The Landscape of Somatic Genetic Alterations in Breast Cancers from Carriers of Germline Pathogenic Variants in DNA-repair Genes

Background

 

Hereditary breast cancer in carriers of germline pathogenic or likely pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2 have unique clinicopathological characteristics compared to sporadic breast cancer. However, very little is known about the underlying differences in somatic genetic alterations between hereditary and sporadic breast cancer.

 

Methods

 

The study included 7,533 individuals with breast cancer subjected to Tempus xT tumor-normal matched sequencing (596-648 genes). The frequencies of the somatic genetic alterations in each gene were compared separately between tumors arising in individuals with incidental germline PVs (g_ATM_, g_BRCA1_, g_BRCA2_, g_CHEK2_, g_PALB2_) and sporadic breast tumors. Sporadic tumors were identified as individuals with no detected incidental germline PVs in these 5 genes. Comparisons were made by either Pearson’s Chi-squared or Fisher’s exact test, with false discovery rate (FDR) correction for multiple testing. Breast cancer subtype was determined based on the record of IHC positivity for ER, PR, or HER2. Detection of ERBB2 (HER2) gene amplifications via DNA sequencing was also used to classify samples as HER2+ in the absence of available IHC data.

 

Results

 

The median age at breast cancer diagnosis for the cohort was 56 years. More than two-thirds of the patients were White (73%) while 14% identified as Black or African American. The overall frequency of incidental germline PVs in each gene was 0.8% for gATM, 1.4% for g_BRCA1_, 2.1% for g_BRCA2_, 1.0% for CHEK2, and 0.7% for PALB2. A total of 3,648 (48.4%) tumors were ER+/PR+/HER2-, 1,297 (17.2%) were triple-negative (TNBC), 841 (11.2%) were HER2+ and 1,747 (23.2%) could not be classified due to missing ER, PR or HER2 status, or absence of detected ERBB2 amplifications. Among ER+/PR+/HER2- breast cancers, compared to sporadic tumors, ESR1 mutations were significantly enriched in g_ATM_ carriers (33% vs. 11%, q- value 0.05), TP53 alterations were significantly enriched in g_BRCA1_ PV carriers (69% vs. 30%, q-value < 0.001) but depleted in g_ATM_ (12% vs. 30%, q- value 0.4) and g_CHEK2_ PV carriers (5.4% vs. 30%, q-value 0.06), and PIK3CA (14% vs. 35%, q-value 0.001) and CCND1 (3.4% vs. 17%, q-value 0.02)
alterations were significantly lower in g_BRCA2_ PV carriers. Among TNBC, TP53 alterations were also significantly higher in g_BRCA1_ PV carriers compared to sporadic tumors (96% vs. 69%, q-value 0.004). In HER2+ breast cancers, ERBB2 alterations were observed in approximately two-thirds of the tumors, and a significant difference was not observed between incidental hereditary and sporadic tumors. Among ER+/PR+/HER2- tumors, although not statistically significant, the frequency of ESR1 (3.1% vs. 11%, q-value >0.9), PIK3CA (12% vs. 35%, q-value 0.2) alterations were lower in incidental g_BRCA1_ versus sporadic tumors, FGFR1 alterations were lower in incidental g_BRCA1_ (6.2% vs. 13%, q-value >0.9) and incidental g_BRCA2_ (3.4% vs. 13%, q-value 0.13) but enriched in incidental g_ATM_ (33% vs. 13%, q-value 0.05).

 

Conclusions

 

The observed differences in the frequencies of CCND1, ESR1, PIK3CA, TP53, and other key genetic alterations between incidental hereditary and sporadic breast cancer highlight the unique tumor biology of breast cancer in germline PV carriers and have significant implications for understanding tumorigenesis and identifying therapeutic strategies for the management of hereditary breast cancer.