Cancer risk i...breast cancer_Jiaming Liu.pdf

Cancer Biol Med 2023.doi:10.20892/j.issn.2095-3941.2022.0593ORIGINAL ARTICLECancer risk in relatives of BRCA1/2 pathogenic variant carriers in a large series of unselected patients with breast cancerJiaming Liu,Lu Yao,Jie Sun,Li Hu,Jiuan Chen,Juan Zhang,Ye Xu,Yuntao XieKey Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Familial&Hereditary Cancer Center,Peking University Cancer Hospital&Institute,Beijing 100142,ChinaABSTRACT Objective:The spectrum and risk of cancer in relatives of BRCA1/2 pathogenic variant carriers in the Chinese population have not been established.Methods:A family history of cancer in 9903 unselected breast cancer patients was retrospectively analyzed.BRCA1/2 status was determined for all patients and relative risks(RRs)were calculated to evaluate cancer risk in relatives of the patients.Results:The incidences of breast cancer in female relatives of BRCA1 carriers,BRCA2 carriers,and non-carriers were 33.0%,32.2%,and 7.7%,respectively.The corresponding incidences of ovarian cancer were 11.5%,2.4%,and 0.5%,respectively.The incidences of pancreatic cancer in male relatives of BRCA1 carriers,BRCA2 carriers,and non-carriers were 1.4%,2.7%,and 0.6%,respectively.The corresponding incidences of prostate cancer were 1.0%,2.1%,and 0.4%,respectively.The risks of breast and ovarian cancers in female relatives of BRCA1 and BRCA2 carriers were significantly higher than female relatives of non-carriers(BRCA1:RR=4.29,P 0.001 and RR=21.95,P 0.001;BRCA2:RR=4.19,P 0.001 and RR=4.65,P 0.001,respectively).Additionally,higher risks of pancreatic and prostate cancers were noted in male relatives of BRCA2 carriers than non-carriers(RR=4.34,P=0.001 and RR=4.86,P=0.001,respectively).Conclusions:Female relatives of BRCA1 and BRCA2 carriers are at increased risk for breast and ovarian cancers,and male relatives of BRCA2 carriers are at increased risk for pancreatic and prostate cancers.KEYWORDS BRCA1 variant;BRCA2 variant;cancer risk in relatives;Chinese breast cancer patients;family history of cancerIntroductionGermline pathogenic variants in BRCA1/2 genes result in increased risks of various cancers via an autosomal dom-inant pattern of inheritance1.A series of studies on the spectrum and risk of cancer in BRCA1/2 pathogenic variant carriers(hereafter referred to BRCA1/2 carriers)have been conducted2-18.It is well-known that BRCA1 and BRCA2 carriers are at increased risk for breast and ovarian cancers,and BRCA2 carriers are at increased risk for pancreatic and prostate cancers2,6,7,9-11,16-18.The cancer risks and spectra appear to differ between BRCA1 and BRCA2 carriers;spe-cifically,the risk for ovarian cancer in BRCA1 carriers is higher than BRCA2 carriers2,7,17,and the risks for pancreatic and prostate cancers in BRCA2 carriers may be higher than BRCA1 carriers7,9-11,18.The associations between BRCA1/2 carriers and other cancers,such as colorectal and gastric cancers,have not been established,thus warrant further investigation3-6,11-15,17,18.Most previous studies involving BRCA-associated cancer have focused on BRCA1/2 carriers;however,a limited number of studies have examined the cancer risk and spectrum in rela-tives of BRCA1/2 carriers.One study reported that relatives of BRCA1 and BRCA2 carriers have an increased risk for breast and ovarian cancers,and relatives of BRCA2 carriers also have an increased risk for pancreatic cancer19.In addition,the data regarding the cancer risks in relatives of BRCA1/2 carriers are largely based on Western popula-tions;scant data exists that pertains to Chinese populations.Correspondence to:Yuntao XieE-mail:ORCID ID:https:/orcid.org/0000-0003-1151-8107Received September 27,2022;accepted December 19,2022Available at www.cancerbiomed.org2023 Cancer Biology&Medicine.Creative Commons Attribution-NonCommercial 4.0 International License148 Liu et al.Cancer risk in relatives of BRCA1/2 carriersChinese individuals have significantly different cancer spec-tra and risks compared with Western individuals,with rela-tively lower risks of breast and prostate cancers and relatively higher risks of gastric,esophageal,and liver cancers20,21.Moreover,the spectrum of BRCA1/2 variants in Chinese women is different from Western women,with approxi-mately 30%of variants not present in Caucasian women22-24.Therefore,the cancer risks in relatives of BRCA1/2 carriers in Chinese women might be different from Caucasian women.In the present study we aimed to clarify and characterize the spectra and risks of cancers in relatives of BRCA1/2 carriers in a large series of unselected Chinese patients with breast cancer.Materials and methodsStudy populationBetween October 2003 and May 2015,a total of 10,341 consec-utive patients with breast cancer who were treated at the Breast Center of Peking University Cancer Hospital&Institute were enrolled in a breast cancer database.All patients were con-firmed to have breast cancer based on preoperative biopsy or postoperative histologic examination.BRCA1/2 germline var-iants were determined in all patients by next-generation and/or Sanger sequencing,or multiplex ligation-dependent probe amplification,as described previously25-27.All of the BRCA1/2 variants have been listed in detail in previous studies25-27.The BRCA1/2 status in 438 patients could not be determined due to insufficient quantity or poor quality of genomic DNA.Therefore,9903 patients with breast cancer were ultimately enrolled in this study.Among these patients,four carried pathogenic variants in both the BRCA1 and BRCA2 genes,and were considered BRCA1 carriers at the time of analysis.Variables,including demographics,clinicopathologic char-acteristics,and a family history of cancers,were extracted from the breast cancer database,and uncertain family history was confirmed and supplemented through telephone calls or out-patient visits.Written informed consent was obtained during hospitali-zation from all patients whose clinical information and blood samples could be used for research,including genetic testing.The study was performed in accordance with the Declaration of Helsinki.Ethical approval for this study was obtained from the Ethics Committee of Peking University Cancer Hospital&Institute(Approval No.2011KT12).DefinitionsBRCA1/2 variants are considered pathogenic when classified as pathogenic or likely pathogenic.Variants with uncertain significance(VUS)or likely benign or benign are consid-ered non-pathogenic based on current American College of Medical Genetics and Genomics guidelines.Only patients with pathogenic variants were defined as carriers;other patients were considered to be non-carriers.A family his-tory of cancers referred to cancers that occurred in first-,second-and third-degree relatives of the participants in our study.The cancer history of the participants and fur-ther relatives were not included in the analysis.A history of cancer in any relative that corresponded to the cancer in a study participant was regarded as a positive family his-tory.Considering data accessibility,we used the family of the participants but not individuals as the unit with which to analyze the cancer risks of relatives;thus,cancer risks in relatives were calculated based on the family history of the study participants.Of note,a very small fraction of patients may have come from the same family,and such families may have been counted more than once.For convenience,related cancers with a low incidence were merged together for the analysis.For example,lymphoma included Hodgkins lym-phoma and non-Hodgkins lymphoma,and urothelial carci-noma included bladder cancer and cancers of the ureter and urethra.Furthermore,fallopian tube cancer was considered ovarian cancer.Statistical analysisWe analyzed all types of cancer with positive family history counts equal to or greater than five among BRCA1/2 car-riers,and those with counts less than five were summarized as“other cancers”.Continuous and categorical variables are described as the means standard deviations(SD)and fre-quencies with a percentage(%),respectively.Students t-test was performed to analyze differences in continuous variables,the Wilcoxon rank-sum test was used to analyze differences in ordered categorical variables,and the Pearson chi square test or Fishers exact test was used to analyze differences in unor-dered categorical variables.In addition,we calculated relative risks(RRs)with 95%confidence intervals(CIs)for compari-son of cancer risks in relatives of BRCA1 carriers,BRCA2 car-riers,and non-carriers.All statistical analyses were performed using StataSE 15(StataCorp LP,College Station,TX,USA).Cancer Biol Med Vol 20,No 2 February 2023 149Only two-tailed P values 0.05 were considered statistically significant.ResultsDistributions of cancers in relatives of patients with breast cancerThere were 538 germline BRCA1/2 pathogenic variant carriers(209 for BRCA1 and 329 for BRCA2)and 9365 non-carriers in this study.The distribution of cancers in the relatives of the patients with breast cancer are presented in Table 1.The incidences of BRCA1 and BRCA2 carriers among relatives with 1,2,and 3 cancer types were signifi-cantly higher than non-carriers(Table 1).Additionally,the proportion of BRCA1 and BRCA2 carriers with 1,2,and 3 affected family members was significantly greater than non-carriers(Table 1).Differences in the number of cancer types and cancer-affected members among relatives between BRCA1 and BRCA2 carriers,however,were not significant(Table 1).Cancer risks in female relatives of BRCA1 and BRCA2 carriersThe most common cancers in female relatives of BRCA1 car-riers were breast(33.0%),ovarian(11.5%),and liver(3.8%)cancers,followed by lung and cervical cancers(2.4%each;Table 2).The risks for breast and ovarian cancers in female rel-atives of BRCA1 carriers were significantly higher than the risks in female relatives of non-carriers(breast cancer:RR=4.29,95%CI=3.50-5.27;P 0.001 and ovarian cancer:RR=21.95,95%=CI 13.73-35.07;P 0.001).Furthermore,the risks for liver(RR=3.73,95%CI=1.84-7.58;P=0.002)and cervical cancers(RR=2.99,95%CI=1.22-7.31;P=0.030)in female relatives of BRCA1 carriers were significantly higher than female relatives of non-carriers.The cancer risks in female relatives of BRCA1 carriers and non-carriers were not significantly differ-ent with respect to gastric,pancreatic,and colorectal cancers(Table 2).The most frequent cancer sites in female relatives of BRCA2 carriers were the breast(32.2%),lung(3.7%),and ovary(2.4%),followed by the cervix and pancreas(1.5%each;Table 2).The risks for breast(RR=4.19,95%CI=3.53-4.98;P Table 1 Demographics of patients with breast cancer and distributions of cancers in their relatives according to BRCA statusVariablesBRCA1(n=209)BRCA2(n=329)Non-carriers(n=9,365)P1 value P2 value P3 valueGender Male1(0.5)1(0.3)19(0.2)0.3570.4991.000 Female208(99.5)328(99.7)9,346(99.8)Age,years(mean SD)44.7 10.147.8 10.551.3 11.60.0010.0010.001Cancer types 076(36.4)146(44.4)6,529(69.7)0.0010.0010.063 187(41.6)124(37.7)2,071(23.1)235(16.8)45(13.7)574(6.1)311(5.3)14(4.3)191(1.3)Affected members 076(36.4)146(44.4)6,529(69.7)0.0010.0010.094 176(36.4)109(33.1)2,071(22.1)240(19.1)42(12.8)574(6.1)317(8.1)32(9.7)191(2.0)P1,BRCA1 vs.non-carriers;P2,BRCA2 vs.non-carriers;P3,BRCA1 vs.BRCA2.Data comparison between two groups using the Fishers exact test.Data comparison between two groups using the Students t-test.Data comparison between two groups using the Wilcoxon rank-sum test.Data are shown as n(%),unlessotherwisespecified,whichreferstopatientswithbreastcancer.150 Liu et al.Cancer risk in relatives of BRCA1/2 carriersTable 2 Cancer risks in female relatives of germline BRCA1 and BRCA2 pathogenic variant carriersCancersBRCA1 (n=209)BRCA2 (n=329)Non-carriers (n=9,365)RR1(95%CI,P value)RR2(95%CI,P value)RR3(95%CI,P value)Breast cancer69(33.0)106(32.2)720(7.7)4.29(3.50-5.27,0.001)4.19(3.53-4.98,0.001)1.02(0.80-1.31,0.848)Ovarian cancer24(11.5)8(2.4)49(0.5)21.95(13.73-35.07,0.001)4.65(2.22-9.73,0.001)4.72(2.16-10.31,0.001)Lung cancer5(2.4)12(3.7)244(2.6)0.92(0.38-2.20,0.848)1.40(0.79-2.47,0.247)0.66(0.23-1.83,0.417)Liver cancer8(3.8)2(0.6)96(1.0)3.73(1.84-7.58,0.002)0.59(0.15-2.40,0.775)6.30(1.35-29.36,0.016)Cervical cancer5(2.4)5(1.5)75(0.8)2.99(1.22-7.31,0.030)1.90(0.77-4.66,0.198)1.57(0.46-5.37,0.521)Gastric cancer3(1.4)4(1.2)113(1.2)1.19(0.38-3.71,0.742)1.01(0.37-2.71,1.000)1.18(0.27-5.22,1.000)Pancreatic cancer2(1.0)5(1.5)56(0.6)1.60(0.39-6.51,0.362)2.54(1.02-6.30,0.055)0.63(0.12-3.22,0.711)Endometrial adenocarcinoma4(1.9)2(0.6)86(0.9)2.08(0.77-5.63,0.134)0.66(0.16-2.68,0.771)3.15(0.58-17.04,0.214)Lymphoma1(0.5)4(1.2)36(0.4)1.24(0.17-9.04,0.559)3.16(1.13-8.83,0.046)0.39(0.04-3.50,0.653)Esophageal cancer4(1.9)1(0.3)117(1.3)1.53(0.57-4.11,0.340)0.24(0.03-1.74,0.192)6.30(0.71-55.95,0.078)Colorectal cancer2(1.0)2(0.6)174(1.9)0.52(0.13-2.06,0.596)0.33(0.08-1.31,0.135)1.57(0.22-11.09,0.644)Kidney cancer0(0.0)3(0.9)21(0.2)0(-,1.000)4.07(1.22-13.56,0.046)0(-,0.286)Urothelial carcinoma0(0.0)1(0.3)23(0.3)0(-,1.000)1.24(0.17-9.14,0.564)0(-,1.000)Other cancers4(1.9)9(2.7)157(1.7)1.14(0.43-3.05,0.781)1.63(0.84-3.17,0.146)0.70(0.22-2.24,0.545)Any cancer110(52.6)142(43.2)1,746(18.6)2.82(2.47-3.23,0.001)2.32(2.03-2.64,0.001)1.22(1.02-1.46,0.032)RR1,BRCA1 vs.non-carriers;RR2,BRCA2 vs.non-carriers;RR3,BRCA1 vs.BRCA2.Data comparison between two groups using the Pearson Chi square test.Data comparison between two groups using the Fishers exact test.Data are shown as n(%),unlessotherwisespecified,whichreferstothenumberofpatientswithafamilyhistoryofcancers.Cancer Biol Med Vol 20,No 2 February 2023 1510.001)and ovarian cancers(RR=4.65,95%CI=2.22-9.73;P=0.001)in female relatives of BRCA2 carriers were also signif-icantly higher than female relatives of non-carriers.Moreover,the risks for lymphoma(RR=3.16,95%CI=1.13-8.83;P=0.046)and kidney cancer(RR=4.07,95%CI=1.22-13.56;P=0.046)in female relatives of BRCA2 carriers were significantly higher than female relatives of non-carriers.The pancreatic can-cer risk for female relatives of BRCA2 carriers was marginally but not significantly higher than female relatives of non-carriers(RR=2.54,95%CI=1.02-6.30;P=0.055).Female relatives of BRCA1 carriers had significantly higher risks for ovarian(RR=4.72,95%CI=2.16-10.31;P 0.001),liver(RR=6.30,95%CI=1.35-29.36;P=0.016),and any cancers(RR=1.22,95%CI=1.02-1.46;P=0.032)than female relatives of BRCA2 carriers(Table 2).Differences in the risks for other cancers(liver,gastric,and colorectal cancers)between female relatives of BRCA1 and BRCA2 carriers were not significant(Table 2).Cancer risks in male relatives of BRCA1 and BRCA2 carriersThe most common cancers in male relatives of BRCA1 carri-ers were lung(7.2%),esophageal(6.2%),and gastric cancers(4.8%),followed by liver cancer and lymphoma(2.4%each;Table 3).Male relatives of BRCA1 carriers had signifi-cantly higher risks of esophageal cancer(RR=2.33,95%CI 1=0.36-4.00;P=0.002)and lymph