bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒05‒24
nine papers selected by
Joanna Zawacka-Pankau



  1. Blood. 2020 May 19. pii: blood.2019000937. [Epub ahead of print]
    Scott HS, Hahn CN, Brown AL.
      Recognition that germline mutations can predispose individuals to blood cancers, often presenting as secondary leukemias, has largely been driven in the last 20 years by studies of families with inherited mutations in the myeloid transcription factors (TFs) RUNX1, GATA2, and CEBPA. The precise incidence of germline mutation carriers in the general population, or various clinically presenting patient groups, remain poorly defined for many reasons including; Somatic mutations in these genes are common in blood cancers; Our ability to distinguish germline (inherited or de novo) and somatic mutations is often limited by the laboratory analyses. Our knowledge of the regulation of these TFs and their mutant alleles, their interaction with other genes and proteins (including at both the germline and somatic allelic level) and the environment, and how these alter the clinical presentation of patients and their secondary leukemias is also incomplete. Principle among the many outstanding questions remaining for patients with these germline mutations as individuals, patient groups and their treating clinicians are; what is the natural course of the disease, what other symptoms may or will I develop and when, can you predict them, how can I prevent them and if they occur what is the best way to treat them. Recognition that germline mutations can predispose individuals to blood cancers, often presenting as secondary leukemias, has largely been driven in the last 20 years by studies of families with inherited mutations in the myeloid transcription factors (TFs) RUNX1,GATA2, and CEBPA. As a result, in 2016, classification of myeloid neoplasms with germline predisposition for each of these and other genes was added to the WHO guidelines. The precise incidence of germline mutation carriers in the general population, or various clinically presenting patient groups, remain poorly defined for many reasons including; somatic mutations in these genes are common in blood cancers; our ability to distinguish germline (inherited or de novo) and somatic mutations is often limited by the laboratory analyses. Our knowledge of the regulation of these TFs and their mutant alleles, their interaction with other genes and proteins (including at both the germline and somatic allelic level) and the environment, and how these alter the clinical presentation of patients and their secondary leukemias is also incomplete. Principle among the many outstanding questions remaining for patients with these germline mutations as individuals, patient groups and their treating clinicians are; what is the natural course of the disease, what other symptoms may or will I develop and when, can you predict them, how can I prevent them and if they occur what is the best way to treat them. The resolution of many of the remaining clinical and biological questions, and effective evidence based treatment of patients with these inherited mutations, will depend on worldwide partnerships between patients, clinicians, diagnosticians and researchers to aggregate sufficient longitudinal clinical and laboratory data, and integrate this data with model systems.
    DOI:  https://doi.org/10.1182/blood.2019000937
  2. Mol Genet Genomic Med. 2020 May 17. e1302
    Tolonen JP, Hekkala A, Kuismin O, Tuominen H, Suo-Palosaari M, Tynninen O, Niinimäki R.
      BACKGROUND: Medulloblastomas (MBs) are a heterogeneous group of childhood brain tumors with four consensus subgroups, namely MBSHH , MBWNT , MBGroup 3 , and MBGroup 4 , representing the second most common type of pediatric brain cancer after high-grade gliomas. They suffer from a high prevalence of genetic predisposition with up to 20% of MBSHH caused by germline mutations in only six genes. However, the spectrum of germline mutations in MBSHH remains incomplete.METHODS: Comprehensive Next-Generation Sequencing panels of both tumor and patient blood samples were performed as molecular genetic characterization. The panels cover genes that are known to predispose to cancer.
    RESULTS: Here, we report on a patient with a pathogenic germline PTEN variant resulting in an early stop codon p.(Glu7Argfs*4) (ClinVar ID: 480383). The patient developed macrocephaly and MBSHH , but reached remission with current treatment protocols.
    CONCLUSIONS: We propose that pathogenic PTEN variants may predispose to medulloblastoma, and show that remission was reached with current treatment protocols. The PTEN gene should be included in the genetic testing provided to patients who develop medulloblastoma at an early age. We recommend brain magnetic resonance imaging upon an unexpected acceleration of growth of head circumference for pediatric patients harboring pathogenic germline PTEN variants.
    Keywords:  carcinogenesis; disease susceptibility; magnetic resonance imaging; medulloblastoma; megalencephaly
    DOI:  https://doi.org/10.1002/mgg3.1302
  3. Cancers (Basel). 2020 May 19. pii: E1286. [Epub ahead of print]12(5):
    Santonocito C, Rizza R, Paris I, Marchis L, Paolillo C, Tiberi G, Scambia G, Capoluongo E.
      Pathogenic variants (PVs) carriers in BRCA1 or BRCA2 are associated with an elevated lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC). The prevalence of BRCA1 and BRCA2 germline alterations is extremely variable among different ethnic groups. Particularly, the rate of variants in Italian BC and/or OC families is rather controversial and ranges from 8% to 37%, according to different reports. By In Vitro Diagnostic (IVD) next generation sequencing (NGS)-based pipelines, we routinely screened thousands of patients with either sporadic or cancer family history. By NGS, we identified new PVs and some variants of uncertain significance (VUS) which were also evaluated in silico using dedicated tools. We report in detail data regarding BRCA1/2 variants identified in 517 out of 2351 BC and OC patients. The aim of this study was to report the incidence and spectrum of BRCA1/2 variants observed in BC and/or OC patients, tested in at Policlinico Gemelli Foundation Hospital, the origin of which is mainly from Central and Southern Italy. This study provides an overview of the variant frequency in these geographic areas of Italy and provides data that could be used in the clinical management of patients.
    Keywords:  BRCA1/2; next-generation sequencing; novel variants
    DOI:  https://doi.org/10.3390/cancers12051286
  4. Genet Med. 2020 May 22.
    Pritzlaff M, Tian Y, Reineke P, Stuenkel AJ, Allen K, Gutierrez S, Jackson M, Dolinsky JS, LaDuca H, Xu J, Black MH, Helfand BT.
      PURPOSE: We describe the pathogenic variant spectrum and identify predictors of positive results among men referred for clinical genetic testing for prostate cancer.METHODS: One thousand eight hundred twelve men with prostate cancer underwent clinical multigene panel testing between April 2012 and September 2017. Stepwise logistic regression determined the most reliable predictors of positive results among clinical variables reported on test requisition forms.
    RESULTS: A yield of 9.4-12.1% was observed among men with no prior genetic testing. In this group, the positive rate of BRCA1 and BRCA2 was 4.6%; the positive rate for the mismatch repair genes was 2.8%. Increasing Gleason score (odds ratio [OR] 1.19; 95% confidence interval [CI] 0.97-1.45); personal history of breast or pancreatic cancer (OR 3.62; 95% CI 1.37-9.46); family history of breast, ovarian, or pancreatic cancer (OR 2.32 95% CI 1.48-3.65); and family history of Lynch syndrome-associated cancers (OR 1.97; 95% CI 1.23-3.15) were predictors of positive results.
    CONCLUSION: These results support multigene panel testing as the primary genetic testing approach for hereditary prostate cancer and are supportive of recommendations for consideration of germline testing in men with prostate cancer. Expanding the criteria for genetic testing should be considered as many pathogenic variants are actionable for treatment of advanced prostate cancer.
    Keywords:  HRD; MMRD; genetic testing; multigene panel testing; prostate cancer
    DOI:  https://doi.org/10.1038/s41436-020-0830-5
  5. Int J Clin Oncol. 2020 May 19.
    Signoroni S, Piozzi GN, Ricci MT, Mancini A, Morabito A, Bertario L, Vitellaro M.
      BACKGROUND: Risk factors for metachronous colorectal cancer (mCRC) in Lynch Syndrome (LS) patients are essential for colorectal cancer (CRC) treatment strategy to perform not only a curative but also preventive surgery. The aim of this study was to evaluate the risk factors for mCRC development in LS patients to define the patient subset that may benefit an extended curative and preventive surgical resection.METHODS: Patient's clinical history, oncological, molecular and follow-up were collected retrospectively from the Hereditary Digestive Tumors Registry at the National Cancer Institute of Milan. The age-related cumulative risk of mCRC was calculated using the Kaplan-Meier method. Factors significantly associated with mCRC were analyzed with a Cox regression model. Overall and specific competitive risks were also calculated.
    RESULTS: In a total of 1346 CRC patients, 159 (11.8%) developed a mCRC after a mean follow-up of 138 months from the primary tumor. The independent risk factors reported by a multivariate analysis were: pathogenetic variants in MLH1 and MSH2 (HR 2.96 and 1.91, respectively) and history of colorectal adenomas (HR 1.54); whereas female sex and extended surgery were protective (HR 0.59 and 0.79, respectively).
    CONCLUSIONS: Among a high-risk population for CRC, in particular LS, an extended surgery may be considered in CRC patients with specific risk factors (MLH1 or MSH2 germline pathogenic variants, history of colorectal adenomas) to reduce the risk of mCRC development.
    Keywords:  Colorectal surgery; DNA mismatch repair genes; Hereditary non-polyposis colorectal cancer; Lynch syndrome; Metachronous colorectal cancer
    DOI:  https://doi.org/10.1007/s10147-020-01700-2
  6. J Natl Cancer Inst. 2020 May 19. pii: djaa040. [Epub ahead of print]
    Palmer JR, Polley EC, Hu C, John EM, Haiman C, Hart SN, Gaudet M, Pal T, Anton-Culver H, Trentham-Dietz A, Bernstein L, Ambrosone CB, Bandera EV, Bertrand KA, Bethea TN, Gao C, Gnanaolivu RD, Huang H, Lee KY, LeMarchand L, Na J, Sandler DP, Shah PD, Yadav S, Yang W, Weitzel JN, Domchek SM, Goldgar DE, Nathanson KL, Kraft P, Couch FJ.
      BACKGROUND: The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies.METHODS: Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer.
    RESULTS: Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer.
    CONCLUSIONS: The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.
    DOI:  https://doi.org/10.1093/jnci/djaa040
  7. Gastroenterology. 2020 May 13. pii: S0016-5085(20)30657-0. [Epub ahead of print]
    Aslanian HR, Lee JH, Canto MI.
      DESCRIPTION: The purpose of this best practice advice article is to describe the indications for screening for pancreas cancer in high risk individuals.METHODS: The evidence reviewed in this work is based on reports of pancreas cancer screening studies in high risk individuals and expert opinion BEST PRACTICE ADVICE 1: Pancreas cancer screening should be considered in patients determined to be at high risk, including first-degree relatives of patients with pancreas cancer with at least two affected genetically related relatives. BEST PRACTICE ADVICE 2: Pancreas cancer screening should be considered in patients with genetic syndromes associated with an increased risk of pancreas cancer, including all patients with Peutz-Jeghers syndrome, hereditary pancreatitis, patients with CDKN2A gene mutation, and patients with one or more first degree relatives with pancreas cancer with Lynch Syndrome, and mutations in BRCA1, BRCA2, PALB2, and ATM genes. BEST PRACTICE ADVICE 3: Genetic testing and counseling should be considered for familial pancreas cancer relatives who are eligible for surveillance. A positive germline mutation is associated with an increased risk of neoplastic progression and may also lead to screening for other relevant associated cancers. BEST PRACTICE ADVICE 4: Participation in a registry or referral to a pancreas center of excellence should be pursued when possible for high risk patients undergoing pancreas cancer screening. BEST PRACTICE ADVICE 5: Clinicians should not screen average-risk individuals for pancreas cancer. BEST PRACTICE ADVICE 6: Pancreas cancer screening in high-risk individuals should begin at age 50, or 10 years younger than the initial age of familial onset. Screening should be initiated at age 40 in CKDN2A and PRSS1 mutation carriers with hereditary pancreatitis and at age 35 in the setting of Peutz-Jeghers syndrome. BEST PRACTICE ADVICE 7: MRI and EUS should be used in combination as the preferred screening modalities in individuals undergoing pancreas cancer screening. BEST PRACTICE ADVICE 8: The target detectable pancreatic neoplasms are resectable stage 1 pancreatic ductal adenocarcinoma, and high risk precursor neoplasms such as intraductal papillary mucinous neoplasms (IPMNs) with high grade dysplasia and some enlarged pancreatic intraepithelial neoplasias (PanINs) BEST PRACTICE ADVICE 9: Screening intervals of 12 months should be considered when there are no concerning pancreas lesions, with shortened intervals and/or the performance of EUS in 6-12 months directed towards lesions determined to be low risk (by a multidisciplinary team). EUS evaluation within 3-6 months for indeterminate lesions and within 3 months for high risk lesions, if surgical resection is not planned. New-onset diabetes in a high risk individual should lead to additional diagnostic studies or change in surveillance interval. BEST PRACTICE ADVICE 10: Decisions regarding therapy directed towards abnormal findings detected during screening should be made by a dedicated multi-disciplinary team together with the high risk individual and their family. BEST PRACTICE ADVICE 11: Surgical resection should be performed at high volume centers. BEST PRACTICE ADVICE 12: Clinicians should consider discontinuing pancreas cancer screening in high risk individuals when they are more likely to die of non-pancreas cancer related causes due to co-morbidity and/or are not candidates for pancreas resection. BEST PRACTICE ADVICE 13: The limitations and potential risks of pancreas cancer screening should be discussed with patients prior to initiating a screening program.
    DOI:  https://doi.org/10.1053/j.gastro.2020.03.088
  8. Breast Cancer Res Treat. 2020 May 22.
    Cragun D, Weidner A, Tezak A, Clouse K, Pal T.
      PURPOSE: Identification of inherited breast cancer may guide cancer risk management. We sought to compare risk management practices across women with inherited breast cancer genes.METHODS: Females with a pathogenic/likely pathogenic (P/LP) variant in BRCA1/2, PALB2, CHEK2, and/or ATM were surveyed about cancer risk management. Comparisons were made across genes.
    RESULTS: The 235 participants with P/LP variants (186 BRCA1/2, 28 PALB2, 15 CHEK2, and 6 ATM) had a median age of 54 and 61% had a prior breast cancer diagnosis. For women with P/LP variants in BRCA1/2, PALB2, and ATM/CHEK2, bilateral mastectomy (BM) rates were 79%, 61%, and 52%, and bilateral oophorectomy (BO) rates were 89%, 30%, and 37%, respectively. Among women with P/LP variants in PALB2 and ATM/CHEK2, 27% of those who had a BO had a family history of ovarian cancer. Contralateral mastectomy rates for women with P/LP variants in PALB2 and ATM/CHEK2 with unilateral breast cancer were 60% and 58%, and BM rates for those without breast cancer were 57% and 29%, respectively.
    CONCLUSION: These findings suggest high rates of both contralateral mastectomies among those with unilateral breast cancer and BM among those without a breast cancer diagnosis across women with P/LP variants in high and moderate penetrance breast cancer genes. BO was also often utilized for risk reduction across these women. These findings suggest potential overtreatment through risk-reducing surgery, and highlight the importance of promoting guideline-adherent, risk-appropriate care.
    Keywords:  Breast cancer; Disease management; Genetic testing; Germline mutation; Public health
    DOI:  https://doi.org/10.1007/s10549-020-05699-y
  9. Cancers (Basel). 2020 May 20. pii: E1289. [Epub ahead of print]12(5):
    Pinheiro M, Lupinacci FCS, Santiago KM, Drigo SA, Marchi FA, Fonseca-Alves CE, Andrade SCDS, Aagaard MM, Basso TR, Dos Reis MB, Villacis RAR, Roffé M, Hajj GNM, Jurisica I, Kowalski LP, Achatz MI, Rogatto SR.
      Multiple primary thyroid cancer (TC) and breast cancer (BC) are commonly diagnosed, and the lifetime risk for these cancers is increased in patients with a positive family history of both TC and BC. Although this phenotype is partially explained by TP53 or PTEN mutations, a significant number of patients are negative for these alterations. We judiciously recruited patients diagnosed with BC and/or TC having a family history of these tumors and assessed their whole-exome sequencing. After variant prioritization, we selected MUS81 c.1292G>A (p.R431H) for further investigation. This variant was genotyped in a healthy population and sporadic BC/TC tissues and investigated at the protein level and cellular models. MUS81 c.1292G>A was the most frequent variant (25%) and the strongest candidate due to its function of double-strand break repair. This variant was confirmed in four relatives from two families. MUS81 p.R431H protein exhibited lower expression levels in tumors from patients positive for the germline variant, compared with wild-type BC, and normal breast and thyroid tissues. Using cell line models, we showed that c.1292G>A induced protein instability and affected DNA damage response. We suggest that MUS81 is a novel candidate involved in familial BC/TC based on its low frequency in healthy individuals and proven effect in protein stability.
    Keywords:  MUS81; breast cancer; exome sequencing; familial cancer; functional analysis; thyroid cancer
    DOI:  https://doi.org/10.3390/cancers12051289