High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer

Abstract

BackgroundWhile the likelihood of identifying constitutional breast cancer-associated BRCA1, BRCA2 and TP53 pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease.MethodsSequencing of BRCA1, BRCA2, TP53 and CHEK2 c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study.ResultsTesting 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in BRCA1, 35 (9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%) CHEK2 c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. BRCA1/2 PVs were more common in women aged 26–30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma in situ (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yield is similar to the 61 (48.8%) BRCA1/2 PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower TP53 PV rates in this group (1.7%).ConclusionThe rates of BRCA1, BRCA2 and TP53 PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.

Detection of pathogenic variants in breast cancer susceptibility genes in bilateral breast cancer

“…None of the aforementioned studies found a high rate of PVs in TP53, almost certainly due to the low numbers of women diagnosed aged <30 years that were tested. The extremely high detection rate in HER2+ and DCIS as the first tumour, with 7 of 11 testing positive, highlights the importance of TP53 testing in this very early-onset group 17. Somewhat surprisingly, the rate of PVs in BRCA1/2 was as high for grade 3 ER+HER2 as for triple negative breast cancer, although this was primarily driven by PVs in BRCA2 .…”

Differential involvement of germline pathogenic variants in breast cancer genes between DCIS and low-grade invasive cancers

“…Disease onset at less than 40 years of age was associated with an even higher PV likelihood (OR 1.8, 95% CI 1.3 to 2.3). We have previously reported a high rate for PVs in additional genes associated with an increased risk of breast cancer, especially TP53, in women with DCIS aged ≤30 years 19…”

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

“…Families with TP53 germline PVs were ascertained from research studies6 10 and subsequent testing of very early onset breast cancer (<31 years)11 and families fulfilling Chompret criteria. Methods for identifying PVs varied from single strand confirmation polymorphism in early studies10 to next-generation sequencing and multiple ligation-dependent probe amplification more recently 11. A total of 74 heterozygous PVs have been identified in unrelated families.…”