Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing

Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing are urgently required. Most prior research has been based on women selected for high-risk features and more data is needed to make inference about breast cancer risk for women unselected for family history, an important consideration of population screening. We tested 1464 women diagnosed with breast cancer and 862 age-matched controls participating in the Australian Breast Cancer Family Study (ABCFS), and 6549 healthy, older Australian women enroled in the ASPirin in Reducing Events in the Elderly (ASPREE) study for rare germline variants using a 24-gene-panel. Odds ratios (ORs) were estimated using unconditional logistic regression adjusted for age and other potential confounders. We identified pathogenic variants in 11.1% of the ABCFS cases, 3.7% of the ABCFS controls and 2.2% of the ASPREE (control) participants. The estimated breast cancer OR [95% confidence interval] was 5.3 [2.1–16.2] for BRCA1, 4.0 [1.9–9.1] for BRCA2, 3.4 [1.4–8.4] for ATM and 4.3 [1.0–17.0] for PALB2. Our findings provide a population-based perspective to gene-panel testing for breast cancer predisposition and opportunities to improve predictors for identifying women who carry pathogenic variants in breast cancer predisposition genes.

Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast

PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

rs10514231 Leads to Breast Cancer Predisposition by Altering ATP6AP1L Gene Expression

Numerous genetic variants located in autophagy-related genes have been identified for association with various cancer risks, but the biological mechanisms underlying these associations remain largely unknown. Here we investigated their regulatory activity with a parallel reporter gene assay system in breast cancer cells and identified multiple regulatory SNP sites, including rs10514231. It was located in the second intron of ATG10 and showed gene regulatory activity in most breast cancer cells we used. Mechanistically, the T allele of rs10514231 led to ATP6AP1L downregulation by decreasing the binding affinity of TCF7L2. Overexpression of the ATP6AP1L gene in cancer cells diminished cell proliferation, migration, and invasion. Notably, ATP6AP1L downregulation correlated with breast cancer risk and with poor prognosis in patients. These results provide a plausible mechanism behind the association of rs10514231 with breast cancer risk and will be important for more effective therapeutic target identification for precision medicine.

Germline pathogenic variants in cancer predisposition genes among women with invasive lobular cancer of breast.

10581 Background: The prevalence of germline pathogenic variants (PVs) in cancer predisposition genes among women with invasive lobular breast cancer (ILC) and the risk of ILC in PV carriers is not well-defined. Methods: The study included 2,999 women with ILC and 32,544 unaffected controls from a population-based cohort; 3,796 women with ILC and 20,323 women with invasive ductal carcinoma (IDC) undergoing clinical multigene panel testing (clinical cohort); and 125,748 exome sequences from unrelated women without a cancer diagnosis in the gnomAD 3.0 dataset. Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected controls in both cohorts and between women with ILC and IDC in the clinical cohort. Results: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analyses, CDH1 and BRCA2 PVs were associated with high risks of ILC (Odds ratio (OR) > 4), and CHEK2, ATM and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. PV frequencies in these genes in ILC and IDC were similar except for PV frequencies in BRCA1 and CDH1. Conclusions: The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2 and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. While, multigene panel testing may be appropriate for women with ILC, CDH1 should be specifically discussed in the context of low prevalence and attendant gastric cancer risk.

Closing the gap: Trends in inconclusive rates on hereditary cancer testing across racial/ethnic groups.

10525 Background: Several groups have described disparities in genetic test results for inherited breast cancer predisposition, with a disproportionate number of variants of unknown significance (VUS) reported in non-Caucasian individuals. These disparities are due in part to the underrepresentation of non-Caucasians in reference databases and clinical genetic testing cohorts. Over the past few years, diversification efforts have been made however, little data exists on how ethnicity- and gene-specific VUS rates have changed over time and whether such disparities have improved or worsened. Methods: We retrospectively reviewed demographic information and test results for individuals who underwent hereditary cancer multigene panel testing between March 2012 and September 2020 at a single laboratory. Individuals who self-reported as African American, Asian, Caucasian, or Hispanic on the test requisition form and whose testing included ATM, BRCA1, BRCA2, CHEK2 and PALB2 (five commonly tested breast cancer predisposition genes with management guidelines) were included in the study (n = 284,130). The frequency of germline variants of unknown significance (VUS) in the five genes was assessed in September 2015 and September 2020. Results: Amongst patients tested between March 2012 and September 2015, 82.8% of the study cohort self-reported as Caucasian and 17.2% were not Caucasian (6.5% African American, 6.0% Hispanic, and 4.6% Asian). The proportion of non-Caucasian individuals in the study cohort increased slightly by September 2020 to 22.8% (77.2% Caucasian, 9.2% African American, 8.4% Hispanic, and 5.3% Asian). Consistent with previous reports, Caucasians had the lowest VUS rate overall in both 2015 and 2020. This was also true at the individual gene level, with the exception of CHEK2. Over time, we observed a relative decrease in VUS rates across all ethnicities. Between 2015 and 2020, the overall VUS rate for the five included genes in non-Caucasian individuals was reduced by 32.0% in non-Caucasians compared to 23.6% in Caucasians. The absolute difference in VUS rate between non-Caucasians and Caucasians decreased from 7.9% in 2015 to 4.5% in 2020. Conclusions: While VUS rates for commonly tested breast cancer predisposition genes remain higher in non-Caucasians relative to Caucasians, our results demonstrate that this gap has been reduced over a five-year time period. These findings may be indicative of efforts by clinicians and laboratories to reduce these disparities. Further studies are necessary to improve the clinical utility of genetic testing in under-represented populations.[Table: see text]

Plasma Metabolome Signature Indicative of BRCA1 Germline Status Independent of Cancer Incidence

Individuals carrying a pathogenic germline variant in the breast cancer predisposition gene BRCA1 (gBRCA1+) are prone to developing breast cancer. Apart from its well-known role in DNA repair, BRCA1 has been shown to powerfully impact cellular metabolism. While, in general, metabolic reprogramming was named a hallmark of cancer, disrupted metabolism has also been suggested to drive cancer cell evolution and malignant transformation by critically altering microenvironmental tissue integrity. Systemic metabolic effects induced by germline variants in cancer predisposition genes have been demonstrated before. Whether or not systemic metabolic alterations exist in gBRCA1+ individuals independent of cancer incidence has not been investigated yet. We therefore profiled the plasma metabolome of 72 gBRCA1+ women and 72 age-matched female controls, none of whom (carriers and non-carriers) had a prior cancer diagnosis and all of whom were cancer-free during the follow-up period. We detected one single metabolite, pyruvate, and two metabolite ratios involving pyruvate, lactate, and a metabolite of yet unknown structure, significantly altered between the two cohorts. A machine learning signature of metabolite ratios was able to correctly distinguish between gBRCA1+ and controls in ~82%. The results of this study point to innate systemic metabolic differences in gBRCA1+ women independent of cancer incidence and raise the question as to whether or not constitutional alterations in energy metabolism may be involved in the etiology of BRCA1-associated breast cancer.

Systemic alterations play a dominant role in epigenetic predisposition to breast cancer in offspring of obese fathers and is transmitted to a second generation

We previously showed that environmentally-induced epigenetic inheritance of cancer occurs in rodent models. For instance, we reported that paternal consumption of an obesity-inducing diet (OID) increased breast cancer susceptibility in the offspring (F1). Nevertheless, it is still unclear whether programming of breast cancer in daughters is due to systemic alterations or mammary epithelium-specific factors and whether the breast cancer predisposition in F1 progeny can be transmitted to subsequent generations. In this study, we show that mammary glands from F1 control (CO) female offspring exhibit enhanced growth when transplanted into OID females compared to CO mammary glands transplanted into CO females. Similarly, carcinogen-induced mammary tumors from F1 CO female offspring transplanted into OID females has a higher proliferation/apoptosis rate. Further, we show that granddaughters (F2) from the OID grand-paternal germline have accelerated tumor growth compared to CO granddaughters. This between-generation transmission of cancer predisposition is associated with changes in sperm tRNA fragments in OID males. Our findings indicate that systemic and mammary stromal alterations are significant contributors to programming of mammary development and likely cancer predisposition in OID daughters. Our data also show that breast cancer predisposition is transmitted to subsequent generations and may explain some familial cancers, if confirmed in humans.