bims-lifras 2023-04-23 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2023–04–23
nine papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Clinical usefulness of NGS multi-gene panel testing in hereditary cancer analysis.
Germline genomic findings in children and young adults with melanocytic tumors.
Patients with deleterious germline mutations: A heterogeneous population for pancreatic cancer screening?
Exceptional Response of Pancreatic Acinar Cell Carcinoma and Bile Duct Cancer to Platinum-Based Chemotherapy in a Family With a Germline BRCA2 Variant.
TP53 c.455C>T p.(Pro152Leu) pathogenic variant is a lower risk allele with attenuated risks of breast cancer and sarcoma.
The association between age at breast cancer diagnosis and prevalence of pathogenic variants.
Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death.
Functional analyses of rare germline BRCA1 variants by transcriptional activation and homologous recombination repair assays.
The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition.

Front Genet. 2023 ;14 1060504

Clinical usefulness of NGS multi-gene panel testing in hereditary cancer analysis.

Federico Anaclerio, Lucrezia Pilenzi, Anastasia Dell'Elice, Rossella Ferrante, Simona Grossi, Luca Maria Ferlito, Camilla Marinelli, Simona Gildetti, Giuseppe Calabrese, Liborio Stuppia, Ivana Antonucci.

  Introduction: A considerable number of families with pedigrees suggestive of a Mendelian form of Breast Cancer (BC), Ovarian Cancer (OC), or Pancreatic Cancer (PC) do not show detectable BRCA1/2 mutations after genetic testing. The use of multi-gene hereditary cancer panels increases the possibility to identify individuals with cancer predisposing gene variants. Our study was aimed to evaluate the increase in the detection rate of pathogenic mutations in BC, OC, and PC patients when using a multi-gene panel. Methods: 546 patients affected by BC (423), PC (64), or OC (59) entered the study from January 2020 to December 2021. For BC patients, inclusion criteria were i) positive cancer family background, ii) early onset, and iii) triple negative BC. PC patients were enrolled when affected by metastatic cancer, while OC patients were all submitted to genetic testing without selection. The patients were tested using a Next-Generation Sequencing (NGS) panel containing 25 genes in addition to BRCA1/2. Results: Forty-four out of 546 patients (8%) carried germline pathogenic/likely pathogenic variants (PV/LPV) on BRCA1/2 genes, and 46 (8%) presented PV or LPV in other susceptibility genes. Discussion: Our findings demonstrate the utility of expanded panel testing in patients with suspected hereditary cancer syndromes, since this approach increased the mutation detection rate of 15% in PC, 8% in BC and 5% in OC cases. In absence of multi-gene panel analysis, a considerable percentage of mutations would have been lost.

Keywords:  BRCA; NGS; breast cancer; cancer predisposition gene; hereditary cancer; multi-gene panel testing; ovarian cancer; pancreatic cancer

DOI:  https://doi.org/10.3389/fgene.2023.1060504
Pediatr Blood Cancer. 2023 Apr 19. e30361

Germline genomic findings in children and young adults with melanocytic tumors.

Margaret B Nagel, Melissa R Perrino, Regina Nuccio, Alise K Blake, Lynn Harrison, Kim E Nichols, Alberto S Pappo.

  In this retrospective study, we examined the prevalence and spectrum of germline variants in selected cancer predisposition genes in 38 children and young adults with melanocytic lesions at St. Jude Children's Research Hospital. Diagnoses included malignant melanoma (n = 16; 42%), spitzoid melanoma (n = 16; 42%), uveal melanoma (n = 5; 13%), and malignant melanoma arising in a giant congenital melanocytic nevus (n = 1; 3%). Six patients (15.8%) harbored pathogenic germline variants: one with bi-allelic PMS2 variants, one with a heterozygous 17q21.31 deletion, and one each with a pathogenic variant in TP53, BRIP1, ATM, or AXIN2. Overall, 15.8% of patients harbored a cancer-predisposing genetic variant.

Keywords:  cancer predisposition; germline testing; melanoma; pathogenic variant; pediatric

DOI:  https://doi.org/10.1002/pbc.30361
J Surg Oncol. 2023 Apr 21.

Patients with deleterious germline mutations: A heterogeneous population for pancreatic cancer screening?

Alexandra M Roch, Rachel C Kim, Trang K Nguyen, Michael G House, Nicholas J Zyromski, Attila Nakeeb, C Max Schmidt, Eugene P Ceppa.

   BACKGROUND AND OBJECTIVES: Modest data exist on the benefits of screening and surveillance for pancreatic cancer (PC) in high-risk individuals. Intraductal papillary mucinous neoplasms (IPMN) are known precursors to PC. We hypothesized that patients with high-risk deleterious germline mutations have a higher prevalence of IPMN.
METHODS: All patients undergoing prospective screening at a single institution from 2013 to 2019 were reviewed.
RESULTS: Of 1166 patients screened, 358 (31%) possessed germline mutations and/or family history of PC (mutations n = 201/358, 56%, family history n = 226/358, 63%) (median follow-up 2.7 years). IPMN was found in 127 patients (35.5%). The prevalence of IPMN in mutation carriers (18%) was higher than in the general population (p < 0.01). Germline mutation was an independent predictor of IPMN (odds ratio [OR] = 3.2; p < 0.01), while family history was not (p = 0.22). IPMN prevalence was distributed unevenly between mutation types (67%-Peutz-Jeghers; 43%-HNPCC, 24%-BRCA2; 17%-ATM; 9%-BRCA1; 0%-CDKN2A and PALB2).
CONCLUSION: In this series, 18% of mutation carriers harbored IPMN, higher than the general population. Germline mutation, but not a family history of PC, was independently associated with IPMN. This prevalence varied across mutation subtypes, suggesting not all mutation carriers develop precancerous lesions. Genetic testing for patients with a positive family history may improve screening modalities for this high-risk population.

Keywords:  germline mutations; hereditary pancreatic cancer; intraductal papillary mucinous neoplasms; pancreatic cancer screening

DOI:  https://doi.org/10.1002/jso.27289
Pancreas. 2022 Oct 01. 51(9): 1258-1262

Exceptional Response of Pancreatic Acinar Cell Carcinoma and Bile Duct Cancer to Platinum-Based Chemotherapy in a Family With a Germline BRCA2 Variant.

Tomohiko Sunami, Atsushi Yamada, Tomohiro Kondo, Masashi Kanai, Kazuyuki Nagai, Yoichiro Uchida, Masataka Yokode, Tomoaki Matsumori, Norimitsu Uza, Hiromi Murakami, Takahiro Yamada, Manabu Muto.

ABSTRACT: Pancreatic cancer and its rare subtype, acinar cell carcinoma (PACC), frequently harbor germline and/or somatic variants in homologous recombinant genes, including BRCA2. Individuals possessing germline pathogenic BRCA2 variants are known to have a higher risk of developing various cancers, including breast, ovarian, pancreatic, and bile duct cancers (BDCs). It has been reported that tumors positive for BRCA1/2 variants are sensitive to platinum-based agents. Thus, BRCA1/2 germline testing and comprehensive genomic profiling are recommended to identify genetic susceptibility and to indicate optimal targeted therapy. Here, we report familial occurrence of PACC and BDC associated with BRCA2; both tumors responded exceptionally well to platinum-based chemotherapy. A 37-year-old man was diagnosed with unresectable PACC with a germline BRCA2 variant. He was treated with oxaliplatin-containing chemotherapy and conversion surgery, and remains alive without tumor recurrence after more than 36 months. His father also possessed the identical germline BRCA2 variant and was diagnosed with extrahepatic BDC with lymph node metastases. The tumors showed marked shrinkage upon treatment with cisplatin-containing chemotherapy. Our cases underscore the importance of comprehensive genomic profiling and genetic testing for BRCA2 to ensure optimal therapeutic options for PACC as well as to identify high-risk individuals with various cancers in the family.

DOI: https://doi.org/10.1097/MPA.0000000000002150
J Med Genet. 2023 Apr 19. pii: jmg-2022-109133. [Epub ahead of print]

TP53 c.455C>T p.(Pro152Leu) pathogenic variant is a lower risk allele with attenuated risks of breast cancer and sarcoma.

D Gareth Evans, Elaine F Harkness, Emma R Woodward.

  Germline (likely) pathogenic TP53 variants cause Li-Fraumeni syndrome (LFS), typically associated with sarcoma, brain, breast and adrenal tumours. Although classical LFS is highly penetrant, the p.R337H variant, common in Brazil, is typically associated with childhood adrenal tumours and an older onset age of other LFS tumours. Previously, we reported the finding of p.P152L in 6 children from 5 families with adrenal tumours. We have now assessed cancer risks over the subsequent 23 years, and in one further family with p.P152L. Cancer risks were compared with those in the 11 families known to our service with classical dominant negative mutations affecting neighbouring codons 245 and 248 (codon 245/248).Compared with codon 245/248 families, we found lower age-related risks for all non-adrenal tumours in codon 152 families (p<0.0001) with an absence of breast cancer as compared with 100% penetrance by age 36 years in codon 245/248 families (p<0.0001), and lower rates of sarcoma in non-irradiated individuals (p=0.0001). Although there were more adrenal tumours in codon 152 families (6/26 individuals, 1/27 for codon 245/248), this was not significant (p=0.05).Understanding codon-specific cancer risks in LFS is important for accurate personalised cancer risk assessment, and subsequent prevention and early detection strategies.

Keywords:  genetics, medical; heredity; mutation; mutation, missense

DOI:  https://doi.org/10.1136/jmg-2022-109133
Breast Cancer Res Treat. 2023 Apr 21.

The association between age at breast cancer diagnosis and prevalence of pathogenic variants.

Mary B Daly, Eric Rosenthal, Shelly Cummings, Ryan Bernhisel, John Kidd, Elisha Hughes, Alexander Gutin, Stephanie Meek, Thomas P Slavin, Allison W Kurian.

   PURPOSE: Young age at breast cancer (BC) diagnosis and family history of BC are strongly associated with high prevalence of pathogenic variants (PVs) in BRCA1 and BRCA2 genes. There is limited evidence for such associations with moderate/high penetrance BC-risk genes such as ATM, CHEK2, and PALB2.
METHODS: We analyzed multi-gene panel testing results (09/2013-12/2019) for women unaffected by any cancer (N = 371,594) and those affected with BC (N = 130,151) ascertained for suspicion of hereditary breast and/or ovarian cancer. Multivariable logistic regression was used to test association between PV status and age at BC diagnosis (≤ 45 vs. > 45 years) or family history of BC after controlling for personal/family non-BC histories and self-reported ancestry.
RESULTS: An association between young age (≤ 45 years) at diagnosis and presence of PVs was strong for BRCA1 (OR 3.95, 95% CI 3.64-4.29) and moderate for BRCA2 (OR 1.98, 95% CI 1.84-2.14). Modest associations were observed between PVs and young age at diagnosis for ATM (OR 1.22, 95% CI 1.08-1.37) and CHEK2 (OR 1.34, 95% CI 1.21-1.47) genes, but not for PALB2 (OR 1.12, 95% CI 0.98-1.27). For women with BC, earliest age of familial BC diagnosis followed a similar pattern. For unaffected women, earliest age of family cancer diagnosis was significantly associated with PV status only for BRCA1 (OR 2.34, 95% CI 2.13-2.56) and BRCA2 (OR 1.25, 95% CI 1.16-1.35).
CONCLUSIONS: Young age at BC diagnosis is not a strong risk factor for carrying PVs in BC-associated genes ATM, CHEK2, or PALB2.

Keywords:  Breast cancer; Cancer risk; Genetic testing

DOI:  https://doi.org/10.1007/s10549-023-06946-8
Cancer Discov. 2023 Apr 17. OF1-OF24

Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death.

Joshua H Choe, Tatsuya Kawase, An Xu, Asja Guzman, Aleksandar Z Obradovic, Ana Maria Low-Calle, Bita Alaghebandan, Ananya Raghavan, Kaitlin Long, Paul M Hwang, Joshua D Schiffman, Yan Zhu, Ruiying Zhao, Dung-Fang Lee, Chen Katz, Carol Prives.

Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li-Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. Further, p53(A347D) induces striking mitochondrial network aberration and associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Thus, dimer-forming p53 demonstrates both loss-of-function (LOF) and gain-of-function (GOF) properties compared with the wild-type form of the protein.
SIGNIFICANCE: A mutant p53 (A347D), which can only form dimers, is associated with increased cancer susceptibility in LFS individuals. We found that this mutant wields a double-edged sword, driving tumorigenesis through LOF while gaining enhanced apoptogenic activity as a new GOF, thereby yielding a potential vulnerability to select therapeutic approaches.

DOI: https://doi.org/10.1158/2159-8290.CD-22-0882
BMC Cancer. 2023 Apr 21. 23(1): 368

Functional analyses of rare germline BRCA1 variants by transcriptional activation and homologous recombination repair assays.

Nicola Bassi, Henrikke Nilsen Hovland, Kashif Rasheed, Elisabeth Jarhelle, Nikara Pedersen, Eunice Kabanyana Mchaina, Sara Marie Engelsvold Bakkan, Nina Iversen, Hildegunn Høberg-Vetti, Bjørn Ivar Haukanes, Per Morten Knappskog, Ingvild Aukrust, Elisabet Ognedal, Marijke Van Ghelue.

   BACKGROUND: Damaging alterations in the BRCA1 gene have been extensively described as one of the main causes of hereditary breast and ovarian cancer (HBOC). BRCA1 alterations can lead to impaired homologous recombination repair (HRR) of double-stranded DNA breaks, a process which involves the RING, BRCT and coiled-coil domains of the BRCA1 protein. In addition, the BRCA1 protein is involved in transcriptional activation (TA) of several genes through its C-terminal BRCT domain.
METHODS: In this study, we have investigated the effect on HRR and TA of 11 rare BRCA1 missense variants classified as variants of uncertain clinical significance (VUS), located within or in close proximity to the BRCT domain, with the aim of generating additional knowledge to guide the correct classification of these variants. The variants were selected from our previous study "BRCA1 Norway", which is a collection of all BRCA1 variants detected at the four medical genetic departments in Norway.
RESULTS: All variants, except one, showed a significantly reduced HRR activity compared to the wild type (WT) protein. Two of the variants (p.Ala1708Val and p.Trp1718Ser) also exhibited low TA activity similar to the pathogenic controls. The variant p.Trp1718Ser could be reclassified to likely pathogenic. However, for ten of the variants, the total strength of pathogenic evidence was not sufficient for reclassification according to the CanVIG-UK BRCA1/BRCA2 gene-specific guidelines for variant interpretation.
CONCLUSIONS: When including the newly achieved functional evidence with other available information, one VUS was reclassified to likely pathogenic. Eight of the investigated variants affected only one of the assessed activities of BRCA1, highlighting the importance of comparing results obtained from several functional assays to better understand the consequences of BRCA1 variants on protein function. This is especially important for multifunctional proteins such as BRCA1.

Keywords:  BRCA1; Functional assay; Hereditary breast and ovarian cancer; Homologous recombination repair; Transcriptional activation

DOI:  https://doi.org/10.1186/s12885-023-10790-w
Cancer Sci. 2023 Apr 17.

The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition.

Kazuki Yamazawa, Kokichi Sugano, Kohji Tanakaya, Satomi Inoue, Haruka Murakami, Moeko Nakashima, Masataka Adachi, Shinya Oki, Takeshi Makabe, Hiroshi Yamashita, Arisa Ueki, Ayako Sasaoka, Ayako Nakashoji, Takayuki Kinoshita, Tatsuo Matsunaga, Masami Arai, Seigo Nakamura, Hiroaki Miyata, Masachika Ikegami, Hiroyuki Mano, Shinji Kohsaka, Akira Matsui.

  Substantial numbers of variants of unknown significance (VUSs) have been identified in BRCA1/2 through genetic testing, which poses a significant clinical challenge because the contribution of these VUSs to cancer predisposition has not yet been determined. Here, we report 10 Japanese patients from seven families with breast or ovarian cancer harboring the BRCA2 c.7847C>T (p.Ser2616Phe) variant that was interpreted as a VUS. This variant recurs only in families from Japan and has not been reported in the global general population databases. A Japanese patient with Fanconi anemia with compound heterozygous variants c.7847C>T (p.Ser2616Phe) and c.475+1G>A in BRCA2 was reported. In silico predictions and quantitative cosegregation analysis suggest a high probability of pathogenicity. The clinical features of the variant carriers were not specific to, but were consistent with, those of patients with hereditary breast and ovarian cancer. A validated functional assay, called the mixed-all-nominated-in-one-BRCA (MANO-B) method and the accurate BRCA companion diagnostic (ABCD) test, demonstrated the deleterious effects of the variant. Altogether, following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, this variant satisfied the "PS3," "PM2," "PM3," and "PP3" criteria. We thus conclude that the BRCA2 c.7847C>T (p.Ser2616Phe) variant is a "likely pathogenic" variant that is specifically observed in the Japanese population, leading to a breast and ovarian cancer predisposition.

Keywords:  BRCA2 gene; genetic testing; hereditary breast and ovarian cancer syndrome; mutation; pedigree

DOI:  https://doi.org/10.1111/cas.15799