Reply to Kratz et al.

Frébourg, Thierry; Lagercrantz, Svetlana; Oliveíra, Carla; Magenheim, R; Evans, D. Gareth

doi:10.1038/s41431-020-00710-y

Cited by 2 publications

(3 citation statements)

References 10 publications

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“…Within the current guidelines of the European Reference Network GENTURIS, Freybourg et al argue for a phenotypic variability, which strongly endorses the existence of genetic and environmental modifying factors [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

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TP53 germline mutations in the context of families with hereditary breast and ovarian cancer: a clinical challenge

Grill

Ramser

Hellebrand

et al. 2020

Arch Gynecol Obstet

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Purpose TP53germline (g) mutations, associated with the Li-Fraumeni syndrome (LFS), have rarely been reported in the context of hereditary breast and ovarian cancer (HBOC). The prevalence and cancer risks in this target group are unknown and counseling remains challenging. Notably an extensive high-risk surveillance program is implemented, which evokes substantial psychological discomfort. Emphasizing the lack of consensus about clinical implications, we aim to further characterize TP53g mutations in HBOC families. Methods Next-generation sequencing was conducted on 1876 breast cancer (BC) patients who fulfilled the inclusion criteria for HBOC. Results (Likely) pathogenic variants in TP53 gene were present in 0.6% of the BC cohort with higher occurrence in early onset BC < 36 years. (1.1%) and bilateral vs. unilateral BC (1.1% vs. 0.3%). Two out of eleven patients with a (likely) pathogenic TP53g variant (c.542G > A; c.375G > A) did not comply with classic LFS/Chompret criteria. Albeit located in the DNA-binding domain of the p53-protein and therefore revealing no difference to LFS-related variants, they only displayed a medium transactivity reduction constituting a retainment of wildtype-like anti-proliferative functionality. Conclusion Among our cohort of HBOC families, we were able to describe a clinical subgroup, which is distinct from the classic LFS-families. Strikingly, two families did not adhere to the LFS criteria, and functional analysis revealed a reduced impact on TP53 activity, which may suit to the attenuated phenotype. This is an approach that could be useful in developing individualized screening efforts for TP53g mutation carrier in HBOC families. Due to the low incidence, national/international cooperation is necessary to further explore clinical implications. This might allow providing directions for clinical recommendations in the future.

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Section: Discussionmentioning

confidence: 99%

“…Agreeing on existing evidence and current guidelines published by the European Reference Network GENTURIS [ 31 ] and based of a lack of consensus, the established surveillance program should currently be recommended to all carriers of a (likely) deleterious TP53g mutation irrespective of the pedigree.…”

Section: Discussionmentioning

confidence: 99%

TP53 germline mutations in the context of families with hereditary breast and ovarian cancer: a clinical challenge

Grill

Ramser

Hellebrand

et al. 2020

Arch Gynecol Obstet

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“…The complexity of germline TP53 variant interpretation can be seen by the potential for ‘over-classification’ of TP53 variants resulting in a frequency of pathogenic or likely-pathogenic variants as high as 1 in 500 in the control database gnomAD [ 23 ], whereas a more parsimonious approach provides a more likely 1 in 5000 frequency [ 24 , 25 ]. Over-classification of TP53 variants has, in particular, resulted in almost certainly overstated risk of colorectal cancer in LFS [ 26 ], with one report misclassifying four/six germline variants as pathogenic or likely-pathogenic [ 27 ]. As such it can be seen that accurate variant classification is vital when dealing with TP53 variants identified on germline testing.…”

Section: Interpretation Of Germline Tp53 Variantsmentioning

confidence: 99%

Germline TP53 Testing in Breast Cancers: Why, When and How?

Evans

Woodward

Bajalica‐Lagercrantz

et al. 2020

Cancers

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Germline TP53 variants represent a main genetic cause of breast cancers before 31 years of age. Development of cancer multi-gene panels has resulted in an exponential increase of germline TP53 testing in breast cancer patients. Interpretation of TP53 variants, which are mostly missense, is complex and requires excluding clonal haematopoiesis and circulating tumour DNA. In breast cancer patients harbouring germline disease-causing TP53 variants, radiotherapy contributing to the development of subsequent tumours should be, if possible, avoided and, within families, annual follow-up including whole-body MRI should be offered to carriers. We consider that, in breast cancer patients, germline TP53 testing should be performed before treatment and offered systematically only to patients with: (i) invasive breast carcinoma or ductal carcinoma in situ (DCIS) before 31; or (ii) bilateral or multifocal or HER2+ invasive breast carcinoma/DCIS or phyllode tumour before 36; or (iii) invasive breast carcinoma before 46 and another TP53 core tumour (breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumour, adrenocortical carcinoma); or (iv) invasive breast carcinoma before 46 and one first- or second-degree relative with a TP53 core tumour before 56. In contrast, women presenting with breast cancer after 46, without suggestive personal or familial history, should not be tested for TP53.

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Reply to Kratz et al.

Cited by 2 publications

References 10 publications

TP53 germline mutations in the context of families with hereditary breast and ovarian cancer: a clinical challenge

TP53 germline mutations in the context of families with hereditary breast and ovarian cancer: a clinical challenge

Germline TP53 Testing in Breast Cancers: Why, When and How?

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