bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022–07–31
fourteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Distinct NSCLC EGFR Variants in a Family With Li-Fraumeni Syndrome: Case Report.
  2. Beyond Pathogenic RUNX1 Germline Variants: The Spectrum of Somatic Alterations in RUNX1-Familial Platelet Disorder with Predisposition to Hematologic Malignancies.
  3. Clinical and immunophenotypic characteristics of familial leukemia predisposition caused by PAX5 germline variants.
  4. Novel Germline Mutations in a Cohort of Men with Familial Prostate Cancer.
  5. Intraductal Papillary Mucinous Neoplasms in Hereditary Cancer Syndromes.
  6. Germline Testing in a Cohort of Patients at High Risk of Hereditary Cancer Predisposition Syndromes: First Two-Year Results from South Italy.
  7. Impact of comprehensive family history and genetic analysis in the multidisciplinary pancreatic tumor clinic setting.
  8. Clinical implications of genetic testing in familial intermediate and late-onset colorectal cancer.
  9. Hereditary Diffuse Gastric Cancer: Molecular Genetics, Biological Mechanisms and Current Therapeutic Approaches.
  10. CDH1 mutations recurrence and global clustering in genetically tested families with hereditary diffuse gastric cancer syndrome: results from a systematic study.
  11. Significance of the Multi-gene Panel myRisk in Japan.
  12. Unravelling genetic variants of a swedish family with high risk of prostate cancer.
  13. Influence of germline BRCA genotype on the survival of patients with triple-negative breast cancer.
  14. Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas.
  1. JTO Clin Res Rep. 2022 Aug;3(8): 100368
    Distinct NSCLC EGFR Variants in a Family With Li-Fraumeni Syndrome: Case Report.
    Shelby Edmondson, Mitchell S von Itzstein, Brian Reys, Melissa Mayer, Jeffrey Gagan, David E Gerber.
       Introduction: Heritable lung cancer may occur in the context of germline TP53 mutations (Li-Fraumeni syndrome). Limited cases of intrafamily tumor genomic characteristics have been reported.
    Main concerns Important Clinical Findings Primary Diagnoses Interventions Outcomes: A 40-year-old woman with no smoking history or known environmental exposure risk was incidentally found to have stage II (T2N1) NSCLC harboring an EGFR exon 19 p.Glu746_Ala750 deletion. Family history was notable for an identical twin sister with colorectal cancer (diagnosed at age 31 y) and a mother with stage I NSCLC harboring an EGFR exon 21 c.2573T>G (p.Leu858Arg) mutation (diagnosed at age 69 y). Genetic testing revealed a germline TP53 c.542G>A (p.Arg181His) mutation in the patient, her mother, and her sister, consistent with Li-Fraumeni syndrome. No germline EGFR mutations were detected.
    Conclusion: Shared germline TP53 mutations may be associated with distinct NSCLC somatic EGFR mutations within families with Li-Fraumeni syndrome. Further understanding of the association between genetic cancer syndromes and lung cancer risk may improve early lung cancer detection in populations not otherwise meeting screening eligibility.
    Keywords:  Case report; Epidermal growth factor receptor; Genetics; Inherited; Lung cancer
    DOI:  https://doi.org/10.1016/j.jtocrr.2022.100368
  2. Cancers (Basel). 2022 Jul 14. pii: 3431. [Epub ahead of print]14(14):
    Beyond Pathogenic RUNX1 Germline Variants: The Spectrum of Somatic Alterations in RUNX1-Familial Platelet Disorder with Predisposition to Hematologic Malignancies.
    Alisa Förster, Melanie Decker, Brigitte Schlegelberger, Tim Ripperger.
      Pathogenic loss-of-function RUNX1 germline variants cause autosomal dominantly-inherited familial platelet disorder with predisposition to hematologic malignancies (RUNX1-FPD). RUNX1-FPD is characterized by incomplete penetrance and a broad spectrum of clinical phenotypes, even within affected families. Heterozygous RUNX1 germline variants set the basis for leukemogenesis, but, on their own, they are not transformation-sufficient. Somatically acquired secondary events targeting RUNX1 and/or other hematologic malignancy-associated genes finally lead to MDS, AML, and rarely other hematologic malignancies including lymphoid diseases. The acquisition of different somatic variants is a possible explanation for the variable penetrance and clinical heterogeneity seen in RUNX1-FPD. However, individual effects of secondary variants are not yet fully understood. Here, we review 91 cases of RUNX1-FPD patients who predominantly harbor somatic variants in genes such as RUNX1, TET2, ASXL1, BCOR, PHF6, SRSF2, NRAS, and DNMT3A. These cases illustrate the importance of secondary events in the development and progression of RUNX1-FPD-associated hematologic malignancies. The leukemia-driving interplay of predisposing germline variants and acquired variants remain to be elucidated to better understand clonal evolution and malignant transformation and finally allow risk-adapted surveillance and targeted therapeutic measures to prevent leukemia.
    Keywords:  RUNX1 germline variants; RUNX1-FPD; hematologic malignancies; leukemia predisposition; somatic mutations
    DOI:  https://doi.org/10.3390/cancers14143431
  3. Leukemia. 2022 Jul 28.
    Clinical and immunophenotypic characteristics of familial leukemia predisposition caused by PAX5 germline variants.
    Adela Escudero, Masatoshi Takagi, Franziska Auer, Ulrike Anne Friedrich, Satoshi Miyamoto, Atsushi Ogawa, Kohsuke Imai, Barbara Pascual, María Vela, Polina Stepensky, Layal Yasin, Sarah Elitzur, Arndt Borkhardt, Antonio Pérez-Martínez, Julia Hauer.
      
    DOI:  https://doi.org/10.1038/s41375-022-01661-7
  4. Cancers (Basel). 2022 Jul 26. pii: 3623. [Epub ahead of print]14(15):
    Novel Germline Mutations in a Cohort of Men with Familial Prostate Cancer.
    Romy Mondschein, Damien Bolton, David Clouston, James Dowty, Liam Kavanagh, Declan Murphy, Prudence Scott, Renea A Taylor, Heather Thorne.
      Background: Germline mutations in BRCA2 are associated with aggressive prostate cancer. Additional information regarding the clinical phenotype of germline pathogenic variants in other prostate cancer predisposition genes is required. Clinical testing has been limited by evidence, further restricting knowledge of variants that contribute to prostate cancer development. Objective: Prostate cancer patients who were first- and second-degree relatives from multi-case prostate cancer families underwent a gene panel screen to identify novel (non-BRCA) germline pathogenic variants in cancer predisposition genes and define clinical phenotypes associated with each gene. Methods: The germline genomic DNA (gDNA) of 94 index cases with verified prostate cancer from families with a minimum of two verified prostate cancer cases was screened with an 84-cancer-gene panel. Families were recruited for multi-case breast/ovarian cancer (n = 66), or multi-case prostate cancer (n = 28). Prostate cancer characteristics associated with each gene were compared with prostate cancer cases of confirmed non-mutation carriers (BRCAX), also from multi-case prostate cancer families (n = 111), and with data from the Prostate Cancer Outcomes Registry (PCOR). Results: Ninety-four prostate cancer index cases underwent gene panel testing; twenty-two index cases (22/94; 23%) were found to carry a class 4-5 (C4/5) variant. Six of twenty-two (27%) variants were not clinically notifiable, and seven of twenty-two (31.8%) variants were in BRCA1/2 genes. Nine of twenty-two (40.9%) index cases had variants identified in ATM (n = 4), CHEK2 (n = 2) and HOXB13G84 (n = 3); gDNA for all relatives of these nine cases was screened for the corresponding familial variant. The final cohort comprised 15 confirmed germline mutation carriers with prostate cancer (ATM n = 9, CHEK2 n = 2, HOXB13G84 n = 4). ATM and CHEK2-associated cancers were D'Amico intermediate or high risk, comparable to our previously published BRCA2 and BRCAX prostate cancer cohort. HOXB13G84 carriers demonstrated low- to intermediate-risk prostate cancer. In the BRCAX cohort, 53.2% of subjects demonstrated high-risk disease compared with 25% of the PCOR cohort. Conclusions:ATM and CHEK2 germline mutation carriers and the BRCAX (confirmed non-mutation carriers) cohort demonstrated high risk disease compared with the general population. Targeted genetic testing will help identify men at greater risk of prostate-cancer-specific mortality. Data correlating rare variants with clinical phenotype and familial predisposition will strengthen the clinical validity and utility of these results and establish these variants as significant in prostate cancer detection and management.
    Keywords:  germline; hereditary; mutations; pathogenic variants; prostate cancer
    DOI:  https://doi.org/10.3390/cancers14153623
  5. Biomedicines. 2022 Jun 22. pii: 1475. [Epub ahead of print]10(7):
    Intraductal Papillary Mucinous Neoplasms in Hereditary Cancer Syndromes.
    Devarshi R Ardeshna, Shiva Rangwani, Troy Cao, Timothy M Pawlik, Peter P Stanich, Somashekar G Krishna.
      Hereditary pancreatic cancer, which includes patients with familial pancreatic cancer (FPC) and hereditary pancreatic cancer syndromes, accounts for about 10% of all pancreatic cancer diagnoses. The early detection of pre-cancerous pancreatic cysts has increasingly become a focus of interest in recent years as a potential avenue to lower pancreatic cancer incidence and mortality. Intraductal papillary mucinous cystic neoplasms (IPMNs) are recognized precursor lesions of pancreatic cancer. IPMNs have high prevalence in patients with hereditary pancreatic cancer and their relatives. While various somatic mutations have been identified in IPMNs, certain germline mutations associated with hereditary cancer syndromes have also been identified in IPMNs, suggesting a role in their formation. While the significance for the higher prevalence of IPMNs or similar germline mutations in these high-risk patients remain unclear, IPMNs do represent pre-malignant lesions that need close surveillance. This review summarizes the available literature on the incidence and prevalence of IPMNs in inherited genetic predisposition syndromes and FPC and speculates if IPMN and pancreatic cancer surveillance in these high-risk individuals needs to change.
    Keywords:  familial pancreatic cancer; hereditary cancer syndromes; hereditary intraductal papillary mucinous neoplasms; intraductal papillary mucinous neoplasms; pancreatic cancer screening; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.3390/biomedicines10071475
  6. Genes (Basel). 2022 Jul 21. pii: 1286. [Epub ahead of print]13(7):
    Germline Testing in a Cohort of Patients at High Risk of Hereditary Cancer Predisposition Syndromes: First Two-Year Results from South Italy.
    Francesco Paduano, Emma Colao, Fernanda Fabiani, Valentina Rocca, Francesca Dinatolo, Adele Dattola, Lucia D'Antona, Rosario Amato, Francesco Trapasso, Francesco Baudi, Nicola Perrotti, Rodolfo Iuliano.
      Germline pathogenic variants (PVs) in oncogenes and tumour suppressor genes are responsible for 5 to 10% of all diagnosed cancers, which are commonly known as hereditary cancer predisposition syndromes (HCPS). A total of 104 individuals at high risk of HCPS were selected by genetic counselling for genetic testing in the past 2 years. Most of them were subjects having a personal and family history of breast cancer (BC) selected according to current established criteria. Genes analysis involved in HCPS was assessed by next-generation sequencing (NGS) using a custom cancer panel with high- and moderate-risk susceptibility genes. Germline PVs were identified in 17 of 104 individuals (16.3%) analysed, while variants of uncertain significance (VUS) were identified in 21/104 (20.2%) cases. Concerning the germline PVs distribution among the 13 BC individuals with positive findings, 8/13 (61.5%) were in the BRCA1/2 genes, whereas 5/13 (38.4%) were in other high- or moderate-risk genes including PALB2, TP53, ATM and CHEK2. NGS genetic testing showed that 6/13 (46.1%) of the PVs observed in BC patients were detected in triple-negative BC. Interestingly, the likelihood of carrying the PVs in the moderate-to-high-risk genes calculated by the cancer risk model BOADICEA was significantly higher in pathogenic variant carriers than in negative subjects. Collectively, this study shows that multigene panel testing can offer an effective diagnostic approach for patients at high risk of hereditary cancers.
    Keywords:  breast and ovarian analysis of disease incidence and carrier estimation algorithm (BOADICEA); breast cancer (BC); genetic testing; hereditary cancer predisposition syndromes (HCPS); next-generation sequencing (NGS); pathogenic variants (PVs)
    DOI:  https://doi.org/10.3390/genes13071286
  7. Cancer Med. 2022 Jul 30.
    Impact of comprehensive family history and genetic analysis in the multidisciplinary pancreatic tumor clinic setting.
    Jessica N Everett, Shenin A Dettwyler, Xiaohong Jing, Cody Stender, Madeleine Schmitter, Ariele Baptiste, Jennifer Chun, Emily A Kawaler, Lauren G Khanna, Seth A Gross, Tamas A Gonda, Nina Beri, Paul E Oberstein, Diane M Simeone.
       BACKGROUND: Genetic testing is recommended for all pancreatic ductal adenocarcinoma (PDAC) patients. Prior research demonstrates that multidisciplinary pancreatic cancer clinics (MDPCs) improve treatment- and survival-related outcomes for PDAC patients. However, limited information exists regarding the utility of integrated genetics in the MDPC setting. We hypothesized that incorporating genetics in an MDPC serving both PDAC patients and high-risk individuals (HRI) could: (1) improve compliance with guideline-based genetic testing for PDAC patients, and (2) optimize HRI identification and PDAC surveillance participation to improve early detection and survival.
    METHODS: Demographics, genetic testing results, and pedigrees were reviewed for PDAC patients and HRI at one institution over 45 months. Genetic testing analyzed 16 PDAC-associated genes at minimum.
    RESULTS: Overall, 969 MDPC subjects were evaluated during the study period; another 56 PDAC patients were seen outside the MDPC. Among 425 MDPC PDAC patients, 333 (78.4%) completed genetic testing; 29 (8.7%) carried a PDAC-related pathogenic germline variant (PGV). Additionally, 32 (9.6%) met familial pancreatic cancer (FPC) criteria. These PDAC patients had 191 relatives eligible for surveillance or genetic testing. Only 2/56 (3.6%) non-MDPC PDAC patients completed genetic testing (p < 0.01). Among 544 HRI, 253 (46.5%) had a known PGV or a designation of FPC, and were eligible for surveillance at baseline; of the remainder, 15/291 (5.2%) were eligible following genetic testing and PGV identification.
    CONCLUSION: Integrating genetics into the multidisciplinary setting significantly improved genetic testing compliance by reducing logistical barriers for PDAC patients, and clarified cancer risks for their relatives while conserving clinical resources. Overall, we identified 206 individuals newly eligible for surveillance or genetic testing (191 relatives of MDPC PDAC patients, and 15 HRI from this cohort), enabling continuity of care for PDAC patients and at-risk relatives in one clinic.
    Keywords:  family history; genetic counseling; genetic testing; germline variants; multidisciplinary care; pancreatic cancer
    DOI:  https://doi.org/10.1002/cam4.5059
  8. Hum Genet. 2022 Jul 29.
    Clinical implications of genetic testing in familial intermediate and late-onset colorectal cancer.
    Malene Djursby, Thomas van Overeem Hansen, Karin A W Wadt, Majbritt Busk Madsen, Lukas Adrian Berchtold, Charlotte Kvist Lautrup, Sara Markholt, Uffe Birk Jensen, Lotte Nylandsted Krogh, Malene Lundsgaard, Anne Marie Gerdes, Mef Nilbert, Christina Therkildsen.
      The genetic background of familial, late-onset colorectal cancer (CRC) (i.e., onset > age 50 years) has not been studied as thoroughly as other subgroups of familial CRC, and the proportion of families with a germline genetic predisposition to CRC remains to be defined. To define the contribution of known or suggested CRC predisposition genes to familial late-onset CRC, we analyzed 32 well-established or candidate CRC predisposition genes in 75 families with late-onset CRC. We identified pathogenic or likely pathogenic variants in five patients in MSH6 (n = 1), MUTYH (monoallelic; n = 2) and NTHL1 (monoallelic; n = 2). In addition, we identified a number of variants of unknown significance in particular in the lower penetrant Lynch syndrome-associated mismatch repair (MMR) gene MSH6 (n = 6). In conclusion, screening using a comprehensive cancer gene panel in families with accumulation of late-onset CRC appears not to have a significant clinical value due to the low level of high-risk pathogenic variants detected. Our data suggest that only patients with abnormal MMR immunohistochemistry (IHC) or microsatellite instability (MSI) analyses, suggestive of Lynch syndrome, or a family history indicating another cancer predisposition syndrome should be prioritized for such genetic evaluations. Variants in MSH6 and MUTYH have previously been proposed to be involved in digenic or oligogenic hereditary predisposition to CRC. Accumulation of variants in MSH6 and monoallelic, pathogenic variants in MUTYH in our study indicates that digenic or oligogenic inheritance might be involved in late-onset CRC and warrants further studies of complex types of inheritance.
    DOI:  https://doi.org/10.1007/s00439-022-02470-9
  9. Int J Mol Sci. 2022 Jul 15. pii: 7821. [Epub ahead of print]23(14):
    Hereditary Diffuse Gastric Cancer: Molecular Genetics, Biological Mechanisms and Current Therapeutic Approaches.
    Lidia-Sabina Cosma, Sophie Schlosser, Hauke C Tews, Martina Müller, Arne Kandulski.
      Hereditary diffuse gastric cancer is an autosomal dominant syndrome characterized by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is caused by inactivating mutations in the tumor suppressor gene CDH1. Genetic testing technologies have become more efficient over the years, also enabling the discovery of other susceptibility genes for gastric cancer, such as CTNNA1 among the most important genes. The diagnosis of pathogenic variant carriers with an increased risk of developing gastric cancer is a selection process involving a multidisciplinary team. To achieve optimal long-term results, it requires shared decision-making in risk management. In this review, we present a synopsis of the molecular changes and current therapeutic approaches in HDGC based on the current literature.
    Keywords:  CDH1 germline mutation; CTNNA1 mutation; hereditary diffuse gastric cancer (HDGC); molecular genetics
    DOI:  https://doi.org/10.3390/ijms23147821
  10. Fam Cancer. 2022 Jul 27.
    CDH1 mutations recurrence and global clustering in genetically tested families with hereditary diffuse gastric cancer syndrome: results from a systematic study.
    Giovanni Corso, Valentina Tagliaferri, Giulia Massari, Antonio Cioffi, Elisabetta Maria Cristina Rossi, Paolo Veronesi, Francesca Magnoni.
      The global distribution of germline CDH1 mutations in hereditary diffuse gastric cancer families, is highly heterogenous. The aim of this study was to determine if there is any geographic clustering of CDH1 mutations in families with the hereditary diffuse gastric cancer syndrome. Data from 1998 to 2021 were collected systematically according to the PRISMA guidelines. 571 germline CDH1 mutations were recorded worldwide, with 387 (67.8%) of them reported in 108 families. The largest clusters of CDH1 mutations were identified in central Europe, north America, northern Europe, New Zealand (Māori), and south America. A high penetrance risk for GC development was observed for c.1008G > T in New Zealand (Māori), c.1565 + 2insT in northern Europe, c.1901C > T in Portugal, and c.1003C > T in the USA. Our observations are consistent with a specific local clustering of some recurrent CDH1 mutations within specific countries.
    Keywords:  E-cadherin germline mutation; Global cancer distribution; Hereditary diffuse gastric cancer
    DOI:  https://doi.org/10.1007/s10689-022-00309-w
  11. Anticancer Res. 2022 Aug;42(8): 4097-4102
    Significance of the Multi-gene Panel myRisk in Japan.
    Saori Hayashi, Makoto Kubo, Sawako Matsuzaki, Masaya Kai, Takafumi Morisaki, Mai Yamada, Kazuhisa Kaneshiro, Yuka Takao, Akiko Shimazaki, Kinuko Nagayoshi, Yusuke Mizuuchi, Masafumi Nakamura.
       BACKGROUND/AIM: Hereditary tumors are estimated to account for approximately 5-10% of all tumors. In Europe and the United States, multi-gene panel testing (MGPT) is the standard method used for identifying potential causative genes. However, MGPT it is still not widely used in Japan. The aim of this study was to assess the risk of hereditary tumors in Japanese cancer patients using germline MGPT and provide an overview of MGPT in the Japanese medical system.
    PATIENTS AND METHODS: We used the myRiskTM, a 35-gene panel that determines the risk for eight hereditary cancers: breast, ovarian, gastric, colorectal, prostate, pancreatic, malignant melanoma, and endometrial cancers.
    RESULTS: From June 2019 to March 2020, 21 patients who were suspected to have hereditary tumors were included, based on their family or medical history. Pathogenic variants were found in 7 patients [BRCA1 (5), MSH6 (1), TP 53 (1)].
    CONCLUSION: In this study, despite the small number of participants, we were able to show the significance of MGPT in Japan. Therefore, MGPT should be used for evaluating hereditary tumors in clinical practice.
    Keywords:  Hereditary cancer; genetic medicine; genetic testing; multigene panel testing; risk reduction
    DOI:  https://doi.org/10.21873/anticanres.15907
  12. Hered Cancer Clin Pract. 2022 Jul 23. 20(1): 28
    Unravelling genetic variants of a swedish family with high risk of prostate cancer.
    Serena Barilla, Annika Lindblom, Hafdis T Helgadottir.
       BACKGROUND: Prostate cancer is the most prevalent cancer in men worldwide. It is a polygenic disease with a substantial proportion of heritability. Identification of novel candidate biomarkers is crucial for clinical cancer prevention and the development of therapeutic strategies. Here, we describe the analysis of rare and common genetic variants that can predispose to the development of prostate cancer.
    METHODS: Whole-genome sequencing was performed on germline DNA of five Swedish siblings which were diagnosed with prostate cancer. The high-risk variants were identified setting the minor allele frequency < 0.01, CADD > 10 and if tested in PRACTICAL, OR > 1.5, while the low-risk variants were identified minor allele frequency > 0.01, CADD > 10 and if tested in PRACTICAL, OR > 1.1.
    RESULTS: We identified 38 candidate high-risk gene variants and 332 candidate low-risk gene variants, where 2 and 14 variants were in coding regions, respectively, that were shared by the brothers with prostate cancer.
    CONCLUSIONS: This study expanded the knowledge of potential risk factor candidates involved in hereditary and familial prostate cancer. Our findings can be beneficial when applying targeted screening in families with a high risk of developing the disease.
    Keywords:  Germline; Hereditary; Prostate cancer; Whole-genome sequencing
    DOI:  https://doi.org/10.1186/s13053-022-00234-0
  13. Cancer Res Commun. 2021 Dec;1(3): 140-147
    Influence of germline BRCA genotype on the survival of patients with triple-negative breast cancer.
    Cynthia Villarreal-Garza, Ana S Ferrigno, Alejandro Aranda-Gutierrez, Paul H Frankel, Nora H Ruel, Alan Fonseca, Steven Narod, Yanin Chavarri-Guerra, Erika Sifuentes, Maria Cristina Magallanes-Hoyos, Josef Herzog, Danielle Castillo, Rosa M Alvarez-Gomez, Alejandro Mohar-Betancourt, Jeffrey N Weitzel.
      The presence of BRCA pathogenic variants (PVs) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with BRCA PVs can develop treatment resistance through the appearance of reversion mutations and restored BRCA expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of BRCA CNVs may have improved survival after treatment compared to carriers of other BRCA PVs or BRCA wild-type. Women diagnosed with stage I-III TNBC at ≤50 years at a cancer center in Mexico City were screened for BRCA PVs using a recurrent PV assay (HISPANEL; 77% sensitivity). The recurrence-free (RFS) and overall survival (OS) were compared according to mutational status. Among 180 women, 17 (9%) were carriers of BRCA1 ex9-12del CNV and 26 (14%) of other BRCA PVs. RFS at ten years for the whole cohort was 79.2% (95% CI 72.3-84.6%), with no significant differences according to mutational status. 10-year OS for the entire cohort was 85.3% (95%CI: 78.7-90.0%), with BRCA CNV carriers demonstrating numerically superior OS rates other PV carriers and non-carriers (100% vs. 78.6% and 84.7%; log-rank p=0.037 and p=0.051, respectively). This study suggests that BRCA1 ex9-12del CNV carriers with TNBC may have a better OS, and supports the hypothesis that the genotype of BRCA PVs may influence survival by limiting treatment resistance mediated by reversion mutations among CNV carriers.
    Keywords:  BRCA; breast cancer; germline mutation; premenopausal; survival; triple-negative; young women
    DOI:  https://doi.org/10.1158/2767-9764.crc-21-0099
  14. Cancers (Basel). 2022 Jul 12. pii: 3388. [Epub ahead of print]14(14):
    Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas.
    Adam Szpechcinski, Malgorzata Szolkowska, Sebastian Winiarski, Urszula Lechowicz, Piotr Wisniewski, Magdalena Knetki-Wroblewska.
      A better understanding of the molecular pathogenesis of thymic epithelial tumours (TETs) could revolutionise their treatment. We evaluated thymomas and thymic carcinomas by next-generation sequencing (NGS) of somatic or germline single nucleotide variants (SNVs) in genes commonly mutated in solid tumours. In total, 19 thymomas and 34 thymic carcinomas were analysed for nonsynonymous SNVs in 15 genes by targeted NGS (reference genome: hg19/GRCh37). Ten SNVs in TP53 (G154V, R158P, L194H, R267fs, R273C, R306 *, Q317 *), ERBB2 (V773M), KIT (L576P), and KRAS (Q61L) considered somatic and pathogenic/likely pathogenic were detected in 10 of 34 (29.4%) thymic carcinomas. No somatic SNVs confirmed as pathogenic/likely pathogenic were found in thymomas. Rare SNVs of uncertain or unknown functional and clinical significance, to our knowledge not reported previously in TETs, were found in ERBB2 (S703R), KIT (I690V), and FOXL2 (P157S) in 3 of 19 (16%) thymomas. The most frequent germline SNVs were TP53 P72R (94% TETs), ERBB2 I655V (40% TETs), and KIT M541L (9% TETs). No significant difference in median disease-free survival (DFS) was found between thymic carcinoma patients with and without pathogenic SNVs (p = 0.190); however, a trend toward a longer DFS was observed in the latter (16.0 vs. 30.0 months, respectively). In summary, NGS analysis of TETs revealed several SNVs in genes related to the p53, AKT, MAPK, and K-Ras signalling pathways. Thymic carcinomas showed greater genetic dysregulation than thymomas. The germline and rare SNVs of uncertain clinical significance reported in this study add to the number of known genetic alterations in TETs, thus extending our molecular understanding of these neoplasms. Druggable KIT alterations in thymic carcinomas have potential as therapeutic targets.
    Keywords:  ERBB2; KIT; TP53; germline variants; next-generation sequencing; single nucleotide variants; somatic variants; thymic carcinoma; thymic epithelial tumours; thymoma
    DOI:  https://doi.org/10.3390/cancers14143388
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