bims-lifras 2023-01-08 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2023–01–08
twelve papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis.
Whole-body MRI surveillance in TP53 carriers is perceived as beneficial with no increase in cancer worry regardless of previous cancer: Data from the Swedish TP53 Study.
Expanded genetic testing of GIST patients identifies high proportion of non-syndromic patients with germline alterations.
Genetic, Surgical and Oncological Approach to Breast Cancer, with BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53 Variants.
Germline mutations in high penetrance genes are associated with worse clinical outcomes in patients with non-small cell lung cancer.
Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines.
Utilization of genetic testing in men with advanced prostate cancer.
Gene of the month: PALB2.
Association of a novel BRCA2 mutation with prostate cancer risk further supports germline genetic testing.
Coincidence of primary adrenocortical carcinoma and melanoma: three CASE reports.
Molecular basis of carotid body tumor and associated clinical features in Japan identified by genomic, immunohistochemical, and clinical analyses.
Comprehensive clinical characterization of patients with BRCA1: c.5017_5019del germline variant.

Nat Commun. 2023 Jan 05. 14(1): 77

Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis.

Nicholas Light, Mehdi Layeghifard, Ayush Attery, Vallijah Subasri, Matthew Zatzman, Nathaniel D Anderson, Rupal Hatkar, Sasha Blay, David Chen, Ana Novokmet, Fabio Fuligni, James Tran, Richard de Borja, Himanshi Agarwal, Larissa Waldman, Lisa M Abegglen, Daniel Albertson, Jonathan L Finlay, Jordan R Hansford, Sam Behjati, Anita Villani, Moritz Gerstung, Ludmil B Alexandrov, Gino R Somers, Joshua D Schiffman, Varda Rotter, David Malkin, Adam Shlien.

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 pathogenic variants. Here, we perform whole-genome sequence (WGS) analysis of tumors from 22 patients with TP53 germline pathogenic variants. We observe somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identify near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurs earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, reveal that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising years prior to tumor diagnosis.

DOI: https://doi.org/10.1038/s41467-022-35727-y
Cancer. 2023 Jan 05.

Whole-body MRI surveillance in TP53 carriers is perceived as beneficial with no increase in cancer worry regardless of previous cancer: Data from the Swedish TP53 Study.

Swedish Clinical TP53 Study Group (SweClinTP53)

   BACKGROUND: To evaluate the psychosocial consequences of surveillance with whole-body MRI (WB-MRI) in individuals with the heritable TP53-related cancer (hTP53rc) syndrome, also known as the Li-Fraumeni syndrome, with regard to cancer worry, perceived benefits and risks to surveillance and overall health.
PATIENTS AND METHODS: Since 2016, the national Swedish TP53 Study (SWEP53) has offered surveillance with WB-MRI to all individuals with hTP53rc syndrome. Seventy-five individuals have been included in the study. Sixty consecutive participants fulfilled a base-line evaluation as well as an evaluation after 1 year with structured questionnaires including the Cancer Worry Scale (CWS), perceived benefits and risks of surveillance, and the 36-item Short Form Survey (SF-36). Individuals with or without previous personal cancer diagnosis were enrolled and results at baseline and after 1 year of surveillance were compared. For SF-36, a comparison with the normal population was also made.
RESULTS: Participants with previous cancer tend to worry more about cancer, but both individuals with and without cancer had a positive attitude toward surveillance with no differences regarding perceived benefits and barriers to surveillance. Participants with a previous cancer scored significantly lower on some of the SF-36 subscales, but between-group differences were found only for social functioning after 1 year.
CONCLUSIONS: Surveillance with WB-MRI is feasible from a psychosocial point of view both among TP53 carriers with as well as without a previous history of cancer and does not increase cancer worry in any of the groups.
PLAIN LANGUAGE SUMMARY: Individuals with heritable TP53-related cancer syndrome (also known as the Li-Fraumeni syndrome) have a high lifetime risk of developing cancer. These TP53 carriers are offered surveillance with whole-body MRI to detect cancer early. There are few reports of the psychosocial impact of surveillance. In this study, we wanted to evaluate cancer worry, benefits and barriers to participation, and perceived overall health. Our study shows no increase in cancer worry after 1 year of surveillance, regardless of previous cancer.

Keywords:  Li-Fraumeni syndrome; cancer worry scale; health-related quality-of-life; hereditary cancer; heritable TP53-related cancer syndromes; surveillance

DOI:  https://doi.org/10.1002/cncr.34631
NPJ Precis Oncol. 2023 Jan 02. 7(1): 1

Expanded genetic testing of GIST patients identifies high proportion of non-syndromic patients with germline alterations.

Diana Mandelker, Antonio Marra, Nikita Mehta, Pier Selenica, Zarina Yelskaya, Ciyu Yang, Joshua Somar, Miika Mehine, Maksym Misyura, Olca Basturk, Alicia Latham, Maria Carlo, Michael Walsh, Zsofia K Stadler, Kenneth Offit, Chaitanya Bandlamudi, Meera Hameed, Ping Chi, Jorge S Reis-Filho, Ozge Ceyhan-Birsoy.

Traditional genetic testing for patients with gastrointestinal stromal tumors (GISTs) focus on those with syndromic features. To assess whether expanded genetic testing of GIST patients could identify hereditary cancer predisposition, we analyzed matched tumor-germline sequencing results from 103 patients with GISTs over a 6-year period. Germline pathogenic/likely pathogenic (P/LP) variants in GIST-associated genes (SDHA, SDHB, SDHC, NF1, KIT) were identified in 69% of patients with KIT/PDGFRA-wildtype GISTs, 63% of whom did not have any personal or family history of syndromic features. To evaluate the frequency of somatic versus germline variants identified in tumor-only sequencing of GISTs, we analyzed 499 de-identified tumor-normal pairs. P/LP variants in certain genes (e.g., BRCA1/2, SDHB) identified in tumor-only sequencing of GISTs were almost exclusively germline in origin. Our results provide guidance for genetic testing of GIST patients and indicate that germline testing should be offered to all patients with KIT/PDGFRA-wildtype GISTs regardless of their history of syndromic features.

DOI: https://doi.org/10.1038/s41698-022-00342-z
Eur J Breast Health. 2023 Jan;19(1): 55-69

Genetic, Surgical and Oncological Approach to Breast Cancer, with BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53 Variants.

Aslı Subaşıoğlu, Zeynep Gülsüm Güç, Emine Özlem Gür, Mustafa Agah Tekindal, Murat Kemal Atahan.

   Objective: The aim of this study was to determine the frequency of germline variants in BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53 in patients admitted to a medical genetics clinic with breast cancer and to assess these identified variants according to published genetic, surgical and oncological perspectives.
Materials and Methods: Medical history, and cancer diagnosis information for 195 independent probands with operated breast cancer were collected from requisition forms and medical records. The exonic regions and exon-intron junctions in BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53 genes were sequenced. Analysis of fastq files was performed on the Qiagen Clinical Insight-Analyse Universal with panel-specific pipeline and vcf files were interpreted clinically using Qiagen Clinical Insight-Interpret.
Results: Gene variants (pathogenic, likely pathogenic and variants of unknown significance) were detected in 53 (27.2%). Detailed information about the patients (age of diagnosis, family history, gender), cancer stage, tumour characteristics (ER, PR, human epidermal growth factor receptor 2 status) and all information related to the detected variants (gene, location, nucleotide and amino acid change, exon number, impact, mutation classification, dbSNP number and HGMD variant class) were assessed. In total, 58 mutations were identified including 14 novel, previously unreported variants.
Conclusion: Molecular characterization and identification of mutations have important implications for predictive, preventive, and personalized medicine, including genetic counseling and development of specific treatment protocols. We emphasize variants of unknown significance (VUS) as the clinical significance of VUS changes over time and variant classification is important for clinical molecular genetic testing and clinical guidance. This study may provide new insights into risk assessment for variants in CDH1, PALB2, PTEN and TP53, in addition to BRCA1 and BRCA2, which may prove useful for clinical management of breast cancer patients. Further studies are needed to identify the common gene variants in the Turkish population and evaluate the pathogenity of VUS.

Keywords:  BRCA1/2; CDH1/PALB2; TP53/PTEN; breast cancer; genetic testing

DOI:  https://doi.org/10.4274/ejbh.galenos.2022.2022-7-2
JTCVS Open. 2022 Dec;12 399-409

Germline mutations in high penetrance genes are associated with worse clinical outcomes in patients with non-small cell lung cancer.

Seth B Krantz, Kanwal Zeeshan, Kristine M Kuchta, Thomas A Hensing, Kathy A Mangold, S Lilly Zheng, Jianfeng Xu.

   Objective: To determine the frequency of pathogenic mutations in high-penetrance genes (HPGs) in patients with non-small cell lung cancer (NSCLC) and identify whether such mutations are associated with clinicopathologic outcomes.
Methods: Patients with NSCLC who had consented to participate in a linked clinical database and biorepository underwent germline DNA sequencing using a next-generation sequencing panel that included cancer-associated HPGs and cancer risk-associated single nucleotide polymorphisms (SNPs). These data were linked to the clinical database to assess for associations between germline variants and clinical phenotype using Fisher's exact test and multivariable logistic and Cox regression.
Results: We analyzed 151 patients, among whom 33% carried any pathogenic HPG mutation and 23% had a genetic risk score (GRS) >1.5. Among the patients without any pathogenic mutation, 31% were at cancer stage II or higher, compared with 55% of those with 2 types of HPG mutations (P = .0293); 40% of patients with both types of HPG mutations had cancer recurrence, compared with 21% of patients without both types (P = .0644). In multivariable analysis, the presence of 2 types of HPG mutations was associated with higher cancer stage (odds ratio [OR], 3.32; P = .0228), increased recurrence of primary tumor (OR, 2.93; P = .0527), shorter time to recurrence (hazard ratio [HR], 3.03; P = .0119), and decreased cancer-specific (HR, 3.53; P = .0039) and overall survival (HR, 2.44; P = .0114).
Conclusions: The presence of mutations in HPGs is associated with higher cancer stage, increased risk of recurrence, and worse cancer-specific and overall survival in patients with NSCLC. Further large studies are needed to better delineate the role of HPGs in cancer recurrence and the potential benefit of adjuvant treatment in patients harboring such mutations.

Keywords:  DNA repair; GRS, genetic risk score; HGS, next-generation sequencing; HPG, high-penetrance gene; HR, hazard ratio; NSCLC, non–small cell lung cancer; OR, odds ratio; OS, overall survival; SNP, single nucleotide polymorphism; germline mutation; high penetrance gene; non–small cell lung cancer; polygenic risk score

DOI:  https://doi.org/10.1016/j.xjon.2022.09.001
J Med Genet. 2022 Dec 07. pii: jmg-2022-108807. [Epub ahead of print]

Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines.

ClinGen CDH1 Variant Curation Expert Panel

   BACKGROUND: Germline pathogenic variants in CDH1 are associated with increased risk of diffuse gastric cancer and lobular breast cancer. Risk reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation of germline CDH1 variants critical for physicians deciding on these procedures. The Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications.
METHODS: CDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen and expert knowledge from ongoing CDH1 variant curations. The CDH1 VCEP reviewed 273 variants using updated CDH1 specifications and incorporated published and unpublished data provided by diagnostic laboratories.
RESULTS: Updated CDH1-specific interpretation guidelines include 11 major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36 of 37) of variants with ClinVar conflicting interpretations were resolved to benign, likely benign, likely pathogenic or pathogenic, and 35% (15 of 43) of VUS were resolved to benign or likely benign. Overall, 88% (239 of 273) of curated variants had non-VUS classifications. To date, variants classified as pathogenic are either nonsense, frameshift, splicing, or affecting the translation initiation codon, and the only missense variants classified as pathogenic or likely pathogenic have been shown to affect splicing.
CONCLUSIONS: The development and evolution of CDH1-specific criteria by the expert panel resulted in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene, which can ultimately lead to more effective clinical management recommendations.

Keywords:  Gastrointestinal Diseases; Genetic Predisposition to Disease; Genetic Variation; Genetics, Medical

DOI:  https://doi.org/10.1136/jmg-2022-108807
Prostate. 2023 Jan 02.

Utilization of genetic testing in men with advanced prostate cancer.

Jonathan A Aguiar, Eric V Li, Mohammad R Siddiqui, Moataz A Soliman, Sai K S R Kumar, Edward M Schaeffer, Mary Kate Keeter, C Hendricks Brown, Brittany M Szymaniak, Ashley E Ross.

   BACKGROUND: Genetic evaluation of men with advanced prostate cancer is recognized as imperative both to guide treatment decisions and to trigger cascade genetic testing of family members. Here we investigate utilization patterns of genetic testing among a contemporary cohort of men with advanced prostate cancer at our institution.
METHODS: We queried the Northwestern Electronic Data Warehouse from January 2021 to present for all men diagnosed with National Comprehensive Cancer Network high-risk/very high-risk, regional, or metastatic prostate cancer. Patients were excluded from analyses if treated at an outside institution and/or presented for a second opinion evaluation. Statistics were performed using t-test, Chi-squared test, and univariable and multivariable logistic regression with significance defined as p < 0.05.
RESULTS: Atotal of 320 men (52.5%) had local/regional disease and 290 (47.5%) had metastatic disease, 53 (18.3%) of whom had castrate resistant prostate cancer. Rates of germline genetic testing rate were low in patients with localized disease (9.4%) and metastatic disease (34.1%). Only 19 (35.8%) men diagnosed with metastatic castrate resistant prostate cancer underwent germline genetic evaluation. Germline testing was most frequently discussed or ordered by medical oncologists (52%) followed by urologists (20%). Men who underwent germline testing were younger (p < 0.001), more likely to have Medicaid or private insurance (p = 0.002), and more likely to have metastatic disease (p < 0.001). There were no statistically significant differences in baseline PSA, ethnicity, race, or castration sensitivity status. Age (odds ratio [OR]: 0.94, 95% confidence interval [CI]: 0.91-0.97, p < 0.001) and metastatic disease (OR: 5.71, 95% CI: 3.63-9.22, p < 0.001) were significant independent predictors of genetic testing on multivariable logistic regression.
CONCLUSIONS: Here we report that utilization of genetic testing is associated with metastatic disease and inversely associated with age. Overall, utilization rates of genetic testing remain low in all patient groups, including in the metastatic castrate resistant setting, where genetic testing can identify patients with homologous recombination repair deficiency who may benefit from use of targeted therapeutics such as PARP inhibitors. Genetic testing in men with aggressive prostate cancer is critical and barriers to routine implementation of testing require further study to develop strategies to improve utilization rates.

Keywords:  germline genetic testing; prostate cancer; targeted therapeutics

DOI:  https://doi.org/10.1002/pros.24480
J Clin Pathol. 2022 Dec 07. pii: jcp-2022-208461. [Epub ahead of print]

Gene of the month: PALB2.

Omar Hamdan, Klaudia M Nowak.

  The partner and localiser of BRCA2 (PALB2) gene, located on chromosome 16, functions as a tumour suppressor that plays a critical role in homologous recombination repair after DNA double-strand breaks. It encodes proteins involved in the BRCA2 and BRCA1, and RAD51 pathways. Heterozygous germline mutations in PALB2 have been implicated in the development of breast, pancreatic and ovarian cancers. Whereas biallelic mutations of PALB2 have been associated with Fanconi anaaemia. Currently, 604 distinct PALB2 variants have been discovered. However, only 140 variants are thought to be pathogenic and approximately 400 are variants of unknown significance. Further studies are needed before the presence of PLAB2 mutations can be implemented as a routine clinical biomarker.

Keywords:  BREAST; Breast Neoplasms; Genes, Neoplasm; PANCREAS; Pancreatic Neoplasms

DOI:  https://doi.org/10.1136/jcp-2022-208461
Eur J Cancer. 2022 Dec 10. pii: S0959-8049(22)01785-3. [Epub ahead of print]180 155-157

Association of a novel BRCA2 mutation with prostate cancer risk further supports germline genetic testing.

Georgea R Foley, James R Marthick, Elaine A Ostrander, Janet L Stanford, Joanne L Dickinson, Liesel M FitzGerald.

DOI: https://doi.org/10.1016/j.ejca.2022.11.034
BMC Endocr Disord. 2023 Jan 06. 23(1): 4

Coincidence of primary adrenocortical carcinoma and melanoma: three CASE reports.

Ye Lynn Ko, Vaishnavi Kumar, Juliane Lippert, Salvador Diaz-Cano, Kassiani Skordilis, Otilia Kimpel, Stefan Kircher, Miriam Asia, Yasir S Elhassan, Barbara Altieri, Cristina L Ronchi.

   BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a heterogeneous prognosis, while adrenal metastasis from other primary cancers, including melanoma, may occur more frequently. ACC may rarely occur as part of familial cancer syndromes, but even in sporadic cases, a significant proportion of patients had other malignancies before or after diagnosis of ACC. Herein we present three cases where sporadic ACC was identified in patients with coexistent or previous history of melanoma.
CASE DESCRIPTION: Patient 1 - A 37-yr-old man with a superficial spreading BRAF-positive melanoma was found to harbour a progressively growing left adrenal mass. Initially, he was suspected of having adrenal metastasis, but the histology after adrenalectomy confirmed ACC. Patient 2 - A 68-year-old man with a history of recurrent BRAF-positive melanoma was diagnosed with disseminated metastatic melanoma recurrence, including a rapidly enlarging left adrenal mass. Consequently, he underwent left adrenalectomy, and histology again confirmed ACC. Patient 3 - A 50-yr-old man was referred with histological diagnosis of metastatic ACC. He had a background history of pT1 melanoma. We undertook targeted sequencing of ACC tissue samples in all cases. Somatic variants were observed in the known driver genes CTNNB1 (Patient 1), APC and KMT2D (Patient 2), and APC and TP53 (Patient 3). Germline TP53 variants (Li-Fraumeni syndrome) were excluded in all cases. Retrospective review of our patient cohort in the last 21 years revealed a frequency of 0.5% of histologically diagnosed melanoma metastasis among patients referred for adrenal masses. On the other hand, 1.6% of patients with histologically confirmed ACC had a previous history of melanoma.
CONCLUSION: Sporadic ACC can occur in the background of melanoma, even if adrenal metastasis might appear to be the most likely diagnosis. Coexistent primary adrenal malignancy should be considered and investigated for in all patients with a history of melanoma with suspicious adrenal lesions.

Keywords:  Adrenal gland; Adrenocortical cancer; Differential diagnosis; Melanoma

DOI:  https://doi.org/10.1186/s12902-022-01253-7
Clin Genet. 2023 Jan 03.

Molecular basis of carotid body tumor and associated clinical features in Japan identified by genomic, immunohistochemical, and clinical analyses.

Keisuke Yoshihama, Hideki Mutai, Mariko Sekimizu, Fumihiro Ito, Shin Saito, Shintaro Nakamura, Takuya Mikoshiba, Ryoto Nagai, Akiko Takebayashi, Fuyuki Miya, Kenjiro Kosaki, Hiroyuki Ozawa, Tatsuo Matsunaga.

  Carotid Body Tumor (CBT) is classified as a paraganglioma (PGL). Here, we report the genetic background, protein expression pattern, and clinical findings of 30 Japanese CBT cases. Germline pathogenic or likely pathogenic (P/LP) variants of genes encoding succinate dehydrogenase subunits (SDHs) were detected in 15 of 30 cases (50%). The SDHB variants were the most frequently detected, followed by SDHA and SDHD variants. One case with SDHAF2 variant was bilateral CBT, and other two multiple PGL cases were not detected P/LP variants. The three cases with germline variants that could be tested did not have somatic P/LP variants of the same genes. Immunohistochemical analysis showed negative SDHB signals in CBT tissues in five cases with germline P/LP variants of SDHB, SDHD, or SDHA. In addition, SDHB signals in CBT tissues were negative in four of nine cases without germline P/LP variants of SDHs. These findings suggest the involvement of unidentified molecular mechanisms affecting SDHs. This article is protected by copyright. All rights reserved.

Keywords:  Paraganglioma; germline variant; succinate dehydrogenase

DOI:  https://doi.org/10.1111/cge.14294
Ann Surg Treat Res. 2022 Dec;103(6): 323-330

Comprehensive clinical characterization of patients with BRCA1: c.5017_5019del germline variant.

Korean Hereditary Breast Cancer Study Group

   Purpose: We provide evidence for the reclassification of the BRCA1:c.5017_5019del variant by presenting the clinicopathological characteristics, clinical outcomes, and family history of breast or ovarian cancer in 17 patients with this variant.
Methods: This study included breast or ovarian cancer patients tested for BRCA1/2 genes between January 2008 and June 2020 at 10 medical centers in Korea. We retrospectively reviewed 17 probands from 15 families who had the BRCA1:c.5017_5019del variant according to the electronic medical records.
Results: We present 10 breast cancer patients and 7 ovarian cancer patients from 15 families identified as having BRCA1:c.5017_5019del and a total of 19 cases of breast cancer and 14 cases of ovarian cancer in these families. The ratio of breast-to-ovarian cancer was 1.3:1. Breast cancer patients with this variant showed a rich family history of breast or ovarian cancer, 8 patients (80.0%). The mean age at diagnosis was 45.4 years and 6 patients (60.0%) were categorized into hormone-receptor-negative breast cancer. Also, the ovarian cancer patients with this variant showed strong family histories of breast and/or ovarian cancer in 4 patients (57.1%).
Conclusion: We presented clinical evidence for the reclassification of BRCA1:c.5017_5019del as a likely pathogenic variant (LPV). Reclassification as LPV could result in the prophylactic treatment and medical surveillance of probands, family testing recommendations, and appropriate genetic counseling of their families.

Keywords:  BRCA1; Breast neoplasms; Genes; Genetic testing; Hereditary breast and ovarian cancer syndrome

DOI:  https://doi.org/10.4174/astr.2022.103.6.323