bims-lifras 2022-01-16 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022–01–16
seventeen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Overview of the Clinical Features of Li-Fraumeni Syndrome and the Current European ERN GENTURIS Guideline.
Homologous Recombination Deficiencies and Hereditary Tumors.
Prevalence of pathogenic germline cancer risk variants in testicular cancer patients: Identifying high risk groups.
Analysis of pathogenic variants in BRCA1 and BRCA2 genes using next-generation sequencing in women with triple negative breast cancer from South India.
Comprehensive characterization of CRC with germline mutations reveals a distinct somatic mutational landscape and elevated cancer risk in the Chinese population.
Increased incidence of pathogenic variants in ATM in the context of testing for breast and ovarian cancer predisposition.
ATM: Functions of ATM Kinase and Its Relevance to Hereditary Tumors.
Clinical significance of gene polymorphisms for hereditary predisposition to breast and ovarian cancer (review of literature).
E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors.
BRCA 1/2 Germline Mutation Predicts the Treatment Response of FOLFIRINOX with Pancreatic Ductal Adenocarcinoma in Korean Patients.
The repertoire of germline variants in patients with early-onset rectal cancer.
Use of Germline BRCA Testing in Patients With Ovarian Cancer and Commercial Insurance.
Validation and clinical application of transactivation assays for RUNX1 variant classification.
Loss of E-Cadherin Leads to Druggable Vulnerabilities in Sphingolipid Metabolism and Vesicle Trafficking.
Somatic loss of the remaining allele occurs approximately in half of CHEK2-driven breast cancers and is accompanied by a border-line increase of chromosomal instability.
Advocating for equitable management of hereditary cancer syndromes.
Universal Germline Panel Testing for Individuals with Pheochromocytoma and Paraganglioma Produces High Diagnostic Yield.

Geburtshilfe Frauenheilkd. 2022 Jan;82(1): 42-49

Overview of the Clinical Features of Li-Fraumeni Syndrome and the Current European ERN GENTURIS Guideline.

Christian Peter Kratz, Verena Steinke-Lange, Isabel Spier, Stefan Aretz, Evelin Schröck, Elke Holinski-Feder.

  Patients with a tumour-risk syndrome have a significantly increased risk of developing cancer during their lifetime. A positive family history of tumour disease or an unusually early age of onset may be indicative of a tumour risk syndrome. With the diagnosis of a tumour risk syndrome it is possible to recommend a risk-adapted tumour surveillance programme for the patient and (asymptomatic) family members at risk. This facilitates early detection of possible tumours and thus often prevents advanced tumour stages. Li-Fraumeni syndrome is associated with a significantly increased risk of sarcoma and breast cancer in particular, but it is often not diagnosed clinically in those affected. This article reviews the clinical picture, genetic cause and special aspects in the diagnosis and care of patients with Li-Fraumeni syndrome. The initiative resulted from the European reference network GENTURIS, which has set itself the task of improving the identification and care of patients with tumour risk syndromes. A first step is the recent publication of a European guideline for Li-Fraumeni syndrome, which is summarised here and discussed in the context of existing recommendations.

Keywords:  Li-Fraumeni syndrome; TP53; cancer screening; guideline; tumour risk syndromes

DOI:  https://doi.org/10.1055/a-1541-7912
Int J Mol Sci. 2021 Dec 29. pii: 348. [Epub ahead of print]23(1):

Homologous Recombination Deficiencies and Hereditary Tumors.

Hideki Yamamoto, Akira Hirasawa.

  Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBS1(NBN), PALB2, RAD51C, and RAD51D, lead to inherited susceptibility to specific types of cancers, including those of the breast, ovaries, prostate, and pancreas. The penetrance of germline pathogenic variants of each gene varies, whereas all their associated protein products are indispensable for maintaining a high-fidelity DNA repair system by HR. The present review summarizes the basic molecular mechanisms and components that collectively play a role in maintaining genomic integrity against DNA double-strand damage and their clinical implications on each type of hereditary tumor.

Keywords:  BRCAness; cancer predisposition; germline; hereditary tumor; homologous recombination deficiency (HRD); multi-gene panel testing (MGPT)

DOI:  https://doi.org/10.3390/ijms23010348
Urol Oncol. 2022 Jan 09. pii: S1078-1439(21)00562-7. [Epub ahead of print]

Prevalence of pathogenic germline cancer risk variants in testicular cancer patients: Identifying high risk groups.

Chethan Ramamurthy, Amin H Nassar, Sarah Abou Alaiwi, Elio Adib, Elie W Akl, Shan Yang, Edward D Esplin, Michael A Liss, Gail E Tomlinson, Guru P Sonpavde.

   BACKGROUND: Germline studies in testicular cancer have focused on unselected populations but so far have not led to recommendations for testicular cancer screening.
OBJECTIVE: Herein, we hypothesized that men with testicular cancer and an additional risk factor for hereditary cancer predisposition carry a higher rate of pathogenic variants than men with testicular cancer without another risk factor.
METHODS AND RESULTS: 187 patients with a personal history of testicular cancer underwent germline testing via Invitae. Patients were divided into low-risk and high-risk patients. Low-risk patients (n=83) had testicular cancer as their only primary malignancy without a family history of testicular cancer. High-risk patients (n=104) had additional primary malignancies and/or a family history of testicular cancer. 23.1% of patients harbored pathogenic germline variants with 19.6% carrying actionable variants. Among low-risk patients, 13.5% carried pathogenic variants versus 29.9% in the high-risk cohort. Of patients with a family history of non-testicular cancers and a personal history of additional primary malignancies, 32% harbored pathogenic variants.
CONCLUSION: High-risk patients are twice as likely to harbor pathogenic variants compared to low-risk patients. Importantly, patients with a family history of cancer and other primary malignancies represent a subset of patients that may benefit from genetic evaluation.

Keywords:  Germline variants; Testicular cancer

DOI:  https://doi.org/10.1016/j.urolonc.2021.12.014
Mol Biol Rep. 2022 Jan 12.

Analysis of pathogenic variants in BRCA1 and BRCA2 genes using next-generation sequencing in women with triple negative breast cancer from South India.

Taruna Rajagopal, Arun Seshachalam, Arunachalam Jothi, Krishna Kumar Rathnam, Srikanth Talluri, Sivaramakrishnan Venkatabalasubranian, Nageswara Rao Dunna.

   BACKGROUND: The frequency of triple-negative breast cancer (TNBC) incidence varies among different populations suggesting the involvement of genetic components towards TNBC development. Previous studies have reported that BRCA1/2 germline mutations confer a lifetime risk of developing TNBC. However, there is hardly any information regarding the common pathogenic variants (PVs) in BRCA1/2 genes that contribute to TNBC in the Indian population. Hence, we screened for PVs in BRCA1/2 and their association with clinico-pathological features in TNBC patients.
METHODS AND RESULTS: The study recruited 59 TNBC patients without hereditary breast and ovarian cancer (HBOC) from South India. The entire BRCA1 and BRCA2 genes were sequenced for the 59 patients using the Illumina HiSeq X Ten sequencer. Among the 59 TNBC genomic DNA samples sequenced, BRCA mutations were identified in 8 patients (13.6%), BRCA1 mutations in 6 patients, and BRCA2 mutations in 2 patients. Among the 6 BRCA1 mutations, three were c.68_69delAG (185delAG) mutation. Remarkably, all the TNBC patients with BRCA mutations exhibited higher-grade tumors (grade 2 or 3). However, among all the BRCA mutation carriers, only one patient with a BRCA2 mutation (p.Glu1879Lys) developed metastasis.
CONCLUSION: Our data advocates that South Indian women with higher grade TNBC tumors and without HBOC could be considered for BRCA mutation screening, thereby enabling enhanced decision-making and preventive therapy.

Keywords:  BRCA1; BRCA2; Pathogenic variants; Triple-negative breast cancer (TNBC)

DOI:  https://doi.org/10.1007/s11033-022-07129-2
Cancer Biol Med. 2022 Jan 12. pii: j.issn.2095-3941.2021.0190. [Epub ahead of print]

Comprehensive characterization of CRC with germline mutations reveals a distinct somatic mutational landscape and elevated cancer risk in the Chinese population.

Jianfei Yao, Yunhuan Zhen, Jing Fan, Yuan Gong, Yumeng Ye, Shaohua Guo, Hongyi Liu, Xiaoyun Li, Guosheng Li, Pan Yang, Xiaohui Wang, Danni Liu, Tanxiao Huang, Huiya Cao, Peisu Suo, Yuemin Li, Jingbo Yu, Lele Song.

   OBJECTIVE: Hereditary colorectal cancer (CRC) accounts for approximately 5%-10% of all CRC cases. The full profile of CRC-related germline mutations and the corresponding somatic mutational profile have not been fully determined in the Chinese population.
METHODS: We performed the first population study investigating the germline mutation status in more than 1,000 (n = 1,923) Chinese patients with CRC and examined their relationship with the somatic mutational landscape. Germline alterations were examined with a 58-gene next-generation sequencing panel, and somatic alterations were examined with a 605-gene panel.
RESULTS: A total of 92 pathogenic (P) mutations were identified in 85 patients, and 81 likely pathogenic (LP) germline mutations were identified in 62 patients, accounting for 7.6% (147/1,923) of all patients. MSH2 and APC was the most mutated gene in the Lynch syndrome and non-Lynch syndrome groups, respectively. Patients with P/LP mutations had a significantly higher ratio of microsatellite instability, highly deficient mismatch repair, family history of CRC, and lower age. The somatic mutational landscape revealed a significantly higher mutational frequency in the P group and a trend toward higher copy number variations in the non-P group. The Lynch syndrome group had a significantly higher mutational frequency and tumor mutational burden than the non-Lynch syndrome group. Clustering analysis revealed that the Notch signaling pathway was uniquely clustered in the Lynch syndrome group, and the MAPK and cAMP signaling pathways were uniquely clustered in the non-Lynch syndrome group. Population risk analysis indicated that the overall odds ratio was 11.13 (95% CI: 8.289-15.44) for the P group and 20.68 (95% CI: 12.89-33.18) for the LP group.
CONCLUSIONS: Distinct features were revealed in Chinese patients with CRC with germline mutations. The Notch signaling pathway was uniquely clustered in the Lynch syndrome group, and the MAPK and cAMP signaling pathways were uniquely clustered in the non-Lynch syndrome group. Patients with P/LP germline mutations exhibited higher CRC risk.

Keywords:  Colorectal cancer; Lynch syndrome; MMR; MSI; Notch signaling pathway; TMB; germline; hereditary cancer; next-generation sequencing

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2021.0190
J Hum Genet. 2022 Jan 12.

Increased incidence of pathogenic variants in ATM in the context of testing for breast and ovarian cancer predisposition.

P Macquere, S Orazio, F Bonnet, N Jones, V Bubien, J Chiron, D Lafon, E Barouk-Simonet, J Tinat, L Venat-Bouvet, P Gesta, M Longy, N Sevenet.

Pathogenic Variants (PV) in major cancer predisposition genes are only identified in approximately 10% of patients with Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Next Generation Sequencing (NGS) leads to the characterization of incidental variants in genes other than those known to be associated with HBOC syndrome. The aim of this study was to determine if such incidental PV were specific to a phenotype. The detection rates of HBOC-associated and incidental PV in 1812 patients who underwent genetic testing were compared with rates in control groups FLOSSIES and ExAC. The rates of incidental PV in the PALB2, ATM and CHEK2 genes were significantly increased in the HBOC group compared to controls with, respective odds ratios of 15.2 (95% CI = 5.6-47.6), 9.6 (95% CI = 4.8-19.6) and 2.7 (95% CI = 1.3-5.5). Unsupervised Hierarchical Clustering on Principle Components characterized 3 clusters: by HBOC (P = 0.01); by ExAC and FLOSSIES (P = 0.01 and 0.02 respectively); and by HBOC, ExAC and FLOSSIES (P = 0.01, 0.04 and 0.04 respectively). Interestingly, PALB2 and ATM were grouped in the same statistical cluster defined by the HBOC group, whereas CHEK2 was in a different cluster. We identified co-occurrences of PV in ATM and BRCA genes and confirmed the Manchester Scoring System as a reliable PV predictor tool for BRCA genes but not for ATM or PALB2. This study demonstrates that ATM PV, and to a lesser extent CHEK2 PV, are associated with HBOC syndrome. The co-occurrence of ATM PV with BRCA PV suggests that such ATM variants are not sufficient alone to induce cancer, supporting a multigenism hypothesis.

DOI: https://doi.org/10.1038/s10038-022-01014-3
Int J Mol Sci. 2022 Jan 04. pii: 523. [Epub ahead of print]23(1):

ATM: Functions of ATM Kinase and Its Relevance to Hereditary Tumors.

Sayaka Ueno, Tamotsu Sudo, Akira Hirasawa.

  Ataxia-telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline ATM pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the ATM gene, function of ATM kinase, clinical significance of ATM germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients.

Keywords:  ATM; DNA damage; hereditary tumors; precision therapy; redox homeostasis; tumor profiling

DOI:  https://doi.org/10.3390/ijms23010523
Klin Lab Diagn. 2021 Dec 21. 66(12): 760-767

Clinical significance of gene polymorphisms for hereditary predisposition to breast and ovarian cancer (review of literature).

D I Vodolazhsky, A V Mayakovskaya, A V Kubyshkin, K A Aliev, I I Fomochkina.

  The review presents classical and modern views on the molecular genetic causes underlying hereditary predisposition to breast and ovarian cancer. A computerized literature search was carried out in the electronic databases MEDLINE, Scopus, and Web of Science, published between January 1994 and May 2021, using the keywords: «hereditary breast and ovarian cancer», «BRCA» and «DNA repair». Current views on the role of germline mutations in genes for susceptibility to breast cancer (BC): BRCA1, BRCA2, PALB2, TP53, CHEK2, PTEN, ATM, and PPM1D are presented. The role of a complex of genes involved in homologous DNA repair and causing other hereditary oncological diseases is considered. The role of the loss of heterozygosity in these genes, which increases the level of chromosomal instability and leads to an increased risk of malignant transformation, is considered. Germinal mutations in the genes under consideration in 90% of clinical cases are the cause of initiation of tissue malignancy and greatly increase the risk of developing hereditary breast cancer and OC. The review emphasizes the complex nature of pathogenesis and significant polymorphism of genetic targets for hereditary breast cancer and OC. It is concluded that it is necessary to use NGS panels for complex screening of genes of hereditary susceptibility to these oncological diseases. The review provides data on the clinical significance of each group of genes of hereditary predisposition in the pathogenesis of breast cancer and OC, and also demonstrates the possible role of methylation of the promoter regions of genes and the state of mitochondrial DNA in the development of these pathologies. The purpose of this review was to broaden the horizons of specialists in the field of oncology and clinical diagnostics in the context of the rapidly expanding spectrum of molecular genetic markers of hereditary breast and ovarian cancers.

Keywords:  BRCA ½; MRN; NBS1; SNP; hereditary breast cancer; hereditary ovarian cancer; mitochondrial DNA; penetrance; review

DOI:  https://doi.org/10.51620/0869-2084-2021-66-12-760-767
Cancers (Basel). 2021 Dec 30. pii: 175. [Epub ahead of print]14(1):

E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors.

Lyvianne Decourtye-Espiard, Nicola Bougen-Zhukov, Tanis Godwin, Tom Brew, Emily Schulpen, Michael A Black, Parry Guilford.

  Inactivating germline mutations in the CDH1 gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic CDH1 mutations are an early event in the development of sporadic diffuse gastric cancer (DGC) and lobular breast cancer (LBC). In this study, histone deacetylase (HDAC) inhibitors were tested for their ability to preferentially inhibit the growth of human cell lines (MCF10A and NCI-N87) and murine organoids lacking CDH1 expression. CDH1-/- breast and gastric cells were more sensitive to the pan-HDAC inhibitors entinostat, pracinostat, mocetinostat and vorinostat than wild-type cells, with an elevated growth inhibition that was, in part, attributable to increased apoptosis. CDH1-null cells were also sensitive to more class-specific HDAC inhibitors, but compared to the pan-inhibitors, these effects were less robust to genetic background. Increased sensitivity to entinostat was also observed in gastric organoids with both Cdh1 and Tp53 deletions. However, the deletion of Tp53 largely abrogated the sensitivity of the Cdh1-null organoids to pracinostat and mocetinostat. Finally, entinostat enhanced Cdh1 expression in heterozygous Cdh1+/- murine organoids. In conclusion, entinostat is a promising drug for the chemoprevention and/or treatment of HDGC and may also be beneficial for the treatment of sporadic CDH1-deficient cancers.

Keywords:  CDH1; E-cadherin; HDAC inhibitors; HDGC; synthetic lethality

DOI:  https://doi.org/10.3390/cancers14010175
Cancers (Basel). 2022 Jan 04. pii: 236. [Epub ahead of print]14(1):

BRCA 1/2 Germline Mutation Predicts the Treatment Response of FOLFIRINOX with Pancreatic Ductal Adenocarcinoma in Korean Patients.

Ji Hoon Park, Jung Hyun Jo, Sung Ill Jang, Moon Jae Chung, Jeong Youp Park, Seungmin Bang, Seung Woo Park, Si Young Song, Hee Seung Lee, Jae Hee Cho.

  We evaluated the proportion of BRCA 1/2 germline mutations in Korean patients with sporadic pancreatic ductal adenocarcinoma (PDAC) and its effect on the chemotherapeutic response of FOLFIRINOX. This retrospective study included patients who were treated at two tertiary hospitals between 2012 and 2020, were pathologically confirmed to have PDAC, and had undergone targeted next-generation sequencing-based germline genetic testing. Sixty-six patients were included in the study (24 men; median age 57.5 years). In the germline test, BRCA 1/2 pathogenic mutations were found in nine patients (9/66, 13%, BRCA 1, n = 3; BRCA 2, n = 5; and BRCA 1/2, n = 1). There was no significant difference in the baseline characteristics according to BRCA mutation positivity. Among patients who underwent FOLFIRINOX chemotherapy, patients with a BRCA 1/2 mutation showed a higher overall response rate than those without a BRCA 1/2 mutation (71.4% vs. 13.9%, p = 0.004). Patients with a germline BRCA 1/2 mutation showed longer progression-free survival than those without a BRCA 1/2 mutation, without a significant time difference (18 months vs. 10 months, p = 0.297). Patients with a BRCA 1/2 mutation in the germline blood test had a higher response rate to FOLFIRINOX chemotherapy in PDAC. The high proportion of BRCA 1/2 germline mutations and response rate supports the need for germline testing in order to predict better treatment response.

Keywords:  BRCA; FOLFIRINOX; breast cancer gene; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.3390/cancers14010236
Cancer Commun (Lond). 2022 Jan 14.

The repertoire of germline variants in patients with early-onset rectal cancer.

Caroline Moraes Beltrami, Luisa Matos do Canto, Rolando André Rios Villacis, Annabeth Høgh Petersen, Mads Malik Aagaard, Sarah Santiloni Cury, Maria Nirvana da Cruz Formiga, Samuel Aguiar Junior, Silvia Regina Rogatto.

DOI: https://doi.org/10.1002/cac2.12262
JAMA Netw Open. 2022 Jan 04. 5(1): e2142703

Use of Germline BRCA Testing in Patients With Ovarian Cancer and Commercial Insurance.

Stephanie Cham, Mary Beth Landrum, Nancy L Keating, Joanne Armstrong, Alexi A Wright.

DOI: https://doi.org/10.1001/jamanetworkopen.2021.42703
Blood Adv. 2022 Jan 13. pii: bloodadvances.2021006161. [Epub ahead of print]

Validation and clinical application of transactivation assays for RUNX1 variant classification.

Melanie Decker, Anupriya Agarwal, Andreas Benneche, Jane E Churpek, Nicolas Duployez, Adam DuVall, Martijn P T Ernst, Alisa Förster, Hildegunn Høberg Vetti, Michelle Nash, Marc H G P Raaijmakers, Tor Henrik Anderson Tvedt, Adrianna Vlachos, Brigitte Schlegelberger, Thomas Illig, Tim Ripperger.

Familial platelet disorder with associated myeloid malignancies (RUNX1-FPD) is caused by heterozygous pathogenic germline variants of RUNX1. In the present study, we evaluate the applicability of transactivation assays to investigate RUNX1 variants in different regions of the protein. We studied 11 variants to independently validate transactivation assays supporting variant classification following the ClinGen Myeloid Malignancies variant curation expert panel guidelines. Variant classification is key for the translation of genetic findings. We showed that new assays need to be developed to assess C-terminal RUNX1 variants. Two variants of uncertain significance (VUS) were reclassified to likely pathogenic. Additionally, our analyses supported the (likely) pathogenic classification of two other variants. We demonstrated functionality of four VUS, but reclassification to (likely) benign was challenging and suggested the need to reevaluate current classification guidelines. Finally, clinical utility of our assays was illustrated in the context of seven families. Our data confirmed RUNX1-FPD suspicion in three families with RUNX1-FPD-specific family history. Whereas for three variants identified in non RUNX1-FPD-typical families, no functional defect was detected. Applying functional assays to support RUNX1 variant classification can be essential for adequate care of index patients and their relatives at risk. It facilitates translation of genetic data into personalized medicine.

DOI: https://doi.org/10.1182/bloodadvances.2021006161
Cancers (Basel). 2021 Dec 26. pii: 102. [Epub ahead of print]14(1):

Loss of E-Cadherin Leads to Druggable Vulnerabilities in Sphingolipid Metabolism and Vesicle Trafficking.

Tom Brew, Nicola Bougen-Zhukov, Wilson Mitchell, Lyvianne Decourtye, Emily Schulpen, Yasmin Nouri, Tanis Godwin, Parry Guilford.

  Germline inactivating variants of CDH1 are causative of hereditary diffuse gastric cancer (HDGC), a cancer syndrome characterized by an increased risk of both diffuse gastric cancer and lobular breast cancer. Because loss of function mutations are difficult to target therapeutically, we have taken a synthetic lethal approach to identify targetable vulnerabilities in CDH1-null cells. We have previously observed that CDH1-null MCF10A cells exhibit a reduced rate of endocytosis relative to wildtype MCF10A cells. To determine whether this deficiency is associated with wider vulnerabilities in vesicle trafficking, we screened isogenic MCF10A cell lines with known inhibitors of autophagy, endocytosis, and sphingolipid metabolism. Relative to wildtype MCF10A cells, CDH1-/- MCF10A cells showed significantly greater sensitivity to several drugs targeting these processes, including the autophagy inhibitor chloroquine, the endocytosis inhibitors chlorpromazine and PP1, and the sphingosine kinase 1 inhibitor PF-543. Synthetic lethality was confirmed in both gastric and mammary organoid models of CDH1 loss, derived from CD44-Cre/Cdh1fl/fl/tdTomato mice. Collectively, these results suggest that both sphingolipid metabolism and vesicle trafficking represent previously unrecognised druggable vulnerabilities in CDH1-null cells and may lead to the development of new therapies for HDGC.

Keywords:  E-cadherin; autophagy; chemoprevention; endocytosis; hereditary diffuse gastric cancer; sphingolipid metabolism; synthetic lethality

DOI:  https://doi.org/10.3390/cancers14010102
Breast Cancer Res Treat. 2022 Jan 12.

Somatic loss of the remaining allele occurs approximately in half of CHEK2-driven breast cancers and is accompanied by a border-line increase of chromosomal instability.

Aglaya G Iyevleva, Svetlana N Aleksakhina, Anna P Sokolenko, Sofia V Baskina, Aigul R Venina, Elena I Anisimova, Ilya V Bizin, Alexandr O Ivantsov, Yana V Belysheva, Alexandra P Chernyakova, Alexandr V Togo, Evgeny N Imyanitov.

   PURPOSE: Germline mutations in CHEK2 gene represent the second most frequent cause of hereditary breast cancer (BC) after BRCA1/2 lesions. This study aimed to identify the molecular characteristics of CHEK2-driven BCs.
METHODS: Loss of heterozygosity (LOH) for the remaining CHEK2 allele was examined in 50 CHEK2-driven BCs using allele-specific PCR assays for the germline mutations and analysis of surrounding single-nucleotide polymorphisms (SNPs). Paired tumor and normal DNA samples from 25 cases were subjected to next-generation sequencing analysis.
RESULTS: CHEK2 LOH was detected in 28/50 (56%) BCs. LOH involved the wild-type allele in 24 BCs, mutant CHEK2 copy was deleted in 3 carcinomas, while in one case the origin of the deleted allele could not be identified. Somatic PIK3CA and TP53 mutations were present in 13/25 (52%) and 4/25 (16%) tumors, respectively. Genomic features of homologous recombination deficiency (HRD), including the HRD score ≥ 42, the predominance of BRCA-related mutational signature 3, and the high proportion of long (≥ 5 bp) indels, were observed only in 1/20 (5%) BC analyzed for chromosomal instability. Tumors with the deleted wild-type CHEK2 allele differed from LOH-negative cases by elevated HRD scores (median 23 vs. 7, p = 0.010) and higher numbers of chromosomal segments affected by copy number aberrations (p = 0.008).
CONCLUSION: Somatic loss of the wild-type CHEK2 allele is observed in approximately half of CHEK2-driven BCs. Tumors without CHEK2 LOH are chromosomally stable. BCs with LOH demonstrate some signs of chromosomal instability; however, its degree is significantly lower as compared to BRCA1/2-associated cancers.

Keywords:  CHEK2 mutation; Hereditary breast cancer; Homologous recombination deficiency; Loss of heterozygosity

DOI:  https://doi.org/10.1007/s10549-022-06517-3
J Genet Couns. 2022 Jan 14.

Advocating for equitable management of hereditary cancer syndromes.

Rikki Gaber Caffrey.

  The potential for preventive medicine to lead to more equitable health outcomes exists with the inclusion of genetic testing in medicine. Because of the medical implications of genetic testing for hereditary cancer syndromes and the financial cost attached to recommended management, ensuring equitable access to cancer screening and prevention must be made a priority. For patients with Hereditary Breast and Ovarian Cancer (HBOC) syndrome, the benefits of early detection and prevention are clear, significant, and create the opportunity to provide more equitable, personalized, preventive healthcare. Thus, for genetics providers who offer testing access for their patients, it is important to reflect on the ethical responsibility of advocating for access to appropriate management. Cancer genetic counselors can advocate for health equity by providing thorough pre-test genetic counseling, collaborating with other disciplines to coordinate care, lobbying state, and national representatives to pass legislation promoting health equity, and developing a management clinic that helps to ensure follow-up. Equitable access to and benefit from hereditary cancer risk management must be achieved in the pursuit of personalized preventive medicine.

Keywords:  disparities; ethics; policy; public health; risk management; service delivery models

DOI:  https://doi.org/10.1002/jgc4.1548
J Clin Endocrinol Metab. 2022 Jan 13. pii: dgac014. [Epub ahead of print]

Universal Germline Panel Testing for Individuals with Pheochromocytoma and Paraganglioma Produces High Diagnostic Yield.

Carolyn Horton, Holly LaDuca, Ashley Deckman, Kate Durda, Michelle Jackson, Marcy Richardson, Yuan Tian, Amal Yussuf, Kory Jasperson, Tobias Else.

   BACKGROUND: Practice guidelines to identify individuals with hereditary pheochromocytomas and paragangliomas (PPGLs) advocate for sequential gene testing strategy guided by specific clinical features and predate the routine use of multigene panel testing (MGPT).
OBJECTIVE: To describe results of MGPT for hereditary PPGL in a clinically and ancestrally diverse cohort.
SETTING: Commercial laboratory based in the United States.
METHODS: Clinical data and test results were retrospectively reviewed in 1727 individuals who had targeted MGPT due to suspicion of hereditary PPGL from August 2013 through December 2019.
RESULTS: Overall, 27.5% of individuals had a pathogenic or likely pathogenic variant (PV), 9.0% had a variant of uncertain significance, and 63.1% had a negative result. Most PVs were identified in SDHB (40.4%), followed by SDHD (21.1%), SDHA (10.1%), VHL (7.8%), SDHC (6.7%), RET (3.7%), and MAX (3.6%). PVs in FH, MEN1, NF1, SDHAF2, and TMEM127 collectively accounted for 6.5% of PVs. Clinical predictors of a PV included extra-adrenal location, early age of onset, multiple tumors, and positive family history of PPGL. Individuals with extra-adrenal PGL and a positive family history were the most likely to have a PV (85.9%). Restricting genetic testing to SDHB/C/D misses a third (32.8%) of individuals with PVs.
CONCLUSION: Our data demonstrate a high diagnostic yield in individuals with and without established risk factors, a low inconclusive result rate, and a substantial contribution to diagnostic yield from rare genes. These findings support universal testing of all individuals with PPGL and the use of concurrent MGPT as the ideal platform.

Keywords:  genetic testing; hereditary cancer; paraganglioma; pheochromocytoma

DOI:  https://doi.org/10.1210/clinem/dgac014