Breast Cancer Phenotype Associated With Li-Fraumeni Syndrome: A Brazilian Cohort Enriched by TP53 p.R337H Carriers

Abstract

Breast cancer (BC) is the most prevalent malignancy in women with Li-Fraumeni syndrome (LFS). The literature on BC in LFS is limited due to its rarity worldwide. A TP53 founder pathogenic variant (c.1010G>A; p.R337H) is responsible for the higher prevalence of this syndrome among women of Brazilian ancestry.PurposeThe aim of the study was to describe the BC phenotype expressed by Brazilian female LFS carriers and compare the data between p.R337H and other TP53 germline pathogenic/likely pathogenic variants (non-p.R337H carriers).MethodsWe searched for cases of TP53 germline pathogenic/likely pathogenic variant carriers affected by BC included between 2015 and 2020 in the BLiSS (Brazilian Li-Fraumeni Study) registry at the Sírio-Libanês Hospital.ResultsAmong 163 adult female carriers from the registry, 91 (56%) had received a BC diagnosis, including 72 p.R337H carriers. BC was the first cancer diagnosed in 90% of cases. Early onset BC (age ≤45 years) was diagnosed in 78.2% of cases (11.5% <31 years; 66.7% 31–45 years; 21.8% >45 years). The median age of BC diagnosis for p.R337H carriers was 39.5 years (range 20–69 years) compared to 34 years (range 21–63 years) for non-p.R337H carriers (p = 0.009). In total, 104 breast tumors were observed in 87 women. Bilateral BC was observed in 29.3% of cases. Histology was available for 96 tumors, comprising 69 invasive breast carcinomas, which were mostly invasive ductal carcinomas (95.6%), 25 ductal in situ carcinomas and 2 soft-tissue sarcomas. Overall, 90.5% of invasive breast carcinomas were hormone receptor (HR)-positive, 39.5% were human epidermal growth factor receptor 2 (HER2)-positive, and 32.8% showed HR and HER2 co-expression. In addition, 55.4% of patients opted for contralateral prophylactic mastectomy after a first BC diagnosis. There were no significant differences in the risk of developing contralateral BC or in the immunohistochemical profile between p.R337H and non-p.R337H groups.ConclusionsThe expressed phenotype of p.R337H is similar to that of other TP53 pathogenic/likely pathogenic variants, except for an average older age at the onset of disease; however, this is still younger than the general population.

Phenotype analysis of families with TP53 germline variants at the Center for Familial Breast and Ovarian Cancer, Cologne

“…1 Conversely, low-penetrance missense mutations such as the Brazilian founder variant have also been reported. 1,31,32 This variant was present in one family with BC in our study and one other patient who developed BC after the age of 40 years and did not fulfill the Chompret criteria. In our sample, the age of onset at first malignancy was the lowest in families with a loss-of-function TP53 variant (32 years), which was not consistent with earlier reports and might be due to the low number of samples used in our study.…”

“…The median age of onset of first malignancy in families with dominant negative variants was lower (34 years) than that in families with other missense (45 years) or lowpenetrance (48 years) variants, which was consistent with earlier observations. 1,[30][31][32] As the classification of variants is complex (e.g., dominant negative or loss-of-function), the missense variants of the DNA binding domains that are associated with a more severe phenotype of LFS, are defined as "hotspot variants". 15 More stringent definitions and knowledge of other modifying factors are urgently needed to guide counseling for disease prevention in patients with de novo germline variants.…”

TP53c.455C>T p.(Pro152Leu) pathogenic variant is a lower risk allele with attenuated risks of breast cancer and sarcoma

“…Although the numbers are small, it is unlikely there is a high risk of breast cancer with this PV. This is in contrast to codons 245/248 with a very high incidence of breast cancer, and codon 337 which has a later onset of breast cancer compared with DNA core binding domain PVs 8. There is also a paucity of sarcomas in codon 152 heterozygotes not exposed to radiotherapy.…”

“…The variant was first identified in children with adrenocortical carcinoma, but was associated with apparently very much reduced penetrance5 and rarely fulfilling classical LFS criteria,4–6 leading some to state that the presence of the p.(Arg337His) variant was insufficient to diagnose LFS 7. However, subsequent data have shown that there is a substantially increased risk of LFS cancers, but at an older age 4 8. This has prompted many to use the term TP53 -associated cancer syndrome to allow for the less penetrant alleles 1–3.…”

Li–Fraumeni Syndrome: Mutation of TP53 Is a Biomarker of Hereditary Predisposition to Tumor: New Insights and Advances in the Treatment

“…For example, the p53-R337H protein mutation was believed to predispose to adrenocortical carcinoma. However, it has recently been revealed that this mutation is also related to the onset of choroid plexus carcinoma and breast cancer [ 20 , 21 ].…”