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Germline mutations in BRCA1 and BRCA2 (gBRCA1/2) are required for a PARP inhibitor therapy in patients with HER2-negative (HER2-) advanced breast cancer (aBC). However, little is known about the prognostic impact of gBRCA1/2 mutations in aBC patients treated with chemotherapy. This study aimed to investigate the frequencies and prognosis of germline and somatic BRCA1/2 mutations in HER2- aBC patients receiving the first chemotherapy in the advanced setting. Patients receiving their first chemotherapy for HER2- aBC were retrospectively selected from the prospective PRAEGNANT registry (NCT02338167). Genotyping of 26 cancer predisposition genes was performed with germline DNA of 471 patients and somatic tumor DNA of 94 patients. Mutation frequencies, progression-free and overall survival (PFS, OS) according to germline mutation status were assessed. gBRCA1/2 mutations were present in 23 patients (4.9%), and 33 patients (7.0%) had mutations in other cancer risk genes. Patients with a gBRCA1/2 mutation had a better OS compared to non-mutation carriers (HR: 0.38; 95%CI: 0.17-0.86). PFS comparison was not statistically significant. Mutations in other risk genes did not affect prognosis. Two somatic BRCA2 mutations were found in 94 patients without gBRCA1/2 mutations. Most frequently somatic mutated genes were TP53 (44.7%), CDH1 (10.6%) and PTEN (6.4%). In conclusion, aBC patients with gBRCA1/2 mutations had a more favorable prognosis under chemotherapy compared to non-mutation carriers. The mutation frequency of ~5% with gBRCA1/2 mutations together with improved outcome indicates that germline genotyping of all metastatic patients for whom a PARP inhibitor therapy is indicated should be considered., (© 2024. The Author(s).)

Variants of uncertain significance (VUSs) in BRCA2 are a common result of hereditary cancer genetic testing. While more than 4,000 unique VUSs, comprised of missense or intronic variants, have been identified in BRCA2, the few missense variants now classified clinically as pathogenic or likely pathogenic are predominantly located in the region encoding the C-terminal DNA binding domain (DBD). We report on functional evaluation of the influence of 462 BRCA2 missense variants affecting the DBD on DNA repair activity of BRCA2 using a homology-directed DNA double-strand break repair assay. Of these, 137 were functionally abnormal, 313 were functionally normal, and 12 demonstrated intermediate function. Comparisons with other functional studies of BRCA2 missense variants yielded strong correlations. Sequence-based in silico prediction models had high sensitivity, but limited specificity, relative to the homology-directed repair assay. Combining the functional results with clinical and genetic data in an American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP)-like variant classification framework from a clinical testing laboratory, after excluding known splicing variants and functionally intermediate variants, classified 431 of 442 (97.5%) missense variants (129 as pathogenic/likely pathogenic and 302 as benign/likely benign). Functionally abnormal variants classified as pathogenic by ACMG/AMP rules were associated with a slightly lower risk of breast cancer (odds ratio [OR] 5.15, 95% confidence interval [CI] 3.43-7.83) than BRCA2 DBD protein truncating variants (OR 8.56, 95% CI 6.03-12.36). Overall, functional studies of BRCA2 variants using validated assays substantially improved the variant classification yield from ACMG/AMP models and are expected to improve clinical management of many individuals found to harbor germline BRCA2 missense VUS., Competing Interests: Declaration of interests R.K., T.P., J.D.W., C.M.C., C.A.S., C.C.Y., K.F., Z.H., and M.E.R. are employees of Ambry Genetics Inc. All other authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Purpose: To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM , BRCA1 , BRCA2 , CHEK2 , and PALB2 ., Methods: The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status., Results: Germline BRCA1 , BRCA2 , and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1 , 27% for BRCA2 , and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1 , 9% for BRCA2 , and 4% for CHEK2 ., Conclusion: Women diagnosed with breast cancer and known to carry germline PVs in BRCA1 , BRCA2 , CHEK2 , or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

Capture-based library preparation for next generation sequencing (NGS) offers a balance between sequencing depth and bioinformatics cost of analysis. Liquid handling automation enhances the reliability of the library preparation process by reducing sample-to-sample variation and substantially enhances throughput, particularly when it can be employed in a 'walk-away' fashion with limited hands-on interaction. This requires complex series of mixing and heating steps like those utilized in capture chemistries to happen on the liquid handler. While developing liquid handling automation for Integrated DNA Technologies (IDT) xGen Exome, Illumina TruSight Oncology 500, and Personal Genome Diagnostics (PGDx) elio Plasma Resolve chemistries on the PerkinElmer Sciclone liquid handler, we found that applying the capture temperatures recommended for manual library preparation results in low yield on automation. To restore the final library yield, we reduced bead binding and/or heated wash temperatures of the Peltier heaters on the liquid handlers by about 10°C. Since this applied across three unique capture-based chemistries, we consider this a generalizable principle of automating capture on the Sciclone. We hypothesize that this is driven by the very different thermodynamic environments represented by a sealed plate on a thermal cycler and a plate with a lid on a Peltier heater. This phenomenon should be considered when automating NGS library preparation on PerkinElmer Sciclone instruments., (Copyright © 2021. Published by Elsevier Inc.)

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., Competing Interests: Jeffrey N. WeitzelSpeakers' Bureau: AstraZeneca Celine M. VachonStock and Other Ownership Interests: Exact Sciences (I)Research Funding: GRAILPatents, Royalties, Other Intellectual Property: Breast Density softwareTravel, Accommodations, Expenses: GRAIL Allison W. KurianResearch Funding: Myriad GeneticsOther Relationship: Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, Genentech Rachid KaramEmployment: Ambry GeneticsResearch Funding: Ambry GeneticsTravel, Accommodations, Expenses: Ambry Genetics Elizabeth ChaoEmployment: Ambry Genetics Amal YussufEmployment: Ambry Genetics Tina PesaranEmployment: Ambry Genetics/Konica Minolta Jill S. DolinskyEmployment: Ambry Genetics Holly LaDucaEmployment: Ambry GeneticsStock and Other Ownership Interests: Ambry Genetics Eric C. PolleyResearch Funding: GRAIL Susan M. DomchekHonoraria: AstraZeneca, Clovis Oncology, Bristol Myers SquibbResearch Funding: AstraZeneca, Clovis Oncology Fergus J. CouchConsulting or Advisory Role: AstraZenecaSpeakers' Bureau: Ambry Genetics, QiagenResearch Funding: GRAILTravel, Accommodations, Expenses: GRAIL, QiagenOther Relationship: Ambry GeneticsNo other potential conflicts of interest were reported.

Purpose: The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years., Methods: A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs., Results: The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1 , BRCA2 , and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)-negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2 , PALB2 , BRCA2 , and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1 , BRCA2 , and PALB2 ., Conclusion: This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening., Competing Interests: Jeffrey N. WeitzelSpeakers' Bureau: AstraZeneca Amal YussufEmployment: Ambry Genetics Celine M. VachonStock and Other Ownership Interests: Exact SciencesResearch Funding: GRAILPatents, Royalties, Other Intellectual Property: Breast Density softwareTravel, Accommodations, Expenses: GRAIL Tina PesaranEmployment: Ambry Genetics/Konica MinoltaTravel, Accommodations, Expenses: Ambry Genetics/Konica Minolta Irene M. OngEmployment: Propeller HealthStock and Other Ownership Interests: AyrFlo Rachid KaramEmployment: Ambry GeneticsResearch Funding: Ambry GeneticsTravel, Accommodations, Expenses: Ambry Genetics Holly LaDucaEmployment: Ambry GeneticsStock and Other Ownership Interests: Ambry Genetics Jill S. DolinskyEmployment: Ambry Genetics Elizabeth ChaoEmployment: Ambry Genetics Eric C. PolleyResearch Funding: GRAIL Susan M. DomchekHonoraria: AstraZeneca, Clovis Oncology, Bristol Myers SquibbResearch Funding: AstraZeneca, Clovis OncologyOpen Payments Link: https://openpaymentsdata.cms.gov/physician/917904 Fergus J. CouchConsulting or Advisory Role: AstraZenecaSpeakers' Bureau: Ambry Genetics, QiagenResearch Funding: GRAILTravel, Accommodations, Expenses: GRAIL, QiagenOther Relationship: Ambry GeneticsNo other potential conflicts of interest were reported.

Purpose: Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome., Patients and Methods: Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed., Results: Germline mutations in 12 established BC predisposition genes (including BRCA1 and BRCA2 ) were detected in 271 (10.4%) patients. A mutation in BRCA1 or BRCA2 was seen in 129 patients (5.0%). BRCA1 mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% v 6.6%, P < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC., Conclusion: Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in BRCA1/2 and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies., Competing Interests: Peter A. FaschingHonoraria: Roche, Novartis, Pfizer, ClinSol GmbH, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, AstraZeneca, Hexal, Lilly, Cepheid, BionTech, Pierre FabreConsulting or Advisory Role: Amgen, Teva, Celgene, Novartis, Pfizer, Roche, Puma Biotechnology, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, AstraZeneca, Hexal, Myelo Therapeutics GmbH, MacrogenicsResearch Funding: Novartis, BioNTech AG, Cepheid Eric C. PolleyResearch Funding: GRAIL Hans TeschHonoraria: Novartis, Roche Pharma AG, Pfizer, Amgen GmbH, AstraZeneca, Vifor Pharma, Lilly, Eisai, MSD Oncology, Grünethal, Bristol Myers Squibb, Mundipharma, ClinSol GmbHTravel, Accommodations, Expenses: Roche Pharma AG, Pfizer, Novartis, Amgen, AstraZeneca, Vifor Pharma, Lilly, Eisai Europe, MSD Oncology Johannes EttlHonoraria: Pfizer, Novartis, Lilly, Roche, Teva, AstraZeneca, Tesaro, Celgene, Pierre FabreConsulting or Advisory Role: Pfizer, Novartis, Lilly, Tesaro, Roche, Pierre Fabre, Daiichi SankyoSpeakers' Bureau: Pfizer, Roche, Lilly, Teva, Celgene, AstraZenecaResearch Funding: LillyTravel, Accommodations, Expenses: Pfizer, Teva, Celgene, Lilly, NovartisOther Relationship: Tesaro Friedrich OverkampHonoraria: Amgen, AstraZeneca, Bayer, Beiersdorf, Bristol Myers Squibb, Boehringer, Chugai, Celgene, Eisai, Gilead, Hexal, Ipsen, Janssen, Merck, Merck Sharp & Dohme, Novartis, Novonordisc, Riemser, Servier, ShireConsulting or Advisory Role: Amgen, Bristol Myers Squibb, Boehringer, Celgene, Clovis, Eusapharma, Hexal, Oncopeptides, Pfizer, Takeda Michael P. LuxHonoraria: Novartis, Pfizer, Lilly, AstraZeneca, Hexal, Eisai, Roche Pharma AG, Genomic Health, MSD OncologyConsulting or Advisory Role: Roche Pharma AG, Lilly, Pfizer, Novartis, AstraZeneca, Grünenthal Group, Genomic Health, Eisai, MSD Oncology, Pierre FabreSpeakers' Bureau: Roche Pharma AG, Novartis, Pfizer, Lilly, AstraZeneca, MSD Oncology, Eisai Germany, Exact SciencesResearch Funding: Discovering Hands, MSD Oncology, German Breast Group, Roche, PRAEGNANT Network, Grünenthal Group, SamantreeTravel, Accommodations, Expenses: Pfizer, Roche Pharma AGOther Relationship: MedacUncompensated Relationships: Pfizer, AstraZeneca Diana LüftnerHonoraria: AstraZeneca, Amgen, GlaxoSmithKline, Lilly, Pfizer, Novartis, L'Oreal, Teva Innovation Canada, SanofiResearch Funding: NovartisTravel, Accommodations, Expenses: Sanofi, Pfizer, Novartis Markus WallwienerHonoraria: Novartis, Pfizer, Roche, AstraZeneca, CelgeneConsulting or Advisory Role: Novartis, Roche, Pfizer, AstraZenecaResearch Funding: Novartis, Pfizer, AstraZeneca Volkmar MüllerHonoraria: AstraZeneca, Amgen, Daiichi Sankyo, Eisai, Pfizer, Novartis, Roche, Teva, Tesaro, MSD Oncology, Pierre Fabre, Nektar, Genomic Health, Lilly, Seattle GeneticsConsulting or Advisory Role: Hexal, Roche, Amgen, Daiichi Sankyo, Nektar, Eisai, Lilly, Seattle GeneticsResearch Funding: Novartis, Seattle Genetics, Roche/GenentechTravel, Accommodations, Expenses: Roche, Pfizer, Daiichi Sankyo Erik BellevilleConsulting or Advisory Role: Novartis, HexalResearch Funding: Novartis, Hexal, Merrimack, AstraZeneca, PfizerTravel, Accommodations, Expenses: Onkowissen Michael UntchHonoraria: AstraZeneca, Art tempi, Bristol Myers Squibb, Celgene, Daiji Sankyo, Roche Pharma AG, Pfizer, Mundipharma, MSD Oncology, Pierre Fabre, Sanofi, Seattle Genetics, AgendiaConsulting or Advisory Role: Amgen, Abbvie, Celgene, Lilly, Mundipharma, Novartis, MSD Oncology, Pfizer, Roche Pharma AG, Agendia, Pierre Fabre, Seattle Genetics Hans-Christian KolbergStock and Other Ownership Interests: Theraclion, Phaon ScientificHonoraria: AstraZeneca, Amgen, Theraclion, Carl Zeiss Meditec, Novartis, Pfizer, Roche, Genomic Health, SurgVision, Theramex, MSD Oncology, OnkowissenConsulting or Advisory Role: SurgVision, AmgenTravel, Accommodations, Expenses: Carl Zeiss Meditec, Novartis, Pfizer, Amgen, Roche, LIV Pharma, Tesaro, Daiichi Sankyo, Genomic Health Arndt HartmannHonoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, AstraZeneca, Boehringer Ingelheim, Abbvie, Janssen-Cilag, IpsenConsulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Cepheid, Qiagen, Janssen-Cilag, AstraZeneca, Ipsen, NanoString Technologies, Illumina, 3DHISTECH, DiaceuticsResearch Funding: Cepheid, BioNTech AG, Roche, Janssen-Cilag, NanoString Technologies, AstraZenecaExpert Testimony: NanoString Technologies Wolfgang JanniHonoraria: Novartis, Roche, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo Europe GmbH, MSD OncologyConsulting or Advisory Role: Menarini Silicon Biosystems, Novartis, Roche, Pfizer, Lilly, AstraZeneca, Daiichi Sankyo, Seattle GeneticsResearch Funding: Janssen Diagnostics, Menarini Silicon Biosystems, Novartis, Roche, Pfizer, Lilly, Amgen Pauline WimbergerHonoraria: AstraZeneca, MSD Oncology, Teva, Eisai, Novartis/Pfizer, Roche Pharma AG, Amgen, PfizerConsulting or Advisory Role: Amgen, AstraZeneca, MSD Oncology, Novartis, Roche Pharma AG, Tesaro, PharmaMarTravel, Accommodations, Expenses: Roche Pharma AG Florin-Andrei TaranHonoraria: Tesaro, NovartisConsulting or Advisory Role: GlaxoSmithKline, Roche, NovartisTravel, Accommodations, Expenses: GlaxoSmithKline Tanja N. FehmConsulting or Advisory Role: Roche, Novartis, Amgen, Pfizer, AstraZeneca, Daiichi Sankyo, MSD OncologyTravel, Accommodations, Expenses: Roche Diethelm WallwienerConsulting or Advisory Role: ConsalResearch Funding: Roche Pharma AG, Pfizer, Novartis Pharmaceuticals UK Ltd, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo/Lilly, Sanofi, GlaxoSmithKline, Merck Sharp & Dohme Sara Y. BruckerConsulting or Advisory Role: Roche, Novartis, Pfizer, Teva, Merck Sharp & Dohme, OlympusResearch Funding: Novartis, Roche, Pfizer, Genomic HealthTravel, Accommodations, Expenses: Novartis, Roche, Pfizer, Olympus, Teva, Merck Sharp & Dohme Andreas SchneeweissHonoraria: Roche Pharma AG, Celgene, AstraZeneca, Pfizer, Novartis, MSD Oncology, Lilly, TesaroResearch Funding: Roche Pharma AG, Celgene, Abbvie, Molecular PartnersExpert Testimony: Roche, AstraZenecaTravel, Accommodations, Expenses: Roche, Celgene Andreas D. HartkopfHonoraria: Roche, Novartis, Lilly, AstraZeneca, Merck Sharp & Dohme, Seagen, Daiichi Sankyo, GlaxoSmithKline, Genomic Health, Agendia, Pfizer, Amgen Fergus J. CouchConsulting or Advisory Role: AstraZenecaSpeakers' Bureau: Ambry Genetics, QiagenResearch Funding: GRAILTravel, Accommodations, Expenses: GRAIL, QiagenOther Relationship: Ambry GeneticsNo other potential conflicts of interest were reported.

Purpose: To compare the clinical characteristics and overall survival (OS) of germline mutation carriers in homologous recombination repair (HRR) genes and noncarriers with pancreatic ductal adenocarcinoma (PDAC)., Experimental Design: Germline DNA from 3,078 patients with PDAC enrolled in a prospective registry at Mayo Clinic between 2000 and 2017 was analyzed for mutations in 37 cancer predisposition genes. Characteristics and OS of patients with mutations in eight genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, and RAD51D) involved in HRR were compared with patients testing negative for mutations in all 37 genes., Results: The 175 HRR mutation carriers and 2,730 noncarriers in the study had a median duration of follow-up of 9.9 years. HRR mutation carriers were younger (median age at diagnosis: 63 vs. 66 years, P < 0.001) and more likely to have metastatic disease at diagnosis (46% vs. 36%, P = 0.004). In a multivariable model adjusting for sex, age at diagnosis, and tumor staging, patients with germline HRR mutations had a significantly longer OS compared with noncarriers [HR, 0.83; 95% confidence interval (CI), 0.70-0.97; P = 0.02]. Further gene-level analysis demonstrated that germline ATM mutation carriers had longer OS compared with patients without germline mutations in any of the 37 genes (HR, 0.72; 95% CI, 0.55-0.94; P = 0.01)., Conclusions: This study demonstrates that germline mutation carrier status in PDAC is associated with longer OS compared with noncarriers. Further research into tumor biology and response to platinum-based chemotherapy in germline mutation carriers with PDAC are needed to better understand the association with longer OS., (©2020 American Association for Cancer Research.)

Background: The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies., Methods: Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer., Results: Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer., Conclusions: The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: In studies of men of European ancestry, rare pathogenic variants in DNA repair pathway genes have been shown to be associated with risk of aggressive prostate cancer. The contribution of rare coding variation to prostate cancer risk in men of African ancestry has not been established., Methods: We sequenced a panel of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan prostate cancer cases and controls. Rare variants were classified as pathogenic or putatively functionally disruptive and examined in association with prostate cancer risk and disease aggressiveness in gene and pathway-level association analyses., Results: Pathogenic variants were found in 75 out of 2,098 cases (3.6%) and 31 out of 1,481 controls (2.1%) (OR=1.82, 95% CI=1.19 to 2.79, P=0.0044) with the association being stronger for more aggressive disease phenotypes (OR=3.10, 95% CI=1.54 to 6.23, P=0.0022). The highest risks for aggressive disease were observed with pathogenic variants in the ATM , BRCA2 , PALB2 and NBN genes, with odds ratios ranging from ~4 to 15 in the combined study sample of African American and Ugandan men. Rare, non-pathogenic, non-synonymous variants did not have a major impact on risk of overall prostate cancer or disease aggressiveness., Conclusions: Rare pathogenic variants in DNA repair genes have appreciable effects on risk of aggressive prostate cancer in men of African ancestry. These findings have potential implications for panel testing and risk stratification in this high-risk population.

Background: Increased risk of malignancies other than pancreatic cancer (PC) has been reported among first-degree relatives (FDRs) of PC patients; however, the roles of susceptibility gene mutations are unclear. We assessed risk for 15 cancers among FDRs of unselected PC probands., Methods: Data on 17 162 FDRs, with more than 336 000 person-years at risk, identified through 2305 sequential PC probands enrolled at Mayo Clinic (2000-2016) were analyzed. Family history data were provided by the probands. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated, comparing malignancies observed among the FDRs with that expected using Surveillance, Epidemiology, and End Results (SEER) data. Genetic testing was performed among a subset of probands (n = 2094), enabling stratified analyses among FDRs based on whether the related proband tested positive or negative for inherited mutation in 22 sequenced cancer susceptibility genes. All statistical tests were two-sided., Results: Compared with SEER, PC risk was twofold higher among FDRs of PC probands (SIR = 2.04, 95% CI = 1.78 to 2.31, P < .001). Primary liver cancer risk was elevated among female FDRs (SIR = 2.10, 95% CI = 1.34 to 3.12, P < .001). PC risk was more elevated among FDRs of mutation-positive probands (SIR = 4.32, 95% CI = 3.10 to 5.86) than FDRs of mutation-negative probands (SIR = 1.77, 95% CI = 1.51 to 2.05, between-group P < .001). FDR PC risk was higher when the related proband was younger than age 60 years at diagnosis and mutation-positive (SIR = 5.24, 95% CI = 2.93 to 8.64) than when the proband was younger than age 60 years but mutation-negative (SIR = 1.76, 95% CI = 1.21 to 2.47, between-group P < .001). Breast (SIR = 1.29, 95% CI = 1.01 to 1.63) and ovarian (SIR = 2.38, 95% CI = 1.30 to 4.00) cancers were elevated among FDRs of mutation-positive probands., Conclusions: Our study substantiates twofold risk of PC among FDRs of PC patients and suggests increased risk for primary liver cancer among female FDRs. FDRs of susceptibility mutation carriers had substantially increased risk for PC and increased risk for breast and ovarian cancers., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)