bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022‒12‒25
25 papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. Unaffected Li-Fraumeni Syndrome Carrier Parent Demonstrates Allele-Specific mRNA Stabilization of Wild-Type TP53 Compared to Affected Offspring.
  2. Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations.
  3. Elbracht M, Meyer R, Kricheldorf K, et al. Germline variants in DNA repair genes, including BRCA1/2, may cause familial myeloproliferative neoplasms. Blood Adv. 2021;5(17):3373-3376.
  4. Rectal leiomyosarcoma as the initial phenotypic manifestation of Li-Fraumeni-like syndrome: a case report and review of the literature.
  5. Exome sequencing of affected duos and trios uncovers PRUNE2 as a novel prostate cancer predisposition gene.
  6. Handling of Germline Findings in Clinical Comprehensive Cancer Genomic Profiling.
  7. A systematic method for detecting abnormal mRNA splicing and assessing its clinical impact in individuals undergoing genetic testing for hereditary cancer syndromes.
  8. The Identification of Large Rearrangements Involving Intron 2 of the CDH1 Gene in BRCA1/2 Negative and Breast Cancer Susceptibility.
  9. Molecular heterogeneity of pediatric choroid plexus carcinomas determines the distinctions in clinical course and prognosis.
  10. Germline and somatic variants in ovarian carcinoma: A next-generation sequencing (NGS) analysis.
  11. Cancer incidence and surveillance strategies in individuals with RASopathies.
  12. Hereditary Diffuse Gastric Cancer: A 2022 Update.
  13. Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma.
  14. Genetic testing women with newly diagnosed breast cancer: What criteria are the most predictive of a positive test?
  15. Development of a comprehensive approach to adult hereditary cancer testing in Ontario.
  16. Epidemiological, Clinical, and Genomic Profile in Head and Neck Cancer Patients and Their Families.
  17. A novel germline SMAD4 variant detected in a Japanese family with juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia.
  18. ALT in Pediatric High-Grade Gliomas Can Occur without ATRX Mutation and is Enriched in Patients with Pathogenic Germline MMR Variants.
  19. Recurrent germline variant in ATM associated with familial myeloproliferative neoplasms.
  20. Cancer prevention in cancer predisposition syndromes: A protocol for testing the feasibility of building a hereditary cancer research registry and nurse navigator follow up model.
  21. Incidence of Hereditary Gastric Cancer May Be Much Higher than Reported.
  22. Hereditary Colorectal Cancer Syndromes: Molecular Genetics and Precision Medicine.
  23. Pathogenic Variant Spectrum in Breast Cancer Risk Genes in Finnish Patients.
  24. Penetrance of Gastric Adenocarcinoma Susceptibility Genes: A Systematic Review.
  25. Clinical Impact of Next-Generation Sequencing Multi-Gene Panel Highlighting the Landscape of Germline Alterations in Ovarian Cancer Patients.
  1. Genes (Basel). 2022 Dec 07. pii: 2302. [Epub ahead of print]13(12):
    Unaffected Li-Fraumeni Syndrome Carrier Parent Demonstrates Allele-Specific mRNA Stabilization of Wild-Type TP53 Compared to Affected Offspring.
    Jeffrey S Buzby, Shirley A Williams, Diane J Nugent.
      Li-Fraumeni Syndrome (LFS) is an autosomal dominant disorder where an oncogenic TP53 germline mutation is inherited by offspring of a carrier parent. p53 is a key tumor suppressor regulating cell cycle arrest in response to DNA damage. Unexpectedly, some mutant TP53 carriers remain unaffected, while their children develop cancer early in life. To begin unravelling this paradox, the response of dermal fibroblasts (dFb) isolated from a child with LFS was compared to those from her unaffected father after UV exposure. Phospho-Chk1[S345], a key activator of cell cycle arrest, was increased by UV induction in the LFS patient compared to their unaffected parent dFb. This result, along with previous findings of reduced CDKN1A/p21 UV induction in affected dFb, suggest that cell cycle dysregulation may contribute to cancer onset in the affected LFS subject but not the unaffected parent. Mutant p53 protein and its promoter binding affinity were also higher in dFb from the LFS patient compared to their unaffected parent. These results were as predicted based on decreased mutant TP53 allele-specific mRNA expression previously found in unaffected dFb. Investigation of the potential mechanism regulating this TP53 allele-specific expression found that, while epigenetic promoter methylation was not detectable, TP53 wild-type mRNA was specifically stabilized in the unaffected dFb. Hence, the allele-specific stabilization of wild-type TP53 mRNA may allow an unaffected parent to counteract genotoxic stress by means more characteristic of homozygous wild-type TP53 individuals than their affected offspring, providing protection from the oncogenesis associated with LFS.
    Keywords:  Li-Fraumeni Syndrome; allele-specific expression; cancer inheritance; mRNA stability; p53; tumor suppression
    DOI:  https://doi.org/10.3390/genes13122302
  2. Ann Oncol. 2022 Dec 15. pii: S0923-7534(22)04771-8. [Epub ahead of print]
    Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations.
    Z Kuzbari, C Bandlamudi, C Loveday, A Garrett, M Mehine, A George, H Hanson, K Snape, A Kulkarni, S Allen, S Jezdic, R Ferrandino, C B Westphalen, E Castro, J Rodon, J Mateo, G J Burghel, M F Berger, D Mandelker, C Turnbull.
      BACKGROUND: The ESMO Precision Medicine Working Group was reconvened to update its 2018/19 recommendations on follow-up of putative germline variants detected on tumour-only sequencing, which were based on an analysis of 17,152 cancers.METHODS: We analysed an expanded dataset including 49,264 paired tumour-normal samples. We applied filters to tumour-detected variants based on variant allele frequency (VAF), predicted pathogenicity and population variant frequency. For 58 cancer susceptibility genes, we then examined the proportion of filtered tumour-detected variants of true germline origin (germline conversion rate (GCR)). We conducted sub-analyses based on the age of cancer diagnosis, specific tumour types and "on-tumour" status (established tumour-gene association).
    RESULTS: Analysis of 45,472 non-hypermutated solid malignancy tumour samples yielded 21,351 filtered tumour-detected variants of which 3,515 were of true germline origin. 3.1% of true germline pathogenic variants were absent from the filtered tumour-detected variants. For genes such as BRCA1, BRCA2, and PALB2, the GCR in filtered tumour-detected variants was >80%; conversely for TP53, APC and STK11 this GCR was <2%.
    CONCLUSION: Strategic germline-focused analysis can prioritise a subset of tumour-detected variants for which germline follow-up will produce the highest yield of most actionable true germline variants. We present updated recommendations around germline follow-up of tumour-only sequencing including (i) revision to 5% for the minimum per-gene GCR, (ii) inclusion of actionable intermediate penetrance genes ATM and CHEK2 (iii) definition of a set of seven 'most-actionable' cancer susceptibility genes (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, RET) in which germline follow-up is recommended regardless of tumour type.
    Keywords:  Cancer susceptibility genes; Germline; Germline conversion rate; Tumour-only sequencing; Variants
    DOI:  https://doi.org/10.1016/j.annonc.2022.12.003
  3. Blood Adv. 2022 Dec 27. 6(24): 6208
    Elbracht M, Meyer R, Kricheldorf K, et al. Germline variants in DNA repair genes, including BRCA1/2, may cause familial myeloproliferative neoplasms. Blood Adv. 2021;5(17):3373-3376.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2021006406
  4. J Med Case Rep. 2022 Dec 19. 16(1): 468
    Rectal leiomyosarcoma as the initial phenotypic manifestation of Li-Fraumeni-like syndrome: a case report and review of the literature.
    Natalia Parisi Severino, Jaques Waisberg, Maria Candida Barisson Villares Fragoso, Luiz Guilherme Cernaglia Aureliano de Lima, Flavia Balsamo, Alexandre Cruz Henriques, Bianca Bianco, Flávia de Sousa Gehrke.
      BACKGROUND: Leiomyosarcoma is a rare malignant tumor of smooth muscle origin and represents 10-20% of all soft tissue sarcomas. Primary colon and rectal sarcomas constitute < 0.1% of all large bowel malignancies. In Li-Fraumeni syndrome, sarcomas are the second most frequent cancer (25%). Li-Fraumeni syndrome is a genetic disease with a familial predisposition to multiple malignant neoplasms. This syndrome has an autosomal dominant pattern of inheritance and high penetrance characterized by germline TP53 mutations. Patients with a history of cancer who do not meet all the "classic" criteria for Li-Fraumeni syndrome are considered to have Li-Fraumeni-like syndrome. To the best of our knowledge, this article is the first report of a patient with rectal leiomyosarcoma as the initial phenotypic manifestation of Li-Fraumeni-like syndrome. The authors also present a literature review.CASE PRESENTATION: A 67-year-old Brazilian woman underwent anterior rectosigmoidectomy and panhysterectomy secondary to rectal leiomyosarcoma. She subsequently developed carcinomatosis and died 2 years after the operation. Her family medical history consisted of a daughter who died at 32 years of age from breast cancer, a granddaughter diagnosed with adrenocortical carcinoma at 6 years of age and two siblings who died from prostate cancer. A genetic study was carried out to identify a pathogenic variant of Li-Fraumeni syndrome. In the DNA extracted from the peripheral blood leukocyte, restriction fragment length polymorphism was analyzed to search for mutations in the TP53 gene. The DNA sequencing identified the germline pathogenic variant p. R337H heterozygous in exon 10 of TP53. The patient was classified as having Li-Fraumeni-like syndrome.
    CONCLUSION: In patients with rectal leiomyosarcoma, it is advisable to investigate the family history of cancer and perform genetic studies to screen for Li-Fraumeni syndrome.
    Keywords:  Case report; Leiomyosarcoma; Li–Fraumeni syndrome; Mutation; TP53 gene
    DOI:  https://doi.org/10.1186/s13256-022-03671-6
  5. Br J Cancer. 2022 Dec 23.
    Exome sequencing of affected duos and trios uncovers PRUNE2 as a novel prostate cancer predisposition gene.
    Marta Cardoso, Sofia Maia, Andreia Brandão, Ruta Sahasrabudhe, Paul Lott, Natalia Belter, Luis G Carvajal-Carmona, Paula Paulo, Manuel R Teixeira.
      BACKGROUND: Prostate cancer (PrCa) is one of the most hereditable human cancers, however, only a small fraction of patients has been shown to carry deleterious variants in known cancer predisposition genes.METHODS: Whole-exome sequencing was performed in multiple affected members of 45 PrCa families to select the best candidate genes behind part of the PrCa missing hereditability. Recurrently mutated genes were prioritised, and further investigated by targeted next-generation sequencing in the whole early-onset and/or familial PrCa series of 462 patients.
    RESULTS: PRUNE2 stood out from our analysis when also considering the available data on its association with PrCa development. Ten germline pathogenic/likely pathogenic variants in the PRUNE2 gene were identified in 13 patients. The most frequent variant was found in three unrelated patients and identical-by-descent analysis revealed that the haplotype associated with the variant is shared by all the variant carriers, supporting the existence of a common ancestor.
    DISCUSSION: This is the first report of pathogenic/likely pathogenic germline variants in PRUNE2 in PrCa patients, namely in those with early-onset/familial disease. Importantly, PRUNE2 was the most frequently mutated gene in the whole series, with a deleterious germline variant identified in 2.8% of the patients, representing a novel prostate cancer predisposition gene.
    DOI:  https://doi.org/10.1038/s41416-022-02125-6
  6. Acta Med Okayama. 2022 Dec;76(6): 673-678
    Handling of Germline Findings in Clinical Comprehensive Cancer Genomic Profiling.
    Mika Okazawa-Sakai, Yasuko Yamamoto, Mashu Futagawa, Miki Okamura, Satoko Miyawaki, Tomohiro Nishina, Kazuhiro Takehara, Toshiyuki Kozuki, Shuta Tomida, Ichinosuke Hyodo, Shozo Ohsumi, Akira Hirasawa.
      Patients found to have presumed germline pathogenic variants (PGPVs) during comprehensive genomic profiling (CGP) require genetic counseling (GC) referrals. We retrospectively investigated the outcomes of patients with PGPVs. Among 159 patients who underwent CGP, we recommended GC for the 16 patients with PGPVs (3 with [FG group] and 13 without [G Group] a family/personal history of hereditary cancer) as well as for the 8 patients with no PGPVs, but a history (F group); 2 (67%), 5 (38%), and 3 (38%) patients received GC in the FG, G, and F groups, respectively. Germline testing results were positive in 1 and 2 patients of the FG and G groups, respectively. Among the patients recommended for GC, 58% did not receive GC due to lack of interest, poor performance status, or death. CGP contributes to the identification of germline variants in patients without a history of hereditary cancer. However, the proportion of patients who undergo GC should be improved.
    Keywords:  comprehensive genomic profiling; genetic counseling; germline findings; hereditary cancer; presumed germline pathogenic variant(s)
    DOI:  https://doi.org/10.18926/AMO/64117
  7. J Mol Diagn. 2022 Dec 20. pii: S1525-1578(22)00348-8. [Epub ahead of print]
    A systematic method for detecting abnormal mRNA splicing and assessing its clinical impact in individuals undergoing genetic testing for hereditary cancer syndromes.
    Nick Kamps-Hughes, Victoria E H Carlton, Laure Fresard, Steve Osazuwa, Elizabeth Starks, John J Vincent, Sarah Albritton, Robert L Nussbaum, Keith Nykamp.
      Nearly 14% of disease-causing germline variants result from disruption of mRNA splicing. Most (67%) DNA variants predicted in silico to disrupt splicing end up classified as variants of uncertain significance (VUS). We developed and validated an analytic workflow - Splice Effect Event Resolver (SPEER) - that uses mRNA sequencing to reveal significant deviations in splicing, pinpoints the DNA variants potentially responsible, and measures the deleterious effect of the altered splicing on mRNA transcripts, providing evidence to assess the pathogenicity of the variant. SPEER was used to analyze leukocyte RNA encoding 63 hereditary cancer syndrome genes in 20,317 individuals undergoing clinical genetic testing. Among 3,563 (17.5%) individuals with at least one DNA variant predicted to affect splicing, 971 (4.8%) had altered splicing with a deleterious effect on the transcript and 40 had altered splicing due to a DNA variant located outside our laboratory's reportable range. Integrating SPEER results into variant interpretation allowed reclassification of VUS to P/LP in 0.4% and to B/LB in 5.9% of the 20,317 patients. SPEER evidence had a significantly higher impact for P/LP and B/LB classifications in non-White individuals compared to non-Hispanic White individuals, illustrating that evidence derived from RNA splicing analysis may help reduce ethnic/ancestral disparities in genetic testing.
    Keywords:  RNA sequencing; diagnostic testing; splice site prediction; splicing; variant interpretation
    DOI:  https://doi.org/10.1016/j.jmoldx.2022.12.002
  8. Genes (Basel). 2022 Nov 25. pii: 2213. [Epub ahead of print]13(12):
    The Identification of Large Rearrangements Involving Intron 2 of the CDH1 Gene in BRCA1/2 Negative and Breast Cancer Susceptibility.
    Jihenne Ben Aissa-Haj, Hugo Pinheiro, François Cornelis, Molka Sebai, Didier Meseure, Adrien Briaux, Philippe Berteaux, Cedric Lefol, Gaëtan Des Guetz, Martine Trassard, Denise Stevens, François Vialard, Ivan Bieche, Catherine Noguès, Roseline Tang, Carla Oliveira, Dominique Stoppat-Lyonnet, Rosette Lidereau, Etienne Rouleau.
      E-cadherin, a CDH1 gene product, is a calcium-dependent cell-cell adhesion molecule playing a critical role in the establishment of epithelial architecture, maintenance of cell polarity, and differentiation. Germline pathogenic variants in the CDH1 gene are associated with hereditary diffuse gastric cancer (HDGC), and large rearrangements in the CDH1 gene are now being reported as well. Because CDH1 pathogenic variants could be associated with breast cancer (BC) susceptibility, CDH1 rearrangements could also impact it. The aim of our study is to identify rearrangements in the CDH1 gene in 148 BC cases with no BRCA1 and BRCA2 pathogenic variants. To do so, a zoom-in CGH array, covering the exonic, intronic, and flanking regions of the CDH1 gene, was used to screen our cohort. Intron 2 of the CDH1 gene was specifically targeted because it is largely reported to include several regulatory regions. As results, we detected one large rearrangement causing a premature stop in exon 3 of the CDH1 gene in a proband with a bilateral lobular breast carcinoma and a gastric carcinoma (GC). Two large rearrangements in the intron 2, a deletion and a duplication, were also reported only with BC cases without any familial history of GC. No germline rearrangements in the CDH1 coding region were detected in those families without GC and with a broad range of BC susceptibility. This study confirms the diversity of large rearrangements in the CDH1 gene. The rearrangements identified in intron 2 highlight the putative role of this intron in CDH1 regulation and alternative transcripts. Recurrent duplication copy number variations (CNV) are found in this region, and the deletion encompasses an alternative CDH1 transcript. Screening for large rearrangements in the CDH1 gene could be important for genetic testing of BC.
    Keywords:  BRCA1/2 negative cases; CDH1 rearrangements; CGH array; CNV; breast carcinoma; gastric carcinoma
    DOI:  https://doi.org/10.3390/genes13122213
  9. Neuro Oncol. 2022 Dec 19. pii: noac274. [Epub ahead of print]
    Molecular heterogeneity of pediatric choroid plexus carcinomas determines the distinctions in clinical course and prognosis.
    Margarita Zaytseva, Andge Valiakhmetova, Ludmila Yasko, Alexey Samarin, Ludmila Papusha, Anastasia Shekhtman, Natalia Usman, Kirill Voronin, Alexander Karachunsky, Galina Novichkova, Alexander Druy.
      BACKGROUND: Choroid plexus carcinomas (CPCs) are rare aggressive pediatric tumors of the brain with no treatment standards. Genetic profiling of CPCs is often confined to possible association with Li-Fraumeni syndrome, though only about a half of CPCs develop from syndromic predispositions. Whole-chromosome gains and losses typical of CPCs reflect genomic instability of these tumors, but only partially explain the aggressive clinical course.METHODS: This retrospective study enrolled 25 pediatric patients with CPC, receiving treatment between January 2009 and June 2022. Molecular genetic testing was performed for 20 cases with available tumor tissue and encompassed mutational status, chromosomal aberrations and gene expression profiles. We analyzed several factors presumably influencing the outcomes, including molecular profiles and clinical parameters. The median follow-up constituted 5.2 years (absolute range 2.8-12.6 years).
    RESULTS: All studied CPCs had smooth mutational profiles with the only recurrent event being TP53 variants, either germline or somatic, encountered in 13 cases. Unbalanced whole-chromosome aberrations, notably multiple monosomies, were highly typical. In seven tumors, chromosome losses were combined with complex genomic rearrangements: segmental gains and losses or signs of chromothripsis. This phenomenon was associated with extremely low 5-year survival: 20.0±17.9% vs. 85.7±13.2%; p=0.009. Transcriptomically, the cohort split into two polar clusters Ped_CPC1 and Ped_CPC2 differing by survival: 31.3±17.8% vs. 100%; p=0.012.
    CONCLUSION: CPCs split into at least two molecular subtypes distinguished both genomically and transcriptomically. Clusterization of the tumors into Ped_CPC1 and Ped_CPC2 significantly correlates with survival. The distinction may prove relevant in clinical trials for dedicated and patient-oriented optimization of clinical protocols for these rare tumors.
    Keywords:   ТР53 ; Li–Fraumeni syndrome; choroid plexus carcinoma; gene expression profiling; ploidy status
    DOI:  https://doi.org/10.1093/neuonc/noac274
  10. Front Oncol. 2022 ;12 1030786
    Germline and somatic variants in ovarian carcinoma: A next-generation sequencing (NGS) analysis.
    Angeliki Andrikopoulou, Eleni Zografos, Kleoniki Apostolidou, Anastasios Kyriazoglou, Alksistis-Maria Papatheodoridi, Maria Kaparelou, Konstantinos Koutsoukos, Michalis Liontos, Meletios-Athanasios Dimopoulos, Flora Zagouri.
      Background: Germline BRCA1/2 mutations are identified in 13-15% of ovarian cancers, while an additional 5-7% of ovarian cancers harbor somatic BRCA1/2 mutations. Beyond these mutations, germline or somatic aberrations in genes of the homologous recombination (HR) pathway such as RAD51B/C/D, PALB2, ATM, BRIP1 may confer an HR deficiency in up to 50% of ovarian tumors. Next-generation sequencing (NGS) is a high-throughput massive parallel sequencing method that enables the simultaneous detection of several mutations in entire genomes.Methods: We performed NGS analysis in 86 patients with ovarian cancer treated in the Oncology Department of Alexandra University Hospital in order to identify the molecular landscape of germline and somatic mutations in ovarian cancer.
    Results: The genes with the highest number of pathogenic somatic mutations in high grade serous carcinoma (HGSC) patients were TP53 [68%; 34/50] and BRCA1 [22%; 11/50] followed by somatic mutations in RB1 [2%; 1/50], NF1 [2%; 1/50], BRCA2 [2%; 1/50], AKT1 [2%; 1/50], RAD50 [2%; 1/50], PIK3CA [2%; 1/50] genes. Of note, the most common TP53 genetic polymorphism was c.524G>A p.Arg175His in exon 5. Variants of unknown significance (VUS) detected in HGSC included ROS1 [26%; 13/50], RAD50 [6%; 3/50], BRCA2 [6%; 3/50], NOTCH1 [6%; 3/50], TP53 [6%; 3/50], AR [6%; 3/50]. As for germline mutations, BRCA1 [8/30; 27%] and BRCA2 [4/30; 13%] were the most common genes bearing pathogenic alterations in HGSC, while VUS germline mutations commonly affected HRR-related genes, including ATM (c.7816A>G), BRIP (c.2327 C>A), CHEK2 (c.320-5T>A).
    Conclusion: Overall, genetic testing should be offered in most patients with ovarian cancer to identify mutations in HRR genes and determine the population that would be susceptible to poly ADP ribose polymerase (PARP) inhibitors.
    Keywords:  BRCA; HRD; NGS; germline mutations; next-generation sequencing; ovarian cancer
    DOI:  https://doi.org/10.3389/fonc.2022.1030786
  11. Am J Med Genet C Semin Med Genet. 2022 Dec 19.
    Cancer incidence and surveillance strategies in individuals with RASopathies.
    Gina Ney, Andrea Gross, Alicia Livinski, Christian P Kratz, Douglas R Stewart.
      RASopathies are a set of clinical syndromes that have molecular and clinical overlap. Genetically, these syndromes are defined by germline pathogenic variants in RAS/MAPK pathway genes resulting in activation of this pathway. Clinically, their common molecular signature leads to comparable phenotypes, including cardiac anomalies, neurologic disorders and notably, elevated cancer risk. Cancer risk in individuals with RASopathies has been estimated from retrospective reviews and cohort studies. For example, in Costello syndrome, cancer incidence is significantly elevated over the general population, largely due to solid tumors. In some forms of Noonan syndrome, cancer risk is also elevated over the general population and is enriched for hematologic malignancies. Thus, cancer surveillance guidelines have been developed to monitor for the occurrence of such cancers in individuals with some RASopathies. These include abdominal ultrasound and urinalyses for individuals with Costello syndrome, while complete blood counts and splenic examination are recommended in Noonan syndrome. Improved cancer risk estimates and refinement of surveillance recommendations will improve the care of individuals with RASopathies.
    Keywords:  RASopathy; cancer predisposition; screening
    DOI:  https://doi.org/10.1002/ajmg.c.32018
  12. J Pers Med. 2022 Dec 08. pii: 2032. [Epub ahead of print]12(12):
    Hereditary Diffuse Gastric Cancer: A 2022 Update.
    Christo Kole, Nikolaos Charalampakis, Stratigoula Sakellariou, George Papaxoinis, Konstantinos G Apostolou, Nikolaos Machairas, Ioannis S Papanikolaou, Dimitrios Schizas.
      Gastric cancer is ranked fifth among the most commonly diagnosed cancers, and is the fourth leading cause of cancer-related deaths worldwide. The majority of gastric cancers are sporadic, while only a small percentage, less than 1%, are hereditary. Hereditary diffuse gastric cancer (HDGC) is a rare malignancy, characterized by early-onset, highly-penetrant autosomal dominant inheritance mainly of the germline alterations in the E-cadherin gene (CDH1) and β-catenin (CTNNA1). In the present study, we provide an overview on the molecular basis of HDGC and outline the essential elements of genetic counseling and surveillance. We further provide a practical summary of current guidelines on clinical management and treatment of individuals at risk and patients with early disease.
    Keywords:  CDH1; CTNNA1; MAP3K6; clinical guidelines; gastrectomy; hereditary diffuse gastric cancer
    DOI:  https://doi.org/10.3390/jpm12122032
  13. Int J Mol Sci. 2022 Dec 16. pii: 16027. [Epub ahead of print]23(24):
    Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma.
    Lorenza Pastorino, Bruna Dalmasso, Eleonora Allavena, Irene Vanni, Filippo Ugolini, Gianna Baroni, Michela Croce, Antonio Guadagno, Francesco Cabiddu, Virginia Andreotti, William Bruno, Gabriele Zoppoli, Lorenzo Ferrando, Enrica Teresa Tanda, Francesco Spagnolo, Chiara Menin, Rosaria Gangemi, Daniela Massi, Paola Ghiorzo.
      ATM germline pathogenic variants were recently found enriched in high-risk melanoma patients. However, ATM loss of heterozygosity (LOH) has never been investigated in melanoma and, therefore, a causal association with melanoma development has not been established yet. The purpose of this study was to functionally characterize 13 germline ATM variants found in high-risk melanoma patients-and classified by in silico tools as pathogenic, uncertain significance, or benign-using multiple assays evaluating ATM/pATM expression and/or LOH in melanoma tissues and cell lines. We assessed ATM status by Immunohistochemistry (IHC), Western Blot, Whole-Exome Sequencing/Copy Number Variation analysis, and RNA sequencing, supported by Sanger sequencing and microsatellite analyses. For most variants, IHC results matched those obtained with in silico classification and LOH analysis. Two pathogenic variants (p.Ser1135_Lys1192del and p.Ser1993ArgfsTer23) showed LOH and complete loss of ATM activation in melanoma. Two variants of unknown significance (p.Asn358Ile and p.Asn796His) showed reduced expression and LOH, suggestive of a deleterious effect. This study, showing a classic two-hit scenario in a well-known tumor suppressor gene, supports the inclusion of melanoma in the ATM-related cancer spectrum.
    Keywords:  ATM; germline variant; loss of heterozygosity; melanoma; susceptibility
    DOI:  https://doi.org/10.3390/ijms232416027
  14. Cancer Med. 2022 Dec 21.
    Genetic testing women with newly diagnosed breast cancer: What criteria are the most predictive of a positive test?
    Kelly A Metcalfe, Steven A Narod, Andrea Eisen, Aletta Poll, Neda Zamani, David McCready, Tulin D Cil, Frances C Wright, Jordan Lerner-Ellis, Jeanna McCuaig, Tracy Graham, Ping Sun, Mohammad R Akbari.
      BACKGROUND: Knowledge of pathogenic variants in cancer-predisposing genes is important when making breast cancer treatment decisions, but genetic testing is not universal and criteria must be met to qualify for genetic testing. The objective of this study was to evaluate the pathogenic variant yield for nine cancer predisposition genes by testing criteria, singly and in combination.METHODS: Women diagnosed with breast cancer between June 2013 and May 2018 were recruited from four centers in Toronto, Canada. Participants completed a demographics and family history questionnaire and clinical characteristics were collected from medical charts. Genetic testing was done for BRCA1, BRCA2, PALB2, ATM, CHEK2, BRIP1, RAD51D, RECQL, and TP53. Pathogenic variant frequencies were calculated according to five criteria (age ≤ 50, triple-negative breast cancer, family history, bilateral breast cancer, or Jewish ethnicity).
    RESULTS: Of the 1006 women studied, 100 women (9.9%) were found to have a pathogenic variant in one of the nine genes tested. The highest prevalence of pathogenic variants was found in women with triple-negative breast cancer (23%). Of the 100 pathogenic variants detected, 78 were detected in women diagnosed at age 50 or less. A total of 96% of the mutations were identified with three criteria (age of diagnosis, family history, and triple-negative status).
    CONCLUSIONS: Genetic testing criteria for women with breast cancer should include women with triple-negative breast cancer, regardless of age. All women aged 50 years or below at time of breast cancer diagnosis should be offered genetic testing.
    DOI:  https://doi.org/10.1002/cam4.5515
  15. J Med Genet. 2022 Dec 23. pii: jmg-2022-108945. [Epub ahead of print]
    Development of a comprehensive approach to adult hereditary cancer testing in Ontario.
    Kathleen Anne Bell, Raymond Kim, Melyssa Aronson, Brittany Gillies, Arif Ali Awan, Kathy Chun, Jennifer Hart, Rachel Healey, Linda Kim, Goran Klaric, Karen Panabaker, Peter J B Sabatini, Bekim Sadikovic, Shamini Selvarajah, Amanda C Smith, Tracy L Stockley, Andrea K Vaags, Andrea Eisen, Aaron Pollett, Harriet Feilotter.
      BACKGROUND: Genetic testing for hereditary cancer susceptibility has advanced over time due to the discovery of new risk genes, improved technology and decreased cost. In the province of Ontario, testing eligibility criteria were initially developed to include hereditary breast, ovarian and colorectal cancer syndromes. The rapid evolution of genetic technologies has facilitated the ability to interrogate a large number of genes concurrently. This, coupled with new knowledge about risk genes, necessitated a coordinated approach to expanding the scope of genes and indications tested and synchronisation of access and test utilisation across the province as required in a publicly funded universal healthcare system.METHODS: Ontario Health-Cancer Care Ontario convened expert working groups to develop a standardised and comprehensive cancer gene list for adults and accompanying hereditary cancer testing (HCT) criteria using an evidence-based framework and broad laboratory and clinical genetics engagement.
    RESULTS: A standardised 76-cancer-gene panel, organised into 13 larger disease site panels and 25 single/small gene panels, was developed and endorsed by the working groups. Provincial genetic testing eligibility criteria were updated to align with the new panels and to guide clinical decision-making. In the first year following the implementation of these changes, 10 564 HCT panels were performed with an overall mutation detection rate of 12.2%.
    CONCLUSION: Using an evidence framework and broad clinical engagement to develop and endorse an updated guidance document, cancer genetic testing for adults in Ontario is now standardised and coordinated across the province.
    Keywords:  evidence-based practice; genetic counselling; genetic predisposition to disease; genetic testing; health services administration
    DOI:  https://doi.org/10.1136/jmg-2022-108945
  16. Biomedicines. 2022 Dec 17. pii: 3278. [Epub ahead of print]10(12):
    Epidemiological, Clinical, and Genomic Profile in Head and Neck Cancer Patients and Their Families.
    Thiago Celestino Chulam, Fernanda Bernardi Bertonha, Rolando André Rios Villacis, João Gonçalves Filho, Luiz Paulo Kowalski, Silvia Regina Rogatto.
      Inherited cancer predisposition genes are described as risk factors in head and neck cancer (HNC) families. To explore the clinical and epidemiological data and their association with a family history of cancer, we recruited 74 patients and 164 relatives affected by cancer. The germline copy number alterations were evaluated in 18 patients using array comparative genomic hybridization. Two or more first-degree relatives with HNC, tobacco-associated tumor sites (lung, esophagus, and pancreas), or other related tumors (breast, colon, kidney, bladder, cervix, stomach carcinomas, and melanoma) were reported in 74 families. Ten index patients had no exposure to any known risk factors. Family members presented tumors of 19 topographies (30 head and neck, 26 breast, 21 colon). In first-degree relatives, siblings were frequently affected by cancer (n = 58, 13 had HNC). Breast cancer (n = 21), HNC (n = 19), and uterine carcinoma (n = 15) were commonly found in first-degree relatives and HNC in second-degree relatives (n = 11). Nineteen germline genomic imbalances were detected in 13 patients; three presented gains of WRD genes. The number of HNC patients, the degree of kinship, and the tumor types detected in each relative support the role of heredity in these families. Germline alterations may potentially contribute to cancer development.
    Keywords:  cancer predisposition; copy number alterations; familial cancer; head and neck cancer; risk factors
    DOI:  https://doi.org/10.3390/biomedicines10123278
  17. Jpn J Clin Oncol. 2022 Dec 22. pii: hyac189. [Epub ahead of print]
    A novel germline SMAD4 variant detected in a Japanese family with juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia.
    Yoshikazu Kananazawa, Takeshi Yamada, Tatsuro Yamaguchi, Yoshinobu Saito, Daisuke Kakinuma, Yuka Masuda, Fumihiko Ando, Ryuji Ohashi, Hidetaka Eguchi, Yasushi Okazaki, Hideyuki Ishida, Hiroshi Yoshida.
      Juvenile polyposis syndrome (JPS) is an autosomal dominant, inherited disorder caused by pathogenic germline variants of mainly SMAD4 or BMPR1A genes. Some patients with JPS, especially with SMAD4 variants, also develop hereditary, hemorrhagic telangiectasia (HHT). HHT is also an autosomal dominant inherited disorder. Herein, we identified a novel germline pathogenic variant of the SMAD4 in a Japanese family with JPS and HHT. A six-base pair deletion in the SMAD4 gene (NM_005359.6:c.1495_1500delTGCATA) was identified in the patients. Two amino acids are deleted from SMAD4 protein (p.Cys499_Ile500del), which are located in MSH2 domain essential for the binding with SMAD3. This is a novel variant that has not been registered in any database surveyed. Amino acid structural analysis predicted significant changes in the secondary and three-dimensional structures in the vicinity of the two amino acids' deletion. The variant is classified as 'Likely Pathogenic' according to the American College of Medical Genetics and Genomics guidelines.
    Keywords:   SMAD4 gene; hereditary hemorrhagic telangiectasia; juvenile polyposis syndrome
    DOI:  https://doi.org/10.1093/jjco/hyac189
  18. Neuro Oncol. 2022 Dec 20. pii: noac278. [Epub ahead of print]
    ALT in Pediatric High-Grade Gliomas Can Occur without ATRX Mutation and is Enriched in Patients with Pathogenic Germline MMR Variants.
    Jennifer L Stundon, Heba Ijaz, Krutika S Gaonkar, Rebecca S Kaufman, Run Jin, Anastasios Karras, Zalman Vaksman, Jung Kim, Ryan J Corbett, Matthew R Lueder, Daniel P Miller, Yiran Guo, Mariarita Santi, Marilyn Li, Gonzalo Lopez, Phillip B Storm, Adam C Resnick, Angela J Waanders, Suzanne P MacFarland, Douglas R Stewart, Sharon J Diskin, Jo Lynne Rokita, Kristina A Cole.
      BACKGROUND: To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available.METHODS: We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n=40/579) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on pediatric high-grade glioma (pHGG) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations.
    RESULTS: ALT is common in pHGG (n=24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ pHGG and in 30% of ALT- pHGG. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT.
    CONCLUSIONS: We demonstrate that ATRX is mutated in only a subset of ALT+ pHGG, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with development of ALT in patients with pHGG.
    Keywords:  ATRX; Alternative lengthening of telomeres; Telomere; mismatch repair; pHGG; pediatric brain tumors
    DOI:  https://doi.org/10.1093/neuonc/noac278
  19. Leukemia. 2022 Dec 21.
    Recurrent germline variant in ATM associated with familial myeloproliferative neoplasms.
    Evan M Braunstein, Eddie Imada, Sergiu Pasca, Shiyu Wang, Hang Chen, Camille Alba, Dan N Hupalo, Matthew Wilkerson, Clifton L Dalgard, Jack Ghannam, Yujia Liu, Luigi Marchionni, Alison Moliterno, Christopher S Hourigan, Lukasz P Gondek.
      Genetic predisposition (familial risk) in the myeloproliferative neoplasms (MPNs) is more common than the risk observed in most other cancers, including breast, prostate, and colon. Up to 10% of MPNs are considered to be familial. Recent genome-wide association studies have identified genomic loci associated with an MPN diagnosis. However, the identification of variants with functional contributions to the development of MPN remains limited. In this study, we have included 630 MPN patients and whole genome sequencing was performed in 64 individuals with familial MPN to uncover recurrent germline predisposition variants. Both targeted and unbiased filtering of single nucleotide variants (SNVs) was performed, with a comparison to 218 individuals with MPN unselected for familial status. This approach identified an ATM L2307F SNV occurring in nearly 8% of individuals with familial MPN. Structural protein modeling of this variant suggested stabilization of inactive ATM dimer, and alteration of the endogenous ATM locus in a human myeloid cell line resulted in decreased phosphorylation of the downstream tumor suppressor CHEK2. These results implicate ATM, and the DNA-damage response pathway, in predisposition to MPN.
    DOI:  https://doi.org/10.1038/s41375-022-01797-6
  20. PLoS One. 2022 ;17(12): e0279317
    Cancer prevention in cancer predisposition syndromes: A protocol for testing the feasibility of building a hereditary cancer research registry and nurse navigator follow up model.
    Holly Etchegary, April Pike, Rebecca Puddester, Kathy Watkins, Mike Warren, Vanessa Francis, Michael Woods, Jane Green, Sevtap Savas, Melanie Seal, Zhiwei Gao, Susan Avery, Fiona Curtis, Jerry McGrath, Donald MacDonald, T Nadine Burry, Lesa Dawson.
      Monogenic, high penetrance syndromes, conferring an increased risk of malignancies in multiple organs, are important contributors to the hereditary burden of cancer. Early detection and risk reduction strategies in patients with a cancer predisposition syndrome can save their lives. However, despite evidence supporting the benefits of early detection and risk reduction strategies, most Canadian jurisdictions have not implemented programmatic follow up of these patients. In our study site in the province of Newfoundland and Labrador (NL), Canada, there is no centralized, provincial registry of high-risk individuals. There is no continuity or coordination of care providing cancer genetics expertise and no process to ensure that patients are referred to the appropriate specialists or risk management interventions. This paper describes a study protocol to test the feasibility of obtaining and analyzing patient risk management data, specifically patients affected by hereditary breast ovarian cancer syndrome (HBOC; BRCA 1 and BRCA 2 genes) and Lynch syndrome (LS; MLH1, MSH2, MSH6, and PMS2 genes). Through a retrospective cohort study, we will describe these patients' adherence to risk management guidelines and test its relationship to health outcomes, including cancer incidence and stage. Through a qualitative interviews, we will determine the priorities and preferences of patients with any inherited cancer mutation for a follow up navigation model of risk management. Study data will inform a subsequent funding application focused on creating and evaluating a research registry and follow up nurse navigation model. It is not currently known what proportion of cancer mutation carriers are receiving care according to guidelines. Data collected in this study will provide clinical uptake and health outcome information so gaps in care can be identified. Data will also provide patient preference information to inform ongoing and planned research with cancer mutation carriers.
    DOI:  https://doi.org/10.1371/journal.pone.0279317
  21. Cancers (Basel). 2022 Dec 12. pii: 6125. [Epub ahead of print]14(24):
    Incidence of Hereditary Gastric Cancer May Be Much Higher than Reported.
    Paula Baraúna de Assumpção, Paulo Pimentel de Assumpção, Fabiano Cordeiro Moreira, Ândrea Ribeiro-Dos-Santos, Amanda F Vidal, Leandro Magalhães, André Salim Khayat, André Maurício Ribeiro-Dos-Santos, Giovanna C Cavalcante, Adenilson Leão Pereira, Inácio Medeiros, Sandro José de Souza, Rommel Mario Rodríguez Burbano, Jorge Estefano Santana de Souza, Sidney Emanuel Batista Dos Santos.
      Hereditary gastric cancers (HGCs) are supposed to be rare and difficult to identify. Nonetheless, many cases of young patients with gastric cancer (GC) fulfill the clinical criteria for considering this diagnosis but do not present the defined pathogenic mutations necessary to meet a formal diagnosis of HGC. Moreover, GC in young people is a challenging medical situation due to the usual aggressiveness of such cases and the potential risk for their relatives when related to a germline variant. Aiming to identify additional germline alterations that might contribute to the early onset of GC, a complete exome sequence of blood samples from 95 GC patients under 50 and 94 blood samples from non-cancer patients was performed and compared in this study. The number of identified germline mutations in GC patients was found to be much higher than that from individuals without a cancer diagnosis. Specifically, the number of high functional impact mutations, including those affecting genes involved in medical diseases, cancer hallmark genes, and DNA replication and repair processes, was much higher, strengthening the hypothesis of the potential causal role of such mutations in hereditary cancers. Conversely, classically related HGC mutations were not found and the number of mutations in genes in the CDH1 pathway was not found to be relevant among the young GC patients, reinforcing the hypothesis that existing alternative germline contributions favor the early onset of GC. The LILRB1 gene variants, absent in the world's cancer datasets but present in high frequencies among the studied GC patients, may represent essential cancer variants specific to the Amerindian ancestry's contributions. Identifying non-reported GC variants, potentially originating from under-studied populations, may pave the way for additional discoveries and translations to clinical interventions for GC management. The newly proposed approaches may reduce the discrepancy between clinically suspected and molecularly proven hereditary GC and shed light on similar inconsistencies among other cancer types. Additionally, the results of this study may support the development of new blood tests for evaluating cancer risk that can be used in clinical practice, helping physicians make decisions about strategies for surveillance and risk-reduction interventions.
    Keywords:  ancestry; epidemiology; exome analyses; germline mutation; hereditary gastric cancer
    DOI:  https://doi.org/10.3390/cancers14246125
  22. Biomedicines. 2022 Dec 10. pii: 3207. [Epub ahead of print]10(12):
    Hereditary Colorectal Cancer Syndromes: Molecular Genetics and Precision Medicine.
    Liuxiang Chen, Liansong Ye, Bing Hu.
      Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Hereditary CRC syndromes account for approximately 5-10% of all CRC, with a lifetime risk of CRC that approaches 50-80% in the absence of endoscopic or surgical treatment. Hereditary CRC syndromes can be phenotypically divided into polyposis and non-polyposis syndrome, mainly according to the conditions of polyps. The typical representatives are familial adenomatous polyposis (FAP) and Lynch syndromes (LS), respectively. Over the past few decades, molecular genetics enhanced the discovery of cancer-predisposing genes and revolutionized the field of clinical oncology. Hereditary CRC syndromes have been a key part of this effort, with data showing that pathogenic variants are present in up to 10% of cases. Molecular phenotypes of tumors can not only help identify individuals with genetic susceptibility to CRC but also guide the precision prevention and treatment for the development of CRC. This review emphasizes the molecular basis and prevention strategies for hereditary CRC syndromes.
    Keywords:  hereditary colorectal cancer syndromes; predisposing genes; prevention strategies
    DOI:  https://doi.org/10.3390/biomedicines10123207
  23. Cancers (Basel). 2022 Dec 14. pii: 6158. [Epub ahead of print]14(24):
    Pathogenic Variant Spectrum in Breast Cancer Risk Genes in Finnish Patients.
    Anna K Nurmi, Maija Suvanto, Joe Dennis, Kristiina Aittomäki, Carl Blomqvist, Heli Nevanlinna.
      Recurrent pathogenic variants have been detected in several breast and ovarian cancer (BC/OC) risk genes in the Finnish population. We conducted a gene-panel sequencing and copy number variant (CNV) analysis to define a more comprehensive spectrum of pathogenic variants in BRCA1, BRCA2, PALB2, CHEK2, ATM, BARD1, RAD51C, RAD51D, BRIP1, and FANCM genes in Finnish BC patients. The combined frequency of pathogenic variants in the BRCA1/2 genes was 1.8% in 1356 unselected patients, whereas variants in the other genes were detected altogether in 8.3% of 1356 unselected patients and in 12.9% of 699 familial patients. CNVs were detected in 0.3% of both 1137 unselected and 612 familial patients. A few variants covered most of the pathogenic burden in the studied genes. Of the BRCA1/2 carriers, 70.8% had 1 of 10 recurrent variants. In the other genes combined, 92.1% of the carrier patients had at least 1 of 11 recurrent variants. In particular, PALB2 c.1592delT and CHEK2 c.1100delC accounted for 88.9% and 82.9%, respectively, of the pathogenic variation in each gene. Our results highlight the importance of founder variants in the BC risk genes in the Finnish population and could be used in the designing of population screening for the risk variants.
    Keywords:  BRCA1; BRCA2; breast cancer; copy number variant; gene-panel sequencing; moderate-risk gene; pathogenic variant
    DOI:  https://doi.org/10.3390/cancers14246158
  24. Ann Surg Oncol. 2022 Dec 17.
    Penetrance of Gastric Adenocarcinoma Susceptibility Genes: A Systematic Review.
    Sahar Hosseini, Ahmet Acar, Meghdeep Sen, Kiersten Meeder, Preeti Singh, Kanhua Yin, Jeffrey M Sutton, Kevin Hughes.
      BACKGROUND: Gastric adenocarcinoma (GAC) is the fifth most common cancer in the world, and the presence of germline pathogenic variants has been linked with approximately 5% of gastric cancer diagnoses. Multiple GAC susceptibility genes have been identified, but information regarding the risk associated with pathogenic variants in these genes remains obscure. We conducted a systematic review of existing studies reporting the penetrance of GAC susceptibility genes.METHODS: A structured search query was devised to identify GAC-related papers indexed in MEDLINE/PubMed. A semi-automated natural language processing algorithm was applied to identify penetrance papers for inclusion. Original studies reporting the penetrance of GAC were included and the full-text articles were independently reviewed. Summary statistics, effect estimates, and precision parameters from these studies were compiled into a table using a predetermined format to ensure consistency.
    RESULTS: Forty-five studies were identified reporting the penetrance of GAC among patients harboring mutations in 13 different genes: APC, ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, PMS2, MUTYH-Monoallelic, NBN, and STK11.
    CONCLUSION: Our systematic review highlights the importance of testing for germline pathogenic variants in patients before the development of GAC. Management of patients who harbor a pathogenic mutation is multifactorial, and clinicians should consider cancer risk for each applicable gene-cancer association throughout the screening and management process. The scarcity of studies we found investigating the risk of GAC among patients with pathogenic variants in GAC susceptibility genes highlights the need for more investigations that focus on producing robust risk estimates for gene-cancer associations.
    DOI:  https://doi.org/10.1245/s10434-022-12829-x
  25. Int J Mol Sci. 2022 Dec 13. pii: 15789. [Epub ahead of print]23(24):
    Clinical Impact of Next-Generation Sequencing Multi-Gene Panel Highlighting the Landscape of Germline Alterations in Ovarian Cancer Patients.
    Giorgia Gurioli, Gianluca Tedaldi, Alberto Farolfi, Elisabetta Petracci, Claudia Casanova, Giuseppe Comerci, Rita Danesi, Valentina Arcangeli, Mila Ravegnani, Daniele Calistri, Valentina Zampiga, Ilaria Cangini, Eugenio Fonzi, Alessandra Virga, Davide Tassinari, Marta Rosati, Paola Ulivi, Ugo De Giorgi.
      BRCA1 and BRCA2 are the most frequently mutated genes in ovarian cancer (OC) crucial both for the identification of cancer predisposition and therapeutic choices. However, germline variants in other genes could be involved in OC susceptibility. We characterized OC patients to detect mutations in genes other than BRCA1/2 that could be associated with a high risk of developing OC and permit patients to enter the most appropriate treatment and surveillance program. Next-generation sequencing analysis with a 94-gene panel was performed on germline DNA of 219 OC patients. We identified 34 pathogenic/likely pathogenic variants in BRCA1/2 and 38 in other 21 genes. The patients with pathogenic/likely pathogenic variants in the non-BRCA1/2 genes mainly developed OC alone compared to the other groups that also developed breast cancer or other tumors (p = 0.001). Clinical correlation analysis showed that the low-risk patients were significantly associated with platinum sensitivity (p &lt; 0.001). Regarding PARP inhibitors (PARPi) response, the patients with pathogenic mutations in the non-BRCA1/2 genes had worse PFS and OS. Moreover, a statistically significantly worse PFS was found for every increase of one thousand platelets before PARPi treatment. To conclude, knowledge about molecular alterations in genes beyond BRCA1/2 in OC could allow for more personalized diagnostic, predictive, prognostic, and therapeutic strategies for OC patients.
    Keywords:  BRCA1/2; PARP inhibitors; cancer predisposition; ovarian cancer; platelets; platinum sensitivity
    DOI:  https://doi.org/10.3390/ijms232415789
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