TP53 Germline Mutations are Associated with HR+/HER2+ in BRCA1/2-Negative Early-Onset Breast Cancer in China

Background: Except for BRCA1/2, there is no data on the relationship between genetic counseling for the range of mutations and early-onset breast cancer populations. We looked for a link between inherited genes and the molecular subtype of early-onset breast cancer.Methods: We genotyped 1214 individuals with early-onset sporadic breast cancer (age≤40 years) who were BRCA1/2-negative in 3 genes: TP53, PALB2, and RECQL. We focus on the immunohistochemistry characteristics that are unique to each patient. Results: The mutation rates of TP53, PALB2, and RECQL in 1214 BRCA-negative young individuals were 4/1214(0.33%), 8/1214(0.66%), 2/1214(0.16%), respectively. The fact that the TP53 mutation rate was 3.49% among estrogen receptor-and/or progesterone receptor-positive, human epidermal growth factor receptor 2 (HER-2) amplification patients under the age of 35 (P<0.001) was particularly noteworthy. Conclusion: According to the findings, TP53 genetic testing should focus on women under 35 with HR-positive and HER2-positve IDC patients.

Genetic testing in women with early-onset breast cancer: a Traceback pilot study

Purpose In Sweden, a Traceback approach, i.e., a retrospective genetic outreach activity, among cancer patients is not normally used in clinical practice. In this pilot study, we wanted to evaluate a Traceback strategy for possible future clinical implementation and investigate why not all women with early-onset breast cancer underwent genetic testing when they were first diagnosed. Methods Out of all women (n = 409) diagnosed with breast cancer at ≤ 35 years in Southern Sweden between 2000 and 2017, 63 had not previously been tested. These women were offered an analysis of the genes BRCA1, BRCA2, PALB2, CHEK2, and ATM through a standardized letter. Subsequently, women with normal test results were informed through a letter and carriers of pathogenic variants were contacted through a telephone call and offered in-person genetic counseling. All tested women were asked to complete a follow-up questionnaire regarding previously not having attended genetic counseling and testing and their experiences of the current retrospective approach. Results Out of the invited women, 29 (46%) underwent genetic testing and 27 (43%) answered the questionnaire. Pathogenic variants were identified in BRCA1 (n = 2), CHEK2 (n = 1), and ATM (n = 1). The main reason for previously not having undergone genetic testing was not having received any information from their physicians. Most study participants were satisfied with both written pre- and post-test information. Conclusion The process with retrospective identification, written pre-test information, and genetic testing, followed by in-person counseling for carriers of pathogenic variants only, was well accepted. This has implications for future Traceback implementation programs.

Pathogenicity Reclassification of Genetic Variants Related to Early-Onset Breast Cancer among Buryat Women

Background: Germline alterations in ATM, BRCA1, BRCA2, and other genes are responsible for early-onset breast cancer. However, up to 20% of molecular tests report genetic variant of unknown significance (VUS) or novel variants that have never been previously described and their clinical significance are unknown. An existing open access databases (ClinVar, BIC, and ENIGMA and other) play an important role in the interpretation of VUS, but in Asian populations the interpretation of VUS is still difficult due to restricted data. This study aimed to reclassify the genetic variants by using the ActiveDriveDB database that annotates variants through the lens of sites of post-translational modifications.Methods: Our study included young Buryat BC patients, anthropologically belonging to the Central Asia. Genomic DNA was used to prepare libraries. NGS sequencing was performed on a NextSeq 500 System. Results: We re-examined 135 rare variants (41 VUS, 25 conflicting, 64 benign and 5 new variants). We identified 10 out of 135 (7.4%) mutations that affected the sites of post-translational modification in proteins. Of 135 rare mutations, 1 benign variant was reclassified as network-rewiring - motif loss mutation, 3 VUS and 1 new variant were reclassified as distal PTM- mutations, 2 new and 1 benign variant were classified as proximal PTM- mutations and 1 benign and 1 conflicting variant were classified as direct PTM- mutations.Conclusions: For the first time, 7.4% (10 out of 135) of mutations that affected the sites of post-translational modification in proteins were identified among Buryat women with early-onset breast cancer.

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

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.