2%-10% of tumor genomic profiling (TGP) reports reveal incidental pathogenic germline variants. A third of these patients would not qualify for genetic testing on the basis of current guidelines. Our study determined the prevalence of potentially pathogenic germline variants (PPGVs) in TGP results of adult patients with solid malignancies in the Philippines.
METHODS: Annotated reports of patients with solid cancers who underwent TGP using FoundationOne or FoundationOne Heme between January 2021 and July 2023 were reviewed. PPGV criteria include having a variant allele frequency of >30% and were categorized as (1) high penetrance gene (HP), founder variant (FV), or variant associated with clinical presentation (VA). Pathogenicity was crosschecked through the ClinVar database.
RESULTS: Of 446 patients, 13 PPGV variants were found in 50 (11.2%) patients at a median age of 60.5 years. Of them, 28 (56%) had HP (BRCA1, BRCA2, MSH2, MSH6, MLH1, RAD51C, RAD51D), 25 (50%) patients had VA (APC, SMAD4, CDH1, CDKN2A, PTEN), and two patients with lung cancer had a FV (EGFR p.Thr790Met). Six patients had more than one PPGV. PPGVs were primarily found in patients with colorectal (42% of 50 patients with PPGVs), breast (16%), ovarian (6%), and lung (6%) cancer (P < .001). HP genes were mostly found in female patients (71.4%; P = .03).
CONCLUSION: With a PPGV prevalence of 11% in this study, it is important to recognize PPGVs as it can prompt genetic counseling and confirmatory germline testing.

DOI: https://doi.org/10.1200/GO.24.00019
Gynecol Oncol. 2024 May 31. pii: S0090-8258(24)00249-X. [Epub ahead of print]187 235-240

Myeloid neoplasms in individuals with breast and ovarian cancer and the association with deleterious germline variants.

Stephanie Franco, Lucy A Godley.

Historically, the increased incidence of myeloid neoplasms observed in individuals with breast and ovarian cancer has been attributed exclusively to prior exposure to cancer-directed therapies. However, as the association between deleterious germline variants and the development of hematopoietic malignancies (HMs) becomes better established, we propose the increased incidence of myeloid neoplasms in those with breast and ovarian cancer may be at least partially related to underlying germline cancer predisposition alleles. Deleterious germline variants in BRCA1/2, ATM, CHEK2, PALB2, and other related genes prevent normal homologous recombination DNA repair of double-strand breaks, leading to reliance on less effective repair mechanisms. This results in a high lifetime risk of breast and ovarian cancer, and likely also increases the risk of subsequent therapy-related myeloid neoplasms (t-MNs). These deleterious germline variants likely increase the risk for de novo HMs as well, as evidenced by the increased incidence of HMs observed in those with deleterious germline BRCA1/2 variants even in the absence of prior cancer-directed therapy. Thus, the association between poly(ADP-ribose) polymerase (PARP) inhibitors and other solid tumor directed therapies and the development of t-MNs may be confounded by the presence of deleterious germline variants which inherently increase the risk of both de novo and t-MNs, and additional data regarding the direct toxic effects of these drugs on bone marrow function are needed.

DOI: https://doi.org/10.1016/j.ygyno.2024.05.026
ESMO Open. 2024 Jun 03. pii: S2059-7029(24)01251-1. [Epub ahead of print]9(6): 103482

Therapeutic applications of germline testing for cancer predisposition genes in Asia in the real world.

S W Cheo, P Y Ong, S G W Ow, G H J Chan, D S P Tan, Y W Lim, H L Kong, A L A Wong, S E Lim, R J Walsh, A S C Wong, J J H Low, N Y L Ngoi, J S L Lim, S C Lee.

   BACKGROUND: Germline genetic testing is traditionally carried out in patients suspected with hereditary cancer syndrome for enhanced cancer surveillance and/or preventive strategies, but is increasingly carried out for therapeutic indications.
MATERIALS AND METHODS: We conducted a retrospective review of patients who underwent germline genetic testing at our centre to determine the prevalence of actionable pathogenic germline variants (PGV) and their clinical utility.
RESULTS: From 2000 to 2022, 1154 cancer patients underwent germline testing, with the majority (945/1154) tested with multi-gene panels. Four hundred and eleven (35.6%) patients harboured a PGV and 334 (81%) were clinically actionable. BRCA1/2 accounted for 62.3% of actionable mutations, followed by mismatch repair (18%), and other homologous recombination repair (HRR) genes (19.7%). One hundred and fifty-two germline-positive patients have advanced cancers, and 79 received germline-directed therapies (poly ADP ribose polymerase inhibitors = 75; immunotherapy = 4). Median duration of immunotherapy and poly ADP ribose polymerase were 20.5 months (range 5-40 months) and 8 months (range 1-76 months), respectively. Among BRCA/HRR mutation carriers who received platinum-based chemotherapy, pathological complete response rate in the neoadjuvant setting was 53% (n = 17 breast cancers) and objective response rate was >80% in the advanced setting (n = 71).
CONCLUSIONS: One-third of cancer patients tested carried a PGV and ∼80% were clinically actionable. Three-quarters of germline-positive advanced cancer patients received germline-directed therapies in the real world, underscoring the practical utility of germline testing to guide cancer therapeutics.

Keywords:  BRCA; cancer predisposition genes; germline testing; pathogenic germline variants; precision oncology; therapeutic applications

DOI:  https://doi.org/10.1016/j.esmoop.2024.103482
Gynecol Oncol. 2024 Jun 03. pii: S0090-8258(24)00250-6. [Epub ahead of print]187 241-248

Comprehensive next-generation sequencing identifies novel putative pathogenic or likely pathogenic germline variants in patients with concurrent tubo-ovarian and endometrial serous and endometrioid carcinomas or precursors.

Omonigho Aisagbonhi, Ida Ghlichloo, Duncan S Hong, Andres Roma, Oluwole Fadare, Ramez Eskander, Cheryl Saenz, Kathleen M Fisch, Wei Song.

   BACKGROUND: Endometrial serous carcinoma (ESC) and tubo-ovarian high-grade serous carcinoma (HGSC) are characterized by late-stage presentation and high mortality. Current guidelines for prevention recommend risk-reducing salpingo-oophorectomy (RRSO) in patients with hereditary mutations in cancer susceptibility genes. However, HGSC displays extensive genetic heterogeneity with alterations in 168 genes identified in TCGA study, but current germline testing panels are often limited to the handful of recurrently mutated genes, leaving families with rare hereditary gene mutations potentially at-risk.
OBJECTIVE: To determine if there are rare germline mutations that may aid in early identification of more patients at-risk for ESC and/or HGSC by evaluating patients with concurrent ESC, HGSC or precursor lesions, and endometrial atypical hyperplasia (CAH) or low-grade endometrial endometrioid adenocarcinoma (LGEEA).
METHODS: We performed targeted next-generation sequencing using TSO 500, a 523 gene panel, on formalin-fixed paraffin-embedded tumor and matched benign non-tumor tissue blocks from 5 patients with concurrent ESC, HGSC or precursor lesions, and CAH or LGEEA.
RESULTS: We identified germline pathogenic, likely pathogenic or uncertain significance variants in cancer susceptibility genes in 4 of 5 patients - affected genes included GLI1, PIK3R1, FOXP1, FANCD2, INPP4B and H3F3C. Notably, none of these genes were included in the commercially available germline testing panels initially used to evaluate the patients at the time of their diagnoses.
CONCLUSION: Comprehensive germline testing of patients with concurrent LGEEA or CAH and ESC, HGSC or precursor lesions may aid in early identification of relatives at-risk for cancer who may be candidates for RRSO with hysterectomy.

Keywords:  Endometrial; Fallopian tube; Genetic; Germline; Molecular; Ovarian; Serous; cancer

DOI:  https://doi.org/10.1016/j.ygyno.2024.05.027
JCO Clin Cancer Inform. 2024 Jun;8 e2300157

Population-Level Identification of Patients With Lynch Syndrome for Clinical Care, Quality Improvement, and Research.

Ravi N Sharaf, Natalia Udaltsova, Dan Li, Rish K Pai, Soham Sinha, Zixuan Li, Douglas A Corley.

PURPOSE: Identification of those at risk of hereditary cancer syndromes using electronic health record (EHR) data sources is important for clinical care, quality improvement, and research. We describe diagnostic processes, previously seldom reported, for a common hereditary cancer syndrome, Lynch syndrome (LS), using EHR data within a community-based, multicenter, demographically diverse health system.
METHODS: Within a retrospective cohort enrolled between 2015 and 2020 at Kaiser Permanente Northern California, we assessed electronic diagnostic domains for LS including (1) family history of LS-associated cancer; (2) personal history of LS-associated cancer; (3) LS screening via mismatch repair deficiency (MMRD) testing of newly diagnosed malignancy; (4) germline genetic test results; and (5) clinician-entered diagnostic codes for LS. We calculated proportions and overlap for each diagnostic domain descriptively.
RESULTS: Among 5.8 million individuals, (1) 28,492 (0.49%) had a family history of LS-associated cancer of whom 3,635 (13%) underwent genetic testing; (2) 100,046 (1.7%) had a personal history of a LS-associated cancer; and (3) 8,711 (0.1%) were diagnosed with colorectal cancer of whom 7,533 (86%) underwent MMRD screening and of the positive screens (486), 130 (27%) underwent germline testing. One thousand seven hundred and fifty-seven (0.03%) were diagnosed with endometrial cancer of whom 1,613 (92%) underwent MMRD screening and of the 195 who screened positive, 55 (28%) underwent genetic testing. (4) 30,790 (0.05%) had LS germline genetic testing with 707 (0.01%) testing positive; and (5) 1,273 (0.02%) had a clinician-entered diagnosis of LS.
CONCLUSION: It is feasible to electronically characterize the diagnostic processes of LS. No single data source comprehensively identifies all LS carriers. There is underutilization of LS genetic testing for those eligible and underdiagnosis of LS. Our work informs similar efforts in other settings for hereditary cancer syndromes.

DOI: https://doi.org/10.1200/CCI.23.00157
JCO Precis Oncol. 2024 Jun;8 e2300518

Implementation of and Systems-Level Barriers to Guideline-Driven Germline Genetic Evaluation in the Care of Patients With Myelodysplastic Syndrome and Acute Myeloid Leukemia.

Lauren G Banaszak, Paloma L Cabral, Kelcy Smith-Simmer, Ayesha Hassan, Matthew Brunner, Michael Fallon, Kyle Shoger, Lauren Lovrien, Danielle Golner, Luke Zurbriggen, Ryan Mattison, Zhubin Gahvari, Aric Hall, Kalyan Nadiminti, Erica Reinig, Jane E Churpek.

PURPOSE: Knowledge of an inherited predisposition to myelodysplastic syndrome (MDS) and AML has important clinical implications for treatment decisions, surveillance, and care of at-risk relatives. National Comprehensive Cancer Network (NCCN) guidelines recently incorporated recommendations for germline genetic evaluation of patients with MDS/AML on the basis of personal and family history features, but the practicality of implementing these recommendations has not been studied.
METHODS: A hereditary hematology quality improvement (QI) committee was formed to implement these guidelines in a prospective cohort of patients diagnosed with MDS/AML. Referral for germline genetic testing was recommended for patients meeting NCCN guideline criteria. Referral patterns and genetic evaluation outcomes were compared with a historical cohort of patients with MDS/AML. Barriers to evaluation were identified.
RESULTS: Of the 90 patients with MDS/AML evaluated by the QI committee, 59 (66%) met criteria for germline evaluation. Implementation of the QI committee led to more referrals for germline evaluation in accordance with NCCN guidelines (31% v 14%, P = .03). However, the majority of those meeting criteria were never referred due to high medical acuity or being deceased or in hospice at the time of QI committee recommendations. Despite this, two (17%) of the 12 patients undergoing genetic testing were diagnosed with a hereditary myeloid malignancy syndrome.
CONCLUSION: Current NCCN guidelines resulted in two thirds of patients with MDS/AML meeting criteria for germline evaluation. A hereditary hematology-focused QI committee aided initial implementation and modestly improved NCCN guideline adherence. However, the high morbidity and mortality and prolonged inpatient stays associated with MDS/AML challenged traditional outpatient genetic counseling models. Further improvements in guideline adherence require innovating new models of genetic counseling and testing for this patient population.

DOI: https://doi.org/10.1200/PO.23.00518
Sci Rep. 2024 06 04. 14(1): 12820

Genetic counseling and genetic testing for pathogenic germline mutations among high-risk patients previously diagnosed with breast cancer: a traceback approach.

Hikmat Abdel-Razeq, Faris Tamimi, Sereen Iweir, Baha Sharaf, Sarah Abdel-Razeq, Osama Salama, Sarah Edaily, Hira Bani Hani, Khansa Azzam, Haneen Abaza.

  Genetic counseling and testing are more accessible than ever due to reduced costs, expanding indications and public awareness. Nonetheless, many patients missed the opportunity of genetic counseling and testing due to barriers that existed at that time of their cancer diagnoses. Given the identified implications of pathogenic mutations on patients' treatment and familial outcomes, an opportunity exists to utilize a 'traceback' approach to retrospectively examine their genetic makeup and provide consequent insights to their disease and treatment. In this study, we identified living patients diagnosed with breast cancer (BC) between July 2007 and January 2022 who would have been eligible for testing, but not tested. Overall, 422 patients met the eligibility criteria, 282 were reached and invited to participate, and germline testing was performed for 238, accounting for 84.4% of those invited. The median age (range) was 39.5 (24-64) years at BC diagnosis and 49 (31-75) years at the date of testing. Genetic testing revealed that 25 (10.5%) patients had pathogenic/likely pathogenic (P/LP) variants; mostly in BRCA2 and BRCA1. We concluded that long overdue genetic referral through a traceback approach is feasible and effective to diagnose P/LP variants in patients with history of BC who had missed the opportunity of genetic testing, with potential clinical implications for patients and their relatives.

Keywords:  BRCA; Breast cancer; Genetic counseling; Pathogenic germline mutation; Traceback

DOI:  https://doi.org/10.1038/s41598-024-63300-8
HPB (Oxford). 2024 May 21. pii: S1365-182X(24)01721-0. [Epub ahead of print]

High frequency of germline variants in CFTR identified in PDAC patients enrolled in an expanded panel multi-gene panel testing program.

Andrew Hendifar, Megan Hitchins, Marie Lauzon, Kathryn E Hatchell, Brandie Heald, Stephen Pandol, Anjaparavanda P Naren, Arsen Osipov.

DOI: https://doi.org/10.1016/j.hpb.2024.05.005
Clin Exp Dermatol. 2024 Jun 04. pii: llae221. [Epub ahead of print]

Retrospective study of germline variants in patients with hereditary melanoma study criteria in a real clinical practice setting.

Jose Maria Villa-Gonzalez, Sergio Carrera Revilla, Lara Lombardero Gutiérrez, Jesús Gardeazabal García.

INTRODUCTION: Five to twelve percent of melanomas show aggregation of melanomas or other related tumors within the same family or individual. Genes such as CDKN2A, or BAP1, among others, have been involved in this condition.
MATERIAL AND METHODS: Retrospective descriptive study that includes patients from Cruces University Hospital (2016-2023) who met any of the following criteria: presence of two or more melanomas (1), or a melanoma and a pancreatic cancer (2) in the same individual; presence of a melanoma in an individual and one or more first- or second-degree relatives with melanoma or pancreatic cancer (3); first- or second-degree relationship with an individual with a known deleterious variant in genes related to melanoma predisposition (4); or incidental discovery of deleterious variants in genes related to predisposition to melanoma, within hereditary cancer panels carried out for reasons other than melanoma (5).
RESULTS: 59 families were included (69 patients; 63.8% women), of which 8.5% (13% of patients) presented pathogenic/likely pathogenic variants (PV/LPV) in CDKN2A (6% of families and patients, excluding criteria 4 and 5), and 1.7% of families (1.4% of patients) presented PV/LPV in BAP1, BRCA2 and TERF2IP.
DISCUSSION AND CONCLUSIONS: The frequencies of PV/LPV in CDKN2A are similar to those previously described. This study could contribute to the knowledge of the characteristics of patients who meet genetic study criteria for hereditary melanoma, in a setting of real clinical practice.

DOI: https://doi.org/10.1093/ced/llae221
JCO Glob Oncol. 2024 Jun;10 e2400068

Implementation of Universal Pan-Cancer Germline Genetic Testing in an Arab Population: The Jordanian Exploratory Cancer Genetics Study.

Hikmat Abdel-Razeq, Baha' Sharaf, Hira Bani Hani, Ramiz Abu Hijlih, Mais Alkyam, Khansa Al-Azzam, Shatha Elemian, Abdelghani Tbakhi, Areej Al-Atary, Rachel E Ellsworth, Emily M Russell, Edward D Esplin, Malek Horani, Zeidan Zeidan, Abdulla Alzibdeh, Brandie Heald, Sarah M Nielsen, Robert L Nussbaum.

PURPOSE: Germline genetic testing (GGT) significantly affects cancer care. While universal testing has been studied in Western societies, less is known about adoption elsewhere.
MATERIALS AND METHODS: In this study, 3,319 unselected, pan-cancer Jordanian patients diagnosed between April 2021 and September 2022 received GGT. Pathogenic germline variant (PGV) frequency among patients who were in-criteria (IC) or out-of-criteria (OOC; 2020 National Comprehensive Cancer Network criteria) and changes in clinical management in response to GGT results were evaluated. Statistical analysis was performed using two-tailed Fisher's exact test with significance level P < .05.
RESULTS: The cohort was predominantly female (69.9%), with a mean age of 53.7 years at testing, and 53.1% were IC. While patients who were IC were more likely than patients who were OOC to have a PGV (15.8% v 9.6%; P < .0001), 149 (34.8%) patients with PGVs were OOC. Clinical management recommendations in response to GGT, including changes to treatment and/or follow-up, were made for 57.3% (161 of 281) of patients with high- or moderate-risk PGVs, including 26.1% (42 of 161) of patients who were OOC.
CONCLUSION: Universal GGT of patients with newly diagnosed cancer was successfully implemented in Jordan and led to identification of actionable PGVs that would have been missed with guidelines-based testing.

DOI: https://doi.org/10.1200/GO.24.00068