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• We're All Not the Same, But We're Still Family
  Renata Lazari Sandoval, Maria Isabel Achatz
  Published on: 7 October 2020

• Published on: 7 October 2020

  We're All Not the Same, But We're Still Family

  • Renata Lazari Sandoval, Clinical geneticist Hospital Sírio-Libanês
  • Other Contributors:
    • Maria Isabel Achatz, Clinical geneticist

  Dear Editor:
  We read with great interest the case report published by De Silva and Winship1 in the September 2020 issue of this journal. They reported the medical history of a 52-year-old male patient who fulfilled the revised Chompret clinical criteria for Li-Fraumeni syndrome (LFS) and carried a germline CHEK2 mutation (NM_007194.4:c.1100del, p.Thr367fs). The authors highlighted the possible link between CHEK2 germline mutations and a Li-Fraumeni like syndrome phenotype.
  The term Li-Fraumeni like syndrome (LFL) was introduced by Birch et al. in 1994 to describe LFS families who did not fulfill the classical LFS criteria, but carried a TP53 germline mutation.2,3 Nevertheless, germline mutations in TP53 gene may not detected in some families with clinical diagnosis of the syndrome. In 1999, Bells et al. reported a family who fulfilled classical LFS criteria and carried a CHEK2 pathogenic mutation, c.1100delC.4 At that time, the authors hypothesized for the first time that heterozygous CHEK2 mutations could be related to LFS phenotype. BRCA2 germline mutations were also described in TP53-negative LFS families.5
  Most cancer predisposition syndromes have an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expressivity. Genetic and environmental modifiers play a role in intra and interfamilial heterogeneity.8 Environmental modifiers were not mentioned by De Silva and Winship, and should have been described in the c...

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  Dear Editor:
  We read with great interest the case report published by De Silva and Winship1 in the September 2020 issue of this journal. They reported the medical history of a 52-year-old male patient who fulfilled the revised Chompret clinical criteria for Li-Fraumeni syndrome (LFS) and carried a germline CHEK2 mutation (NM_007194.4:c.1100del, p.Thr367fs). The authors highlighted the possible link between CHEK2 germline mutations and a Li-Fraumeni like syndrome phenotype.
  The term Li-Fraumeni like syndrome (LFL) was introduced by Birch et al. in 1994 to describe LFS families who did not fulfill the classical LFS criteria, but carried a TP53 germline mutation.2,3 Nevertheless, germline mutations in TP53 gene may not detected in some families with clinical diagnosis of the syndrome. In 1999, Bells et al. reported a family who fulfilled classical LFS criteria and carried a CHEK2 pathogenic mutation, c.1100delC.4 At that time, the authors hypothesized for the first time that heterozygous CHEK2 mutations could be related to LFS phenotype. BRCA2 germline mutations were also described in TP53-negative LFS families.5
  Most cancer predisposition syndromes have an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expressivity. Genetic and environmental modifiers play a role in intra and interfamilial heterogeneity.8 Environmental modifiers were not mentioned by De Silva and Winship, and should have been described in the case report. Inclusion of environmental risk factors 9 such as tabacco exposure, obesity, sun exposure, alcohol consumption, hypertension could be associated with a higher risk for the multiple primary cancers (clear cell renal cancer, low-grade urothelial tumor, cutaneous basal cell cancer). Furthermore, co-segregation analysis was not performed in affected family members. Her mother, who was diagnosed with a Non-Hodgkin lymphoma at age 47, and her sister, diagnosed with a breast cancer at age 26, were deceased. Nevertheless, her maternal aunt, who developed a pheochromocytoma at age 56 and breast cancer at age 66 was not tested for CHEK2 c.1100delC variant, despite being tested for BRCA1, BRCA2, VHL, MAX, RET, TMEM 127 and SDHx genes.
  Differences in CHEK2 penetrance and clinical expressivity may be also modified by polygenic risk and family history (Cybulski et al., 2011; Gallangher et al., 2020). We agree with the authors that more studies are required to translate genetic testing clinical validity to clinical utility, mainly for moderate penetrance genes. Nevertheless, patients who have been diagnosed with LFS and who carry a germline mutation in TP53 gene should undergo high risk surveillance with whole body MRI and genetic testing of minors.6,7 The authors should make clear recommendations that we still don´t have enough data to consider CHEK2 as a causing gene for LFS. There aren´t any indications in this report or any further published data of a higher risk of childhood cancer in CHEK2 carries. Therefore, this information should be evaluated with caution in order to avoid scientific data extrapolation, such as CHEK2 genetic testing for asymptomatic minors, and iatrogenic interventions, such as bilateral mastectomy that is suggested in TP53 mutation carriers and not in CHEK2 mutation carriers (unless strong family history of bilateral breast cancer).
  CHEK2 is a moderate penetrance gene that is part of the breast cancer predisposition genes´ family and predisposes also to a higher risk for colorectal cancer. Although patients may carry a higher risk to other cancers, the phenotype is clearly different from high penetrance TP53 carriers, which is the underlying cause of LFS. Cancer predisposition syndromes may share cancer risks, but management clearly differs in carriers of germline mutations in TP53 and CHEK2.

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  Conflict of Interest:
  None declared.

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