Unselected Breast Cancer Cases Research Articles

Germline pathogenic variants associated with triple-negative breast cancer in US Hispanic and Guatemalan women using hospital and community-based recruitment strategies

PurposeRecruit and sequence breast cancer subjects in Guatemalan and US Hispanic populations. Identify optimum strategies to recruit Latin American and Hispanic women into genetic studies of breast cancer.MethodsWe used targeted gene sequencing to identify pathogenic variants in 19 familial breast cancer susceptibility genes in DNA from unselected Hispanic breast cancer cases in the US and Guatemala.Recruitment across the US was achieved through community-based strategies. In addition, we obtained patients receiving cancer treatment at major hospitals in Texas and Guatemala.ResultsWe recruited 287 Hispanic US women, 38 (13%) from community-based and 249 (87%) from hospital-based strategies. In addition, we ascertained 801 Guatemalan women using hospital-based recruitment. In our experience, a hospital-based approach was more efficient than community-based recruitment. In this study, we sequenced 103 US and 137 Guatemalan women and found 11 and 10 pathogenic variants, respectively. The most frequently mutated genes were BRCA1, BRCA2, CHEK2, and ATM. In addition, an analysis of 287 US Hispanic patients with pathology reports showed a significantly higher percentage of triple-negative disease in patients with pathogenic variants (41% vs. 15%). Finally, an analysis of mammography usage in 801 Guatemalan patients found reduced screening in women with a lower socioeconomic status (p < 0.001).ConclusionGuatemalan and US Hispanic women have rates of hereditary breast cancer pathogenic variants similar to other populations and are more likely to have early age at diagnosis, a family history, and a more aggressive disease. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients to reduce breast cancer mortality in Hispanic women.

Exome sequencing identified rare recurrent copy number variants and hereditary breast cancer susceptibility.

Copy number variants (CNVs) are a major source of genetic variation and can disrupt genes or affect gene dosage. They are known to be causal or underlie predisposition to various diseases. However, the role of CNVs in inherited breast cancer susceptibility has not been thoroughly investigated. To address this, we performed whole-exome sequencing based analysis of rare CNVs in 98 high-risk Northern Finnish breast cancer cases. After filtering, selected candidate alleles were validated and characterized with a combination of orthogonal methods, including PCR-based approaches, optical genome mapping and long-read sequencing. This revealed three recurrent alterations: a 31 kb deletion co-occurring with a retrotransposon insertion (delins) in RAD52, a 13.4 kb deletion in HSD17B14 and a 64 kb partial duplication of RAD51C. Notably, all these genes encode proteins involved in pathways previously identified as essential for breast cancer development. Variants were genotyped in geographically matched cases and controls (altogether 278 hereditary and 1983 unselected breast cancer cases, and 1229 controls). The RAD52 delins and HSD17B14 deletion both showed significant enrichment among cases with indications of hereditary disease susceptibility. RAD52 delins was identified in 7/278 cases (2.5%, P = 0.034, OR = 2.86, 95% CI = 1.10-7.45) and HSD17B14 deletion in 8/278 cases (2.9%, P = 0.014, OR = 3.28, 95% CI = 1.31-8.23), the frequency of both variants in the controls being 11/1229 (0.9%). This suggests a role for RAD52 and HSD17B14 in hereditary breast cancer susceptibility. The RAD51C duplication was very rare, identified only in 2/278 of hereditary cases and 2/1229 controls (P = 0.157, OR = 4.45, 95% CI = 0.62-31.70). The identification of recurrent CNVs in these genes, and especially the relatively high frequency of RAD52 and HSD17B14 alterations in the Finnish population, highlights the importance of studying CNVs alongside single nucleotide variants when searching for genetic factors underlying hereditary disease predisposition.

Abstract 1938: Germline mutations in breast cancer genes are associated with early age of diagnosis and triple negative disease in Guatemalan and US Hispanic women

Abstract Abstract Background: Mutations in hereditary breast cancer genes play an essential role in cancer risk. Little is known of the type and frequency of mutations in Hispanic populations in the United States and Central American countries, including Guatemala. Methods: We used exome sequencing to identify mutations in blood DNA from unselected Hispanic breast cancer cases from community recruitment and from two hospitals each in Texas and Guatemala. Data from a structured questionnaire was used to compare mutation carriers of medium and high penetrance genes. Variants were annotated with ClinVar and VarSome. Results: We recruited 262 Hispanic US women, 37 (14%) from community-based recruitment and 225 (86%) from hospitals in Texas. In addition, we ascertained 633 patients from two hospitals in Guatemala City. A total of 91 out of 895 subjects (10%) had a variant classified as pathogenic in a gene with known high or medium penetrance for inherited breast cancer. The most frequently mutated genes were the high penetrance BRCA1 (44/895, 4.9%) followed by BRCA2 (23/895, 2.6%), PALB2 (5/895, 0.6%), CHEK2 (5/895 0.6%), ATM (6/895, 0.7%) and TP53 (6/895, 0.7%). Pathogenic variants were also detected in the moderate penetrance genes BARD1 and MSH6, and rare pathogenic variants detected in the low penetrance genes AXIN2, FH, MLH1, MSH2, MUTYH, NF1, and SDHB. The high ratio of BRCA1/BRCA2 mutations is due to the presence of two potential founder mutations, BRCA1 c.212+1G&amp;gt;A splice mutation (18 cases) and BRCA1 c.799delT (9 cases) in Guatemala. Compared to all others, cases with pathogenic mutations had a significantly earlier age at diagnosis (45 vs. 52 years, P&amp;lt;0.001) and were more likely to have a diagnosis before menopause. A higher percentage of mutation carriers had a relative with any cancer (51% vs. 37%, P=0.038) or breast cancer (33% vs. 15%, P&amp;lt;0.001). Patients with pathogenic mutations had a significantly higher percentage of triple-negative disease (60% vs. 13%, P=0.00046). Finally, mammography usage was less frequent in women with a lower socioeconomic status, indicating that this group is less likely to be screened for breast cancer (P&amp;lt;0.001). Conclusions: Guatemalan women have rates of hereditary breast cancer mutations like other populations, and these women are more likely to have early age at diagnosis, triple-negative disease, and family history. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients and those at high risk as part of a strategy to reduce breast cancer mortality in Hispanic women. Citation Format: Jesica Godinez Paredes, Isabel Rodriguez, Megan Ren, Anali Orozco, Jeremy Ortiz, Anaseidy Albanez, Catherine Jones, Zeina Nahleh, Lilian Barreda, Lisa Garland, Dongjing Wu, Jiahui Wang, Victor Argueta, Roberto Orozco, Eduardo Gharzouzi, Michael Dean. Germline mutations in breast cancer genes are associated with early age of diagnosis and triple negative disease in Guatemalan and US Hispanic women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1938.

A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.31

Most breast cancer heritability is unexplained. We hypothesized that analysis of unrelated familial cases in a GWAS context could enable the identification of novel susceptibility loci. In order to examine the association of a haplotype with breast cancer risk, we performed a genome-wide haplotype association study using a sliding window analysis of window sizes 1-25 SNPs in 650 familial invasive breast cancer cases and 5021 controls. We identified five novel risk loci on 9p24.3 (OR 3.4; p 4.9 × 10-11), 11q22.3 (OR 2.4; p 5.2 × 10-9), 15q11.2 (OR 3.6; p 2.3 × 10-8), 16q24.1 (OR 3; p 3 × 10-8) and Xq21.31 (OR 3.3; p 1.7 × 10-8) and confirmed three well-known loci on 10q25.13, 11q13.3, and 16q12.1. In total, 1593 significant risk haplotypes and 39 risk SNPs were distributed on the eight loci. In comparison with unselected breast cancer cases from a previous study, the OR was increased in the familial analysis in all eight loci. Analyzing familial cancer cases and controls enabled the identification of novel breast cancer susceptibility loci.

Predominance of BRCA2 Mutation and Estrogen Receptor Positivity in Unselected Breast Cancer with BRCA1 or BRCA2 Mutation.

Simple SummaryWe performed a meataanalysis of BRCA1 or BRCA2 germline pathogenic or likely pathogenic variant (gBRCA) in 108,699 unselected breast cancer patients and in 238,972 unaffected individuals. The metanalysis shows that 3.4% unselected breast cancer patients have a gBRCA. In unselected breast cancer patients with gBRCA, more than half of tumors are estrogen receptor-positive. 0.5% of unaffected individuals of the studied populations are gBRCA carriers. The frequency of gBRCA2 and gBRCA1 heterozygosity is estimated at 1/288 and 1/434, respectively. In unselected breast cancer and in unfafected individuals gBRCA2 is more frequent than gBRCA1.Background: Poly(ADP-ribose) polymerase 1 inhibitor (PARPi) agents can improve progression-free survival of patients with breast cancer who carry a germline BRCA1 or BRCA2 pathogenic or likely pathogenic variant (gBRCA) in both the metastatic and adjuvant setting. Therefore, we need to reassess the frequency of gBRCA1 and gBRCA2 in order to redefine the criteria for women and tumor phenotype that should be tested. Objective: We studied the relative distribution of gBRCA1 and gBRCA2 in unselected populations of women with breast cancer and in unaffected individuals. We also analyzed the proportion of estrogen receptor (ER)-positive (ER+) tumors in unselected breast cancer patients with gBRCA. Design: We performed a meta-analysis of studies of unselected breast cancer that analyzed the relative contribution of gBRCA1 versus gBRCA2 among unselected breast cancer cases in gBRCA carriers. We then performed a meta-analysis of gBRCA carriage in unaffected individuals from genome-wide population studies, the gnomAD databank, and case–control studies. Results: The BRCA2 gene was involved in 54% of breast cancer cases in unselected patients with gBRCA (n = 108,699) and 60% of unaffected individuals (n = 238,973) as compared with 38% of the largest gBRCA family cohort (n = 29,700). The meta-analysis showed that 1.66% (95% CI 1.08–2.54) and 1.71% (95% CI 1.33–2.2) of unselected breast cancer patients carried gBRCA1 and gBRCA2, respectively. In a population of unaffected individuals, the frequency of heterozygosity for gBRCA1 and gBRCA2 was estimated at 1/434 and 1/288, respectively. Nearly 0.5% of unaffected individuals in the studied populations carried a gBRCA. Carriage of a gBRCA was 2.5% for patients with ER+ tumors (95% CI 1.5–4.1) and 5.7% (95% CI 5.1–6.2) for those with ER- tumors. Overall, 58% of breast tumors occurring in women carrying a gBRCA were ER+ (n = 86,870). Conclusions: This meta-analysis showed that gBRCA2 carriage is predominant in unselected breast cancer patients and unaffected individuals. ER+ tumors among women with gBRCA-related breast cancer are predominant and have been underestimated. Because PARPi agents improve progression-free survival with ER+ gBRCA breast cancer in most clinical trials, breast cancer should be considered, regardless of ER status, for BRCA1/2 screening for therapeutic purposes.

Germline variants in hereditary breast cancer genes are associated with early age at diagnosis and family history in Guatemalan breast cancer

PurposeMutations in hereditary breast cancer genes play an important role in the risk for cancer.MethodsCancer susceptibility genes were sequenced in 664 unselected breast cancer cases from Guatemala. Variants were annotated with ClinVar and VarSome.ResultsA total of 73 out of 664 subjects (11%) had a pathogenic variant in a high or moderate penetrance gene. The most frequently mutated genes were BRCA1 (37/664, 5.6%) followed by BRCA2 (15/664, 2.3%), PALB2 (5/664, 0.8%), and TP53 (5/664, 0.8%). Pathogenic variants were also detected in the moderate penetrance genes ATM, BARD1, CHEK2, and MSH6. The high ratio of BRCA1/BRCA2 mutations is due to two potential founder mutations: BRCA1 c.212 + 1G > A splice mutation (15 cases) and BRCA1 c.799delT (9 cases). Cases with pathogenic mutations had a significantly earlier age at diagnosis (45 vs 51 years, P < 0.001), are more likely to have had diagnosis before menopause, and a higher percentage had a relative with any cancer (51% vs 37%, P = 0.038) or breast cancer (33% vs 15%, P < 0.001).ConclusionsHereditary breast cancer mutations were observed among Guatemalan women, and these women are more likely to have early age at diagnosis and family history of cancer. These data suggest the use of genetic testing in breast cancer patients and those at high risk as part of a strategy to reduce breast cancer mortality in Guatemala.

A novel frequent BRCA1 recurrent variant c.5117G > A (p.Gly1206Glu) identified after 20\u2009years of BRCA1/2 research in the Baltic region: cohort study and literature review

BackgroundSeveral recent studies in the Baltic region have found extended spectrum of pathogenic variants (PV) of the BRCA1/2 genes. The aim of current study is to analyze the spectrum of the BRCA1/2 PV in population of Latvia and to compare common PV between populations of the Baltic region.MethodsWe present a cohort of 9543 unrelated individuals including ones with cancer and unaffected individuals from population of Latvia, who were tested for three most common BRCA1 founder PV. In second line testing, 164 founder negative high-risk individuals were tested for PV of the BRCA1/2 using next generation sequencing (NGS). Local spectrum of the BRCA1/2 PV was compared with the Baltic region by performing a literature review.ResultsFounder PV c.5266dupC, c.4035delA or c.181 T > G was detected in 369/9543 (3.9%) cases. Other BRCA1/2 PV were found in 44/164 (26.8%) of NGS cases. Four recurrent BRCA1 variants c.5117G > A (p.Gly1706Glu), c.4675G > A (p.Glu1559Lys), c.5503C > T (p.Arg1835*) and c.1961delA (p.Lys654fs) were detected in 18/44 (41.0%), 5/44 (11.4%), 2/44 (4.5%) and 2/44 (4.5%) cases respectively. Additionally, 11 BRCA1 PV and six BRCA2 PV were each found in single family.ConclusionsBy combining three studies by our group of the same cohort in Latvia, frequency of the BRCA1/2 PV for unselected breast and ovarian cancer cases is 241/5060 (4.8%) and 162/1067 (15.2%) respectively. The frequency of three “historical” founder PV is up to 87.0% (369/424). Other non-founder PV contribute to at least 13.0% (55/424) and this proportion probably will rise by increasing numbers of the BRCA1/2 sequencing. In relative numbers, c.5117G > A is currently the third most frequent PV of the BRCA1 in population of Latvia, overcoming previously known third most common founder variant c.181 T > G. In addition to three BRCA1 founder PV, a total of five recurrent BRCA1 and two recurrent BRCA2 PV have been reported in population of Latvia so far. Many of the BRCA1/2 PV reported in Latvia are shared among other populations of the Baltic region.

The BRCA1 c.4096+3A>G Variant Displays Classical Characteristics of Pathogenic BRCA1 Mutations in Hereditary Breast and Ovarian Cancers, But Still Allows Homozygous Viability.

Mutations in BRCA1 result in predisposal to breast and ovarian cancers, but many variants exist with unknown clinical significance (VUS). One is BRCA1 c.4096+3A>G, which affects production of the full-length BRCA1 transcript, while augmenting transcripts lacking most or all of exon 11. Nonetheless, homozygosity of this variant has been reported in a healthy woman. We saw this variant cosegregate with breast and ovarian cancer in several family branches of four Icelandic pedigrees, with instances of phenocopies and a homozygous woman with lung cancer. We found eight heterozygous carriers (0.44%) in 1820 unselected breast cancer cases, and three (0.15%) in 1968 controls (p = 0.13). Seeking conclusive evidence, we studied tumors from carriers in the pedigrees for wild-type-loss of heterozygosity (wtLOH) and BRCA1-characteristic prevalence of estrogen receptor (ER) negativity. Of 15 breast and six ovarian tumors, wtLOH occurred in nine breast and all six ovarian tumours, and six of the nine breast tumors with wtLOH were ER-negative. These data accord with a pathogenic BRCA1-mutation. Our findings add to the current knowledge of BRCA1, and the role of its exon 11 in cancer pathogenicity, and will be of use in clinical genetic counselling.

Inherited Variants in BLM and the Risk and Clinical Characteristics of Breast Cancer.

Bloom Syndrome is a rare recessive disease which includes a susceptibility to various cancers. It is caused by homozygous mutations of the BLM gene. To investigate whether heterozygous carriers of a BLM mutation are predisposed to breast cancer, we sequenced BLM in 617 patients from Polish families with a strong family history of breast cancer. We detected a founder mutation (c.1642C>T, p.Gln548Ter) in 3 of the 617 breast cancer patients (0.49%) who were sequenced. Then, we genotyped 14,804 unselected breast cancer cases and 4698 cancer-free women for the founder mutation. It was identified in 82 of 14,804 (0.55%) unselected cases and in 26 of 4698 (0.55%) controls (OR = 1.0; 95%CI 0.6–1.6). Clinical characteristics of breast cancers in the BLM mutation carriers and non-carriers were similar. Loss of the wild-type BLM allele was not detected in cancers from the BLM mutation carriers. No cancer type was more common in the relatives of mutation carriers compared to relatives of non-carriers. The BLM founder mutation p.Gln548Ter, which in a homozygous state is a cause of Bloom syndrome, does not appear to predispose to breast cancer in a heterozygous state. The finding casts doubt on the designation of BLM as an autosomal dominant breast cancer susceptibility gene.

Inherited variants in XRCC2 and the risk of breast cancer

BackgroundXRCC2 participates in homologous recombination and in DNA repair. XRCC2 has been reported to be a breast cancer susceptibility gene and is now included in several breast cancer susceptibility gene panels.MethodsWe sequenced XRCC2 in 617 Polish women with familial breast cancer and found a founder mutation. We then genotyped 12,617 women with breast cancer and 4599 controls for the XRCC2 founder mutation.ResultsWe identified a recurrent truncating mutation of XRCC2 (c.96delT, p.Phe32fs) in 3 of 617 patients with familial breast cancer who were sequenced. The c.96delT mutation was then detected in 29 of 12,617 unselected breast cancer cases (0.23%) compared to 11 of 4599 cancer-free women (0.24%) (OR = 0.96; 95% CI 0.48–1.93). The mutation frequency in 1988 women with familial breast cancer was 0.2% (OR = 0.84, 95% CI 0.27–2.65). Breast cancers in XRCC2 mutation carriers and non-carriers were similar with respect to age of diagnosis and clinical characteristics. Loss of the wild-type XRCC2 allele was observed only in one of the eight breast cancers from patients who carried the XRCC2 mutation. No cancer type was more common in first- or second-degree relatives of XRCC2 mutation carriers than in relatives of the non-carriers.ConclusionXRCC2 c.96delT is a protein-truncating founder variant in Poland. There is no evidence that this mutation predisposes to breast cancer (and other cancers). It is premature to consider XRCC2 as a breast cancer-predisposing gene.

Multigene panel testing in unselected Israeli breast cancer cases: mutational spectrum and use of BRCA1/2 mutation prediction algorithms.

Studies assessing the contribution of non-BRCA1/2 gene mutations to inherited breast cancer (BC) predisposition consistently reported low (up to 4%) yield. The current study aimed at assessing the spectrum of non-BRCA mutations in unselected Israeli BC cases and the utility of BRCAPRO and Penn II models, as tools for prediction of detecting non-BRCA1/2 mutations in Israeli BC patients who tested negative for the predominant Jewish BRCA1/2 mutations. All consecutive Jewish Israeli BC patients at the Sheba Medical center who tested negative for the predominant BRCA1/2 mutations and elected to perform multigene panel testing were included. For each patient probability of BRCA mutation detection was calculated by the Penn II algorithm and the BRCAPRO tool. Overall, 144 cases were included (median age at diagnosis was 48, range 20-73years); 48% were Ashkenazim. One patient harbored a non-founder BRCA1 mutation (c.5434C>G; p.P1812A). Pathogenic/likely pathogenic (P/LP) mutations in non-BRCA1/2 genes were detected in additional 14/144 patients, including CHEK2 (n = 5), RAD51D (n = 2), MSH6 (n = 2), and one each in ATM, RET, TP53, NBN, and BAP1. Using a cutoff of 15% probability of BRCA mutation detection, both models accurately predicted the observed carrier rate of non-BRCA mutations. In unselected Jewish Israeli BC patients, the rate of detecting non-founder BRCA1/2 mutations is low, with CHEK2 mutations detected in 3.4% of cases. BRCA1/2 mutation prediction models may be utilized for selecting patients eligible for further multigene panel testing after exclusion of predominant BRCA1/2 mutations.

Prevalence and Penetrance of BRCA1 and BRCA2 Germline Mutations in Colombian Breast Cancer Patients

Pathogenic BRCA1/2 germline mutations confer high risks of breast and ovarian cancer to women of European ancestry. Characterization of BRCA1/2 mutations in other ethnic groups is also medically important. We comprehensively screened 68 Colombian breast/ovarian cancer families for small-range mutations, 221 families for large-genomic rearrangements, and 1,022 unselected breast cancer cases for Colombian founder mutations in BRCA1/2. The risk of cancer among relatives of mutation carriers and the mutation penetrance were estimated by survival analysis. Identified BRCA2 mutations included 6310delGA and the recurrent 1991del4 mutations. A novel large BRCA2 deletion was found in 0.9% of the screened families. Among unselected breast cancer cases, 3.3% tested positive for BRCA1/3450del4, 2.2% for BRCA1/A1708E, 1.1% for BRCA2/3034del4, and 0.4% for BRCA2/1991del4. Female relatives of carriers of BRCA1/2 founder mutations showed a 5.90 times higher risk of breast cancer, when the woman herself carried a BRCA1 mutation compared to a non-carrier (95% CI 2.01–17.3). The estimated cumulative risk of breast cancer by age 70 years for BRCA1 mutations carriers was 14% (95% CI 5–38) compared to 3% for the general Colombian population (relative risk of breast cancer 4.05). Together with known founder mutations, reported novel variants may ease a cost-effective BRCA1/2 screening in women with Colombian ancestry.

Abstract 1294: Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia

Abstract Germline mutations in the BRCA1 and BRCA2 genes result in predisposition to breast and ovarian cancer. Detection of BRCA mutation carriers can lead to improved prevention and therapeutic interventions such as the targeted therapy using poly ADP ribose polymerase (PARP) inhibitors, which are particularly effective in BRCA mutation carriers. The spectrum of BRCA mutations varies depending on geographic origin, population, and ethnic group; however, the prevalence of BRCA mutations in non-Caucasian populations has been poorly characterized, particularly in a population-based setting. The goal of this study was to characterize the spectrum of germline mutations in BRCA1/2 and PALB2 in unselected breast cancer cases who were seen in Sarawak General Hospital, Malaysia, where 93% of the breast cancer patients in Sarawak are treated. We performed targeted sequencing using a validated AmpliSeq panel on 467 cases with available risk factor questionnaire and clinical follow-up data. Breast cancer subtypes were defined by the joint expression of ER, PR, and HER2. Common variants with frequency &amp;gt;1% in any public database (1000 Genome, Exome Sequencing Project, The Exome Aggregation Consortium) were excluded. Pathogenic variants included known pathogenic variants in ClinVar, loss of function variants (frameshift and stop-gain), and variants that alter the first or second base of the splice site. Variants of unknown significance (VUS) were also defined using the ClinVar classification. We found 10 BRCA1 pathogenic variants in 12 patients, 10 BRCA2 pathogenic variants in 15 patients, and 4 PALB2 pathogenic variants in 4 patients, which gave a BRCA mutation prevalence of 5.78% among the unselected breast cancer cases in this population. All these variants were extremely rare in the general population (&amp;lt;0.05%). Only 4 of them were recurrent variants (2 in BRCA1 and 2 in BRCA2) and all four are known variants that were reported previously in other populations. In addition, we identified a novel deleterious mutation (stop-gain) that has never been reported and a number of VUS variants in this population. Patients with pathogenic BRCA and PALB2 variants were associated with an earlier age at onset (7 years younger, p=0.0005), a positive family history (20% higher, p=0.01), and the triple-negative (TN) subtype (56% vs. 18%, p&amp;lt;0.0001), compared to patients without mutations. Mutation carrier cases had worse survival compared to non-carriers, however, the association was mostly driven by the higher frequency of TN in mutation carriers. Our study for the first time reported the prevalence of germline mutations in BRCA and PALB2 in a quasi-population-based case series unselected for age and family history in an under-studied Asian population. Our results may have important clinical implications for performing genetic testing on selected patients in a low-resource setting. Citation Format: Xiaohong (Rose) Yang, Beena Devi, Hyuna Sung, Jennifer Guida, Yanzi Xiao, Lisa Garland, Nan Hu, Maria Rodriguez-Herrera, Chaoyu Wang, Kristine Jones, Wen Luo, Belynda Hicks, Tieng Swee Tang, Karobi Moitra, Mike Dean. Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1294. doi:10.1158/1538-7445.AM2017-1294

Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia.

To characterize the spectrum of germline mutations in BRCA1, BRCA2, and PALB2 in population-based unselected breast cancer cases in an Asian population. Germline DNA from 467 breast cancer patients in Sarawak General Hospital, Malaysia, where 93% of the breast cancer patients in Sarawak are treated, was sequenced for the entire coding region of BRCA1; BRCA2; PALB2; Exons 6, 7, and 8 of TP53; and Exons 7 and 8 of PTEN. Pathogenic variants included known pathogenic variants in ClinVar, loss of function variants, and variants that disrupt splice site. We found 27 pathogenic variants (11 BRCA1, 10 BRCA2, 4 PALB2, and 2 TP53) in 34 patients, which gave a prevalence of germline mutations of 2.8, 3.23, and 0.86% for BRCA1, BRCA2, and PALB2, respectively. Compared to mutation non-carriers, BRCA1 mutation carriers were more likely to have an earlier age at onset, triple-negative subtype, and lower body mass index, whereas BRCA2 mutation carriers were more likely to have a positive family history. Mutation carrier cases had worse survival compared to non-carriers; however, the association was mostly driven by stage and tumor subtype. We also identified 19 variants of unknown significance, and some of them were predicted to alter splicing or transcription factor binding sites. Our data provide insight into the genetics of breast cancer in this understudied group and suggest the need for modifying genetic testing guidelines for this population with a much younger age at diagnosis and more limited resources compared with Caucasian populations.

Polygenic risk score is associated with increased disease risk in 52 Finnish breast cancer families.

The risk of developing breast cancer is increased in women with family history of breast cancer and particularly in families with multiple cases of breast or ovarian cancer. Nevertheless, many women with a positive family history never develop the disease. Polygenic risk scores (PRSs) based on the risk effects of multiple common genetic variants have been proposed for individual risk assessment on a population level. We investigate the applicability of the PRS for risk prediction within breast cancer families. We studied the association between breast cancer risk and a PRS based on 75 common genetic variants in 52 Finnish breast cancer families including 427 genotyped women and pedigree information on ~4000 additional individuals by comparing the affected to healthy family members, as well as in a case–control dataset comprising 1272 healthy population controls and 1681 breast cancer cases with information on family history. Family structure was summarized using the BOADICEA risk prediction model. The PRS was associated with increased disease risk in women with family history of breast cancer as well as in women within the breast cancer families. The odds ratio (OR) for breast cancer within the family dataset was 1.55 [95 % CI 1.26–1.91] per unit increase in the PRS, similar to OR in unselected breast cancer cases of the case–control dataset (1.49 [1.38–1.62]). High PRS-values were informative for risk prediction in breast cancer families, whereas for the low PRS-categories the results were inconclusive. The PRS is informative in women with family history of breast cancer and should be incorporated within pedigree-based clinical risk assessment.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-016-3897-6) contains supplementary material, which is available to authorized users.

Abstract 1786: One in four Hispanic women with early onset breast cancer carry BRCA1, BRCA2, or PALB2 mutations: Results from a population-based study in South America

Abstract Breast cancer is the leading cause of cancer incidence and mortality among Hispanic women, who are often diagnosed with late stage tumors and are more likely to die after diagnosis when compared to non-Hispanic whites. While strides have been made in understanding Hispanic breast cancer genetics, most studies have been limited to investigating cases from high-risk clinics. In this study, we aimed to assess the prevalence of pathogenic mutations in three most important breast cancer genes (BRCA1, BRCA2 and PALB2) in an unselected Hispanic breast cancer cohort. Initially, six hundred and forty-six unselected Colombian breast cancer cases were screened for four known Hispanic BRCA1/2 mutations by genotyping. Subsequently, cases that remained mutation negative, as well as 186 cancer-free controls, were screened for BRCA1, BRCA2 and PALB2 mutations using targeted next generation sequencing. We identified 67 cases with pathogenic mutations, one case with a likely-pathogenic variant, and 16 carriers of variants of unknown significance. Among the pathogenic mutation carriers, 88.1% harbored a founder mutation (n = 59), which includes the known BRCA1 3450del4 mutation, strikingly found in 32 unrelated cases. Remarkably, we found that 1 in 4 of the cases diagnosed with breast cancer by age 40 years, regardless of family history of cancer, carried a pathogenic mutation. The high frequency of pathogenic mutations in this unselected cohort (10.4%), in particular those with an early age of onset (25.3%), suggests that population-based genetic testing among Hispanic communities can identify most carriers who would otherwise ineligible for testing. Identifying mutation carriers of these genes has implications in clinical management and surveillance for Hispanic women, a population that is vulnerable to breast cancer disparities in the U.S. and Latin America. Citation Format: Anna Marie Tuazon, Mabel Bohorquez, Carolina Ramirez, Paul Lott, Ana Estrada, Angel Criollo, Cathy Wang, Magdalena Echeverry, John Suarez, COLUMBUS Consortium, LaFamilia Consortium, Luis G. Carvajal Carmona. One in four Hispanic women with early onset breast cancer carry BRCA1, BRCA2, or PALB2 mutations: Results from a population-based study in South America. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1786.

Abstract P2-09-05: Multiple-gene panel sequencing prompts no change in care compared to BRCA1 and BRCA2 testing in male breast cancer patients and their families

Abstract Male breast cancer is a rare cancer entity, representing just 1% of all cancers diagnosed in men. It shares clinical and biological characteristics with post-menopausal female breast cancer, although recent reports showed that they are not identical. Approximately 10% of unselected male breast cancer cases carry BRCA1 &amp; BRCA2 mutations, with the most frequently mutated gene being BRCA2. Multiple-gene sequencing has already entered clinical practice and leads in detection of potential pathogenic variants in other cancer predisposition genes, in as many as 15% female breast cancer patients without BRCA1 &amp; BRCA2 mutations. We evaluated the performance of a customized panel for cancer risk assessment in a representative sample of male breast cancer patients. Ninety eight male individuals diagnosed with breast cancer (mean age 59y, range 38y-81y) and referred for genetic counseling between 2010 and 2015 were invited to donate a research blood sample. Patients were eligible irrespectively of family history and age at diagnosis. Genomic DNAs were used to prepare libraries for the capture of the entire coding regions of twenty six known -or suspected- breast cancer genes. These were: BRCA1, BRCA2, TP53, STK11, CDH1, PTEN, PALB2, ATM, CHEK2, NBN, BRIP1, BARD1, RAD51C, RAD51D, RAD50, BLM, SLX4, MRE11A, FAM175A, MLH1, MSH2, EPCAM, MHS6, PMS2, MUTYH, NF1. Loss-of-function mutations have been found in three genes; BRCA2, BRCA1 and PMS2. Not surprisingly, the most frequently mutated gene was BRCA2 accounting for 5% of the cases, while BRCA1 and PMS2 mutations have been detected in single cases, accounting each for 1%. Interestingly, no mutations were identified in any of other genes that have been reported in female breast-ovarian cancer families (PALB2, TP53, ATM, CDH1, RAD51C, RAD51D, etc). Compared to BRCA1 &amp; BRCA2 testing, gene panel prompted consideration of change in care (early colon cancer screening) in a single family (1%). This is the first evaluation of the performance a multiple-gene panel in male patients with breast cancer. Our findings confirm that genetic counseling and BRCA1 &amp; BRCA2 should be the primary concern for these patients and their families. Mutations in other genes been reported in female breast-ovarian cancer families were not identified in this cohort. If larger studies confirm our results, then multiple-gene sequencing panels may be of limited benefit for male breast cancer patients and their families. Citation Format: Fostira F, Saloustros E, Konstantopoulou I, Tryfonopoulos D, Barbounis V, Mauroudis D, Georgoulias V, Fountzilas G, Yannoukakos D. Multiple-gene panel sequencing prompts no change in care compared to BRCA1 and BRCA2 testing in male breast cancer patients and their families. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-05.

The spectrum of BRCA1 and BRCA2 alleles in Latin America and the Caribbean: a clinical perspective.

Hereditary cancer predisposition gene testing allows the identification of individuals at high risk of cancer that may benefit from increased surveillance, chemoprevention, and prophylactic surgery. In order to implement clinical genetic strategies adapted to each population’s needs and intrinsic genetic characteristic, this review aims to present the current status of knowledge about the spectrum of BRCA pathogenic variants in Latin American populations. We have conducted a comprehensive review of 33 studies published between 1994 and 2015 reporting the prevalence and/or spectrum of BRCA1 (OMIM 113705) and BRCA2 (OMIM 600185) variants. The combined sample size for these studies consisted of 4835 individuals from 13 countries in Latin America and the Caribbean, as well as in Hispanics in the United States. A total of 167 unique pathogenic variants have been reported in the existing literature. In unselected breast cancer cases, the prevalence ranged from 1.2 to 27.1 %. Some countries presented a few recurrent pathogenic variants, while others were characterized by diverse, non-recurrent variants. The proportion of BRCA pathogenic variants shared between Hispanics in the United States and Latin American populations was estimated at 10.4 %. Within Latin America and the Caribbean, 8.2 % of the BRCA variants reported were present in more than one country. Countries with high prevalence of BRCA pathogenic variants may benefit from more aggressive testing strategies, while testing of recurrent variant panels might present a cost-effective solution for improving genetic testing in some, but not all, countries.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-015-3629-3) contains supplementary material, which is available to authorized users.

Abstract IA23: Steps to address the profound disparity in access to genetic cancer risk assessment in Mexico: Documenting hereditary breast and ovarian cancer and the beginning of a prevention program

Abstract IA23: Steps to address the profound disparity in access to genetic cancer risk assessment in Mexico: Documenting hereditary breast and ovarian cancer and the beginning of a prevention program

Abstract P3-08-06: Demographics of breast cancer in a cohort of Afro-Caribbean women

Abstract Objectives: In Latin America and the Caribbean, non – communicable chronic diseases are now the leading cause of premature mortality. The incidence of cancer has increased in the region as a result of population aging and growth but also as more people adopt lifestyle choices like smoking, physical inactivity, and ‘‘westernized’’ diets. In women, fertility factors such as decreased parity, earlier onset of menses and later age at time of first pregnancy are known epidemiologically to increase incidence of hereditary and sporadic breast cancer. Recently there has also been a strong link to a genetic etiology of the breast and ovarian cancer in the Bahamas (27% in unselected breast cancer cases). A study was designed to address the prevalence and spectrum of BRCA1 and BRCA2 mutations in the Afro-Caribbean population. Methods: Demographic and clinical pathologic data was collected from 347 women of Afro-Caribbean decent. The cohort included women with breast cancer from the following countries: the Cayman Islands, Jamaica, Barbados, Dominica, Trinidad and Haiti. Summary statistics and t-tests and ANOVA were used to analyze population characteristics. A Bahamian mutation panel was created and detailed analyses of samples are ongoing. Results: The mean age of onset in the cohort is 48.1 yrs with a mean BMI of 27.7. 70% of breast cancer cases ER+ (n=241 informative cases) and in Jamaica 27% (n=105) of breast cancer cases were Her2+. 67.8% cases were diagnosed at stages II/III (n=90). TAH-BSO delayed invasive breast cancer from 48 to 53 years, p=0.005. Parity was a statistically significant factor (p&amp;lt;0.0001), which delayed age of onset by 8 yrs. Additionally, pregnancy alone delayed age of onset (p&amp;lt;0.005) also by 8 yrs in our cohort (n=379). Only three women out of 347 were found to have a mutation. Summary demographics of Caribbean women with breast cancerCountryNo. of ParticipantsMean age at diagnosis (yrs)ER+Her2+BRCA1/2 +BMICayman Islands6651.429/443/431/2730.3Barbados8946.652/739/734/8727.5Dominica6052.29/132/70/4628.7Jamaica13748.669/10528/105128.7Trinidad and Tobago645.54/61/51/527.4Haiti3448.5NANANA24.9 Reproductive Characteristics of Caribbean women with breast cancerNMean Agep-valueTAH-BSOPerformed71530.005Not Performed30448ParityNulliparous6042⟨ 0.0001Multiparous31950PregnancyNone4843⟨ 0.0001More than 133150 Conclusions: This population-based study provides an insight into pattern of risk factors – both genetic and environmental of breast cancer incidence and subtype across the Caribbean. In conclusion 1) genetic causes of breast cancer appear rare outside of the Bahamas, 2) fertility factors appear important in the development of breast cancer, 3) TAH-BSO is common as both a form of contraception and because of the high incidence of fibroids in the Caribbean and it may be protective, 4) BMI may impact on breast cancer development and 5) screening mammography is rare and the vast majority of mammography performed is diagnostic in nature. Citation Format: Sophia HL George, Talia Donenberg, Mohammed Akbari, Cheryl Alexis, Gillian Wharfe, Sook Yin, Hedda Dyer, Theodore Turnquest, Vincent DeGennaro, Steven Narod, Judith Hurley. Demographics of breast cancer in a cohort of Afro-Caribbean women [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-08-06.