bims-lifras 2021-06-20 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021‒06‒20
nine papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

Implications of ACMG guidelines to identify high-risk acute lymphoblastic leukemia patients with hereditary cancer susceptibility syndromes (HCSS) in a highly consanguineous population.
Therapeutic Implications of Germline Testing in Patients With Advanced Cancers.
Recent advances in Lynch syndrome.
Pancreas in Hereditary Syndromes: Cross-sectional Imaging Spectrum.
Impact of changing guidelines on genetic testing and surveillance recommendations in a contemporary cohort of breast cancer survivors with family history of pancreatic cancer.
A novel BRCA1 duplication and new insights on the spectrum and frequency of germline large genomic rearrangements in BRCA1/BRCA2.
A Direct Comparison of Patients With Hereditary and Sporadic Pancreatic Neuroendocrine Tumors: Evaluation of Clinical Course, Prognostic Factors and Genotype-Phenotype Correlations.
A hereditary ovarian cancer family with rare pathogenic splicing mutation: Implications for variant interpretation.
In vitro assessment of the sensitivity to APR-246 + azacitidine combination predicts response to this combination in myelodysplastic/acute myeloid leukaemia patients.

BMC Pediatr. 2021 Jun 16. 21(1): 282

Implications of ACMG guidelines to identify high-risk acute lymphoblastic leukemia patients with hereditary cancer susceptibility syndromes (HCSS) in a highly consanguineous population.

Sara Aslam, Shabana, Mehboob Ahmed.

  BACKGROUND: Hereditary cancer susceptibility syndrome (HCSS) contributes to the cancer predisposition at an early age, therefore, identification of HCSS has found to be crucial for surveillance, managing therapeutic interventions and refer the patients and their families for genetic counselling. The study aimed to identify ALL patients who meet the American College of Medical Genetics (ACMG) criteria and refer them for the genetic testing for HCSS as hereditary leukemia and hematologic malignancy syndrome, and to elucidate the significance of high consanguinity with the prevalence of inherited leukemia in Pakistani population.METHODS: A total of 300 acute lymphoblastic leukemia patients were recruited from the Children's Hospital, Lahore, Pakistan from December 2018 to September 2019. A structured self-reporting questionnaire based on family and medical history of the disease was utilized for the data collection.
RESULTS: In our cohort, 60.40% of ALL patients were identified to meet ACMG criteria. Among them, a large number of patients (40.65%) solely fulfil the criteria due to the presence of parental consanguinity. However, parental consanguinity showed protective impact on the onset at early age of disease [OD = 0.44 (0.25-0.77), p-value = 0.00] while, a family history of cancer increased the risk of cardiotoxicity [OD = 2.46 (1.15-5.24), p-value = 0.02]. Parental consanguinity shows no significant impact on the family history of cancer and the number of relatives with cancer.
CONCLUSIONS: More than 50% of the ALL patients were considered the strong candidates' for genetic testing of HCSS in the Pakistani population, and parental consanguinity was the leading criteria fulfilled by the individuals when assessed through ACMG guidelines. Our study suggests revisiting ACMG guidelines, especially for the criterion of parental consanguinity, and formulating the score based criteria based on; genetic research, the toxicology profile, physical features, personal and family history of cancer for the identification of patients for the genetic testing.

Keywords:  ACMG guidelines; Acute lymphoblastic leukemia (ALL); Consanguinity; Hereditary cancer susceptibility syndrome (HCSS); Risk assessment

DOI:  https://doi.org/10.1186/s12887-021-02749-2
J Clin Oncol. 2021 Jun 16. JCO2003661

Therapeutic Implications of Germline Testing in Patients With Advanced Cancers.

Zsofia K Stadler, Anna Maio, Debyani Chakravarty, Yelena Kemel, Margaret Sheehan, Erin Salo-Mullen, Kaitlyn Tkachuk, Christopher J Fong, Bastien Nguyen, Amanda Erakky, Karen Cadoo, Ying Liu, Maria I Carlo, Alicia Latham, Hongxin Zhang, Ritika Kundra, Shaleigh Smith, Jesse Galle, Carol Aghajanian, Nadeem Abu-Rustum, Anna Varghese, Eileen M O'Reilly, Michael Morris, Wassim Abida, Michael Walsh, Alexander Drilon, Gowtham Jayakumaran, Ahmet Zehir, Marc Ladanyi, Ozge Ceyhan-Birsoy, David B Solit, Nikolaus Schultz, Michael F Berger, Diana Mandelker, Luis A Diaz, Kenneth Offit, Mark E Robson.

PURPOSE: Tumor mutational profiling is increasingly performed in patients with advanced cancer. We determined the extent to which germline mutation profiling guides therapy selection in patients with advanced cancer.METHODS: Patients with cancer undergoing tumor genomic profiling were prospectively consented for germline cancer predisposition gene analysis (2015-2019). In patients harboring germline likely pathogenic or pathogenic (LP/P) alterations, therapeutic actionability was classified using a precision oncology knowledge base. Patients with metastatic or recurrent cancer receiving germline genotype-directed therapy were determined.
RESULTS: Among 11,947 patients across > 50 malignancies, 17% (n = 2,037) harbored a germline LP/P variant. By oncology knowledge base classification, 9% (n = 1042) had an LP/P variant in a gene with therapeutic implications (4% level 1; 4% level 3B; < 1% level 4). BRCA1/2 variants accounted for 42% of therapeutically actionable findings, followed by CHEK2 (13%), ATM (12%), mismatch repair genes (11%), and PALB2 (5%). When limited to the 9,079 patients with metastatic or recurrent cancer, 8% (n = 710) harbored level 1 or 3B genetic findings and 3.2% (n = 289) received germline genotype-directed therapy. Germline genotype-directed therapy was received by 61% and 18% of metastatic cancer patients with level 1 and level 3B findings, respectively, and by 54% of BRCA1/2, 75% of mismatch repair, 43% of PALB2, 35% of RAD51C/D, 24% of BRIP1, and 19% of ATM carriers. Of BRCA1/2 patients receiving a poly(ADP-ribose) polymerase inhibitor, 45% (84 of 188) had tumors other than breast or ovarian cancer, wherein the drug, at time of delivery, was delivered in an investigational setting.
CONCLUSION: In a pan-cancer analysis, 8% of patients with advanced cancer harbored a germline variant with therapeutic actionability with 40% of these patients receiving germline genotype-directed treatment. Germline sequence analysis is additive to tumor sequence analysis for therapy selection and should be considered for all patients with advanced cancer.

DOI: https://doi.org/10.1200/JCO.20.03661
Exp Hematol Oncol. 2021 Jun 12. 10(1): 37

Recent advances in Lynch syndrome.

Xi Li, Guodong Liu, Wei Wu.

  Lynch syndrome is one of the most common hereditary cancer syndromes and is characterized by the development of many cancers, such as colorectal cancer (CRC), endometrial cancer, ovarian cancer, stomach cancer and many other cancers. Lynch syndrome is caused by pathogenic germline variants in one of four DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) or by an EPCAM deletion. The MLH1 variant is correlated with the highest risk of CRC, while the MSH2 variant is correlated with the highest risk of other cancers. CRC is the most common cancer type that develops in individuals with Lynch syndrome, followed by endometrial cancer. Recent advances have been made to help us further understand the molecular pathogenesis of this disease and help improve diagnostic testing efficiency and surveillance strategies. Moreover, recent advances in immunotherapy provided by clinical trials also provide clinicians with more chances to better treat Lynch syndrome. This study aims to review many advances in the molecular genetics, clinical features, diagnosis, surveillance and treatment of Lynch syndrome.

Keywords:  Colorectal cancer; DNA mismatch repair; Endometrial cancer; Immunotherapy; Lynch syndrome

DOI:  https://doi.org/10.1186/s40164-021-00231-4
Radiographics. 2021 Jun 18. 200164

Pancreas in Hereditary Syndromes: Cross-sectional Imaging Spectrum.

Venkata S Katabathina, Suryakala Buddha, Hamid Rajebi, Jignesh N Shah, Ajay C Morani, Meghan G Lubner, Anil Dasyam, Alia Nazarullah, Christine O Menias, Srinivasa R Prasad.

A wide spectrum of hereditary syndromes predispose patients to distinct pancreatic abnormalities, including cystic lesions, recurrent pancreatitis, ductal adenocarcinoma, nonductal neoplasms, and parenchymal iron deposition. While pancreatic exocrine insufficiency and recurrent pancreatitis are common manifestations in cystic fibrosis and hereditary pancreatitis, pancreatic cysts are seen in von Hippel-Lindau disease, cystic fibrosis, autosomal dominant polycystic kidney disease, and McCune-Albright syndrome. Ductal adenocarcinoma can be seen in many syndromes, including Peutz-Jeghers syndrome, familial atypical multiple mole melanoma syndrome, Lynch syndrome, hereditary breast and ovarian cancer syndrome, Li-Fraumeni syndrome, and familial pancreatic cancer syndrome. Neuroendocrine tumors are commonly seen in multiple endocrine neoplasia type 1 syndrome and von Hippel-Lindau disease. Pancreatoblastoma is an essential component of Beckwith-Wiedemann syndrome. Primary hemochromatosis is characterized by pancreatic iron deposition. Pancreatic pathologic conditions associated with genetic syndromes exhibit characteristic imaging findings. Imaging plays a pivotal role in early detection of these conditions and can positively affect the clinical outcomes of those at risk for pancreatic malignancies. Awareness of the characteristic imaging features, imaging-based screening protocols, and surveillance guidelines is crucial for radiologists to guide appropriate patient management. ©RSNA, 2021.

DOI: https://doi.org/10.1148/rg.2021200164
Sci Rep. 2021 Jun 14. 11(1): 12491

Impact of changing guidelines on genetic testing and surveillance recommendations in a contemporary cohort of breast cancer survivors with family history of pancreatic cancer.

Annie Wang, Jessica N Everett, Jennifer Chun, Cindy Cen, Diane M Simeone, Freya Schnabel.

Changing practice guidelines and recommendations have important implications for cancer survivors. This study investigated genetic testing patterns and outcomes and reported family history of pancreatic cancer (FHPC) in a large registry population of breast cancer (BC) patients. Variables including clinical and demographic characteristics, FHPC in a first or second-degree relative, and genetic testing outcomes were analyzed for BC patients diagnosed between 2010 and 2018 in the NYU Langone Health Breast Cancer Database. Among 3334 BC patients, 232 (7%) had a positive FHPC. BC patients with FHPC were 1.68 times more likely to have undergone genetic testing (p < 0.001), but 33% had testing for BRCA1/2 only and 44% had no genetic testing. Pathogenic germline variants (PGV) were identified in 15/129 (11.6%) BC patients with FHPC, and in 145/1315 (11.0%) BC patients without FHPC. Across both groups, updates in genetic testing criteria and recommendations could impact up to 80% of this cohort. Within a contemporary cohort of BC patients, 7% had a positive FHPC. The majority of these patients (56%) had no genetic testing, or incomplete testing by current standards, suggesting under-diagnosis of PC risk. This study supports recommendations for survivorship care that incorporate ongoing genetic risk assessment and counseling.

DOI: https://doi.org/10.1038/s41598-021-91971-0
Mol Biol Rep. 2021 Jun 19.

A novel BRCA1 duplication and new insights on the spectrum and frequency of germline large genomic rearrangements in BRCA1/BRCA2.

Ibrahim Sahin, Hanife Saat.

  Heritable breast cancers account for 5% to 10% of all breast cancers, and monogenic, highly penetrant genes cause them. Around 90% of pathogenic variants in BRCA1 and BRCA2 are observed using gene sequencing, with another 10% identified through gene duplication/deletion analysis, which differs across various communities. In this study, we performed a next-generation sequencing panel and MLPA on 1484 patients to explain the importance of recurrent germline duplications/deletions of BRCA1-2 and their clinical results and determine how often BRCA gene LGRs were seen in people suspected of hereditary breast and ovarian cancer syndrome. The large genomic rearrangements (LGRs) frequency was approximately 1% (14/1484). All 14 mutations were heterozygous and detected in patients with breast cancer. BRCA1 mutations were more predominant (n = 8, 57.1%) than BRCA2 mutations (6, 42.9%). The most common recurrent mutations were BRCA2 exon three and BRCA1 exon 24 (23) deletions. To the best of our knowledge, BRCA1 5'UTR-exon11 duplication has never been reported before. Testing with MLPA is essential to identify patients at high risk. Our data demonstrate that BRCA1-2 LGRs should be considered when ordering genetic testing for individuals with a personal or family history of cancer, particularly breast cancer. Further research could shed light on BRCA1-2 LGRs' unique carcinogenesis roles.

Keywords:  BRCA1; BRCA2; Deletion; Duplication; Hereditary breast and ovarian cancer syndrome

DOI:  https://doi.org/10.1007/s11033-021-06499-3
Front Endocrinol (Lausanne). 2021 ;12 681013

A Direct Comparison of Patients With Hereditary and Sporadic Pancreatic Neuroendocrine Tumors: Evaluation of Clinical Course, Prognostic Factors and Genotype-Phenotype Correlations.

Przemysław Soczomski, Beata Jurecka-Lubieniecka, Aleksandra Krzywon, Alexander Jorge Cortez, Stanisław Zgliczynski, Natalia Rogozik, Małgorzata Oczko-Wojciechowska, Agnieszka Pawlaczek, Tomasz Bednarczuk, Barbara Jarzab.

  Introduction: Pancreatic neuroendocrine tumors (PNETs) in hereditary syndromes pose a significant challenge to clinicians. The rarity of these syndromes and PNETs itself make it difficult to directly compare them with sporadic PNETs. Despite research suggesting differences between these two entities, the same approach is used in hereditary and sporadic PNETs.Methods: We included 63 patients with hereditary PNET (GpNET) and 145 with sporadic PNET (SpNET) in a retrospective observational study. Clinical and genetic data were collected in two Polish endocrine departments from January 2004 to February 2020. Only patients with confirmed germline mutations were included in the GpNET cohort. We attempted to establish prognostic factors of metastases and overall survival in both groups and genotype-phenotype correlations in the GpNET group.
Results: Patients with GpNET were younger and diagnosed earlier, whereas their tumors were smaller and more frequently multifocal compared with patients with SpNET. Metastases occurred more frequently in the SpNET group, and their appearance was associated with tumor size in both groups. GpNET patients had longer overall survival (OS). OS was affected by age, age at diagnosis, sex, grade, stage, tumor diameter, occurrence and localization of metastases, type of treatment, and comorbidities. In the MEN1 group, carriers of frameshift with STOP codon, splice site, and missense mutations tended to have less advanced disease, while patients with mutations in exon 2 tended to have metastases more frequently.
Conclusions: Direct comparisons of GpNET and SpNET demonstrate significant differences in the clinical courses of both entities, which should force different approaches. A larger group of patients with GpNET should be assessed to confirm genotype-phenotype correlations.

Keywords:  Von Hippel–Lindau Syndrome; comparison; genotype-phenotype correlation; hereditary pancreatic neuroendocrine tumor (PNET); multiple neuroendocrine neoplasia type 1; pancreatic neuroendocrine tumor

DOI:  https://doi.org/10.3389/fendo.2021.681013
Cancer Genet. 2021 May 26. pii: S2210-7762(21)00113-7. [Epub ahead of print]256-257 127-130

A hereditary ovarian cancer family with rare pathogenic splicing mutation: Implications for variant interpretation.

Ke Wang, Yingnan Ye, Lewen Bao, Yanan Cheng, Yandong Cao, Jinpu Yu.

  The BRCA1/2 gene is important for assessing the risk of familial/hereditary ovarian cancer (OC). This case is a patient with OC, and two of her immediate family members are cancer patients. We sequenced the coding and splicing regions of 42 OC susceptibility genes, and found a rare pathogenic splicing mutation BRCA1:c.132C > T (p.cys44 =) in 2 patients. Although the mutation is synonymous, software prediction and functional verification have shown that it affects alternative splicing and leads to frameshift mutations (c.131_134del). Chromosome microarray analysis of the tissue samples revealed the presence of a BRCA1 gene deletion with a fragment size of 1.42 Mb and an HRD score of 71. In addition, the proband showed a sensitive response to platinum treatment. This case suggests the clinical significance of OC susceptibility genes sequencing and HRD scoring in screening hereditary OC families.

Keywords:  Familial/hereditary ovarian cancer syndrome; Genatic detection; Homologous recombination deficiency

DOI:  https://doi.org/10.1016/j.cancergen.2021.05.007
Br J Haematol. 2021 Jun 17.

In vitro assessment of the sensitivity to APR-246 + azacitidine combination predicts response to this combination in myelodysplastic/acute myeloid leukaemia patients.

Nabih Maslah, Yantcha Diawara, Marie Sebert, Stephane Giraudier, Pierre Fenaux, Bruno Cassinat.



Keywords:  AML; MDS; TP53; prognosis; treatment

DOI:  https://doi.org/10.1111/bjh.17548