bims-lifras Biomed News
on Li-Fraumeni Syndrome
Issue of 2019‒09‒01
eight papers selected by
Joanna Zawacka-Pankau



  1. Acta Neuropathol. 2019 Aug 30.
    Orr BA, Clay MR, Pinto EM, Kesserwan C.
      Li-Fraumeni syndrome (LFS), caused by the germline mutations in the TP53 gene, leads to significant lifetime risk to cancer in the central nervous system. Recognition of LFS, and elucidating its underlying cause has had a remarkable effect on our knowledge of the biology of brain tumors and represents a significant opportunity for cancer surveillance and screening. In this review, we discuss the historical context of the LFS with an emphasis on the clinicopathologic implications in clincal diagnosis, germline testing, and clinical management of brain tumor patients.
    Keywords:  Astrocytoma; Choroid plexus carcinoma; Glioblastoma; Li–Fraumeni syndrome; Medulloblastoma; TP53; p53;  Germline surveillance
    DOI:  https://doi.org/10.1007/s00401-019-02055-3
  2. Breast Cancer Res Treat. 2019 Aug 24.
    Cerretini R, Mercado G, Morganstein J, Schiaffi J, Reynoso M, Montoya D, Valdéz R, Narod SA, Akbari MR.
      PURPOSE: Each year, 17,000 new breast cancer cases are diagnosed in Argentina, and 5400 women die of breast cancer. The contribution of cancer-related mutations to the incidence of breast cancer in Argentina has not yet been explored.METHODS: We sequenced the entire coding regions of BRCA1, BRCA2, PALB2 and RAD51C in 112 unselected Argentinian breast cancer patients.
    RESULTS: A pathogenic genetic variant was found in 12 of 112 (10.7%) patients; two in BRCA1 (1.8%), five in BRCA2 (4.5%), four in PALB2 (3.6%) and one in RAD51C (0.9%). Three of four (75%) PALB2 mutation carriers carried the same variant (c.1653T > A).
    CONCLUSIONS: A founder mutation in PALB2 accounts for up to 4% of breast cancer patients in Argentina. BRCA1, BRCA2, PALB2 and RAD51C should be included in the genetic testing panel of breast cancer patients in Argentina.
    Keywords:  Argentina; Breast cancer; Founder mutation; Genetics; Hereditary; PALB2
    DOI:  https://doi.org/10.1007/s10549-019-05411-9
  3. Melanoma Res. 2019 Oct;29(5): 483-490
    Johansson PA, Nathan V, Bourke LM, Palmer JM, Zhang T, Symmons J, Howlie M, Patch AM, Read J, Holland EA, Schmid H, Warrier S, Glasson W, Höiom V, Wadt K, Jönsson G, Olsson H, Ingvar C, Mann G, Brown KM, Hayward NK, Pritchard AL.
      Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1 or BRCA2 by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1 and BRCA2 germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1 variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N = 763). We identified one individual with a deleterious BRCA1 variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1 was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1 mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2 mutations and UM susceptibility represents a rare source of increased risk.
    DOI:  https://doi.org/10.1097/CMR.0000000000000613
  4. Med Pharm Rep. 2019 Jul;92(3): 220-225
    Catana A, Apostu AP, Antemie RG.
      Breast cancer is one of the most common malignancies and the leading cause of death among women worldwide. About 20% of breast cancers are hereditary. Approximately 30% of the mutations have remained negative after testing BRCA1/2 even in families with a Mendelian inheritance pattern for breast cancer. Additional non-BRCA genes have been identified as predisposing for breast cancer. Multi gene panel testing tries to cover and explain the BRCA negative inherited breast cancer, improving efficiency, speed and costs of the breast cancer screening. We identified 23 studies reporting results from individuals who have undergone multi gene panel testing for hereditary breast cancer and noticed a prevalence of 1-12% of non-BRCA genes, but also a high level of variants of uncertain significance. A result with a high level of variants of uncertain significance is likely to be more costly than bring benefits, as well as increase the anxiety for patients. Regarding further development of multi gene panel testing, more research is required to establish both the optimal care of patients with cancer (specific treatments like PARP inhibitors) and the management of unaffected individuals (chemoprevention and/or prophylactic surgeries). Early detection in these patients as well as prophylactic measures will significantly increase the chance of survival. Therefore, multi gene panel testing is not yet ready to be used outside clear guidelines. In conclusion, studies on additional cohorts will be needed to better define the real prevalence, penetrance and the variants of these genes, as well as to describe clear evidence-based guidelines for these patients.
    Keywords:  hereditary breast cancer; multi gene panel; non-BRCA genes; prevalence; prophylactic measures
    DOI:  https://doi.org/10.15386/mpr-1083
  5. Clin Gastroenterol Hepatol. 2019 Aug 27. pii: S1542-3565(19)30918-8. [Epub ahead of print]
    Goverde A, Eikenboom EL, Viskil EL, Bruno MJ, Doukas M, Dinjens WNM, Dubbink HJ, van den Ouweland AMW, Hofstra RMW, Wagner A, Spaander MCW.
      BACKGROUND & AIMS: Patients with Lynch syndrome are offered the same colorectal cancer (CRC) surveillance programs (colonoscopy every 2 years), regardless of the pathogenic DNA mismatch repair gene variant the patient carries. We aimed to assess the yield of surveillance for patients with these variants in MLH1, MSH2, MSH6, and PMS2.METHODS: We analyzed data on colonoscopy surveillance, including histopathology analysis, from all patients diagnosed with Lynch syndrome (n=264) at a single center. We compared the development of (advanced) adenomas and CRC among patients with pathogenic variants in the DNA mismatch repair genes MLH1 (n=55), MSH2 (n=44), MSH6 (n=143), or PMS2 (n=22) over 1836 years of follow-up (median follow-up of 6 years per patient).
    RESULTS: At first colonoscopy, CRC was found in 8 patients. During 916 follow-up colonoscopies, CRC was found in 9 patients. No CRC was found in patients with variants in MSH6 or PMS2 over the entire follow-up period. There were no significant differences in the number of colonoscopies with adenomas or advanced adenomas among the groups. The median time of adenoma development was 3 years (IQR, 2-6 years). There were no significant differences in time to development of adenoma. However, patients with variants in MSH6 had a significant longer time to development of advanced neoplasia (advanced adenoma or CRC) than patients in the other groups. Six carriers died during follow up (5 from cancer, 3 from pancreatic cancer).
    CONCLUSIONS: No CRC was found during follow-up of patients with Lynch syndrome carrying pathogenic variants in MSH6; advanced neoplasia developed over shorter follow-up time periods in patients with pathogenic variants in MLH1 or MSH2. The colonoscopy interval for patients with pathogenic variants in MSH6 might be increased to 3 years from the regular 2-year interval.
    Keywords:  MMR; colon; genetics; hereditary cancer prevention
    DOI:  https://doi.org/10.1016/j.cgh.2019.08.043
  6. Cancer Prev Res (Phila). 2019 Aug 26. pii: canprevres.0056.2019. [Epub ahead of print]
    Ebrahimi E, Sellars E, Shirkoohi R, Harirchi I, Ghiasvand R, Mohebbi E, Zendehdel K, Akbari MR.
      Since the contribution of genetic factors to the burden of breast cancer has not well investigated in Iran, we aimed to examine the prevalence of mutations in breast cancer susceptibility genes, BRCA1/2 and PALB2, and to investigate the predictive potential of hereditary breast cancer risk criteria for genetic testing in Iranian population. Next Generation Sequencing (NGS) was conducted on a population consisted of 299 and 125 breast cancer patients, with and without hereditary cancer risk criteria for genetic testing, respectively. The pathogenic mutation frequency rate was 10.7% in patients with hereditary cancer criteria versus 1.6% in no criteria group (P = 0.0017). None of the 107 tested patients with only young age at onset (<40) criterion had a pathogenic mutation. Patients who had only a single heritable risk criterion (OR: 6.15, 95%CI: 1.26, 58.59, P = 0.009) and patients with multiple heritable risk criteria (OR: 22.5, 95%CI: 5.19, 201.31, P < 0.0001) had higher probabilities of carrying a mutation compared with no criteria group. Our results showed that young age at onset alone is not an indicator of hereditary breast cancer at least in the Iranian population. This is while women with multiple hereditary breast cancer risk criteria were enriched for BRCA1/2 mutations. Given such high risk of identification of a disease-causing mutation, multiple hereditary criteria should be regarded as a strong predictor for a hereditary breast cancer syndrome. These findings are important concerning the optimization of genetic counseling and furthermore establishing criteria for BRCA1/2 testing of the Iranian population.
    DOI:  https://doi.org/10.1158/1940-6207.CAPR-19-0056
  7. Dermatol Clin. 2019 Oct;pii: S0733-8635(19)30058-0. [Epub ahead of print]37(4): 607-613
    Hamid RN, Akkurt ZM.
      Cutaneous findings that appear in childhood may be the first sign of a hereditary tumor syndrome. Early detection of genodermatoses allows the patient and at-risk family members to be screened for associated malignancies. This article provides a brief description of the pathogenesis and clinical manifestations of various inherited disorders with skin involvement, along with treatment updates. Advances in molecular-based therapy have spurred development of novel treatment methods for various genodermatoses such as xeroderma pigmentosum (XP) and Gorlin-Goltz syndrome. Further studies are needed to better assess the efficacy of many of these new treatment options.
    Keywords:  Genodermatoses; Gorlin-Goltz syndrome; Hereditary tumor syndrome; Xeroderma pigmentosum
    DOI:  https://doi.org/10.1016/j.det.2019.05.016