Multiple cancer susceptible genes sequencing in BRCA-negative breast cancers with high hereditary risk Guan-Tian Lang1,2, MD; Xin Hu1, PhD; Zhi-Ming Shao1,2, MD 1 Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University, Shanghai, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, Fudan University Shanghai Cancer Center, China Background Mutations were classified as pathogenic/likely-pathogenic if they Table 1. The mutations identified as pathogenic/likely pathogenic had a truncating, initiation codon or splice donor/acceptor effect, in our 32-gene panel screening. or if pathogenicity was demonstrated in published literature. Gene Chromosome Reference Alternation Mutation type Systematic nomenclature Breast cancer susceptibility is strongly associated with a name position patient’s hereditary background. Comprehensive BRCA TP53 chr17:7577538 C T nonsynonymous SNV NM_000546.5:c.743G>C PALB2 chr16:23619236 G GT frameshift insertion NM_024675.3:c.3298dupA mutation screening in our cancer center shows a lower BRCA PALB2 chr16:23634321 C CTT frameshift insertion NM_024675.3:c.2964_2965insAA mutation prevalence (9.1%) in Chinese breast cancer patients RESULTS PALB2 chr16:23646515 A C stopgain NM_024675.3:c.T1352G PALB2 chr16:23646815 GTT G frameshift insertion NM_024675.3:c.1050_1051del with hereditary risk. Multiple cancer susceptible genes PALB2 chr16:23647116 G A stopgain NM_024675.3:c.751C>T CHEK2 chr22:29091846 G A nonsynonymous SNV NM_007194.3:c.1111C>T sequencing can assist in discovering detrimental germline In total, we acquired 39 patients (10.2%) with pathogenic/likely- RET chr10:43597793 G A nonsynonymous SNV NM_020975.4:c.341G>A mutation in BRCA-negative breast cancers. pathogenic germline mutations, including one carrying two RET chr10:43597793 G A nonsynonymous SNV NM_020975.4:c.341G>A RET chr10:43597793 G A nonsynonymous SNV NM_020975.4:c.341G>A distinct mutations. Major mutant non-BRCA genes were RET chr10:43597793 G A nonsynonymous SNV NM_020975.4:c.341G>A RET chr10:43601830 G A nonsynonymous SNV NM_020975.4:c.874G>A MUTYH (n=11), PTCH1 (n=7), RET (n=6) and PALB2 (n=5). RET chr10:43601830 G A nonsynonymous SNV NM_020975.4:c.874G>A Other mutant genes included TP53 (n=3), RAD51D (n=2), MUTYH chr1:45797760 T C splicing NM_001128425.1:c.934-2A>G Methods MUTYH chr1:45797760 T C splicing NM_001128425.1:c.934-2A>G CHEK2 (n=1), BRIP1 (n=1), CDH1 (n=1), MRE11 (n=1), RAD50 MUTYH chr1:45797760 T C splicing NM_001128425.1:c.934-2A>G (n=1) and PALLD (n=1). In addition, PTCH1 mutation carriers MUTYH chr1:45797760 T C splicing NM_001128425.1:c.934-2A>G From 2005-2014, BRCA-negative breast cancer patients with MUTYH chr1:45797760 T C splicing NM_001128425.1:c.934-2A>G were found to be associated with the clinical features of triple- MUTYH chr1:45797760 T C splicing NM_001128425.1:c.934-2A>G any two of the following risk factors were recruited: (1) MUTYH chr1:45797760 T C splicing NM_001128425.1:c.934-2A>G negative and early-age onset breast cancer. MUTYH chr1:45797760 T C splicing NM_001128425.1:c.934-2A>G pathological diagnosis of triple-negative breast cancer, (2) male MUTYH chr1:45797760 T C splicing NM_001128425.1:c.934-2A>G breast cancer, (3) primary bilateral breast cancers in one MUTYH chr1:45798130 G A nonsynonymous SNV NM_001128425.1:c.721C>T MUTYH chr1:45800165 G A stopgain NM_001128425.1:c.C55T individual, regardless of synchrony or asynchrony, (4) early-age BRIP1 chr17:59876486 G A stopgain NM_032043.2:c.1315C>T CONCLUSIONS CDH1 chr16:68846047 A G nonsynonymous SNV NM_004360.4:c.1018A>G onset breast cancer (less than or equal to 40 years of age at MRE11 chr11:94211948 G A nonsynonymous SNV NM_005591.3:c.497C>T diagnosis), or (5) patients with a family history of breast and/or PTCH1 chr9:98211548 TG T frameshift deletion NM_000264.3:c.3606del PTCH1 chr9:98229479 T C nonsynonymous SNV NM_000264.3:c.2479A>G ovarian cancer (at least one first- and/or second-degree relative Among BRCA-negative breast cancer patients with high PTCH1 chr9:98229479 T C nonsynonymous SNV NM_000264.3:c.2479A>G hereditary risk in China, 10.2% carried mutations in breast PTCH1 chr9:98229479 T C nonsynonymous SNV NM_000264.3:c.2479A>G with breast cancer or ovarian cancer). A total of 384 Chinese PTCH1 chr9:98229479 T C nonsynonymous SNV NM_000264.3:c.2479A>G subjects were screened by next-generation sequencing for 32 cancer associated susceptibility genes. MUTYH and PTCH1 PTCH1 chr9:98229479 T C nonsynonymous SNV NM_000264.3:c.2479A>G had relatively high mutation rates (2.9% and 1.8%). Some PTCH1 chr9:98229479 T C nonsynonymous SNV NM_000264.3:c.2479A>G breast cancer associated susceptibility genes (APC, ATM, RAD50 chr5:131930733 C T stopgain NM_005732.3:c.C1966T ATTCAAATCC clinical features might be associated with germline mutations of NM_001166108.1:c.949_950insTTCAAA BARD1, BMPR1A, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, PALLD chr4:169589381 A ACTGTGAGG frameshift insertion TCCACTGTGAGGGAGGG particular genes in breast cancer. GAGGG EPCAM, MEN1, MET, MLH1, MRE11A, MSH2, MSH6, MUTYH, TP53 chr17:7574034 C G splicing NM_000546.4:c.994-1G>A NBN, NF1, PALB2, PALLD, PMS2, PTCH1, PTEN, RAD50, TP53 chr17:7578407 G C nonsynonymous SNV NM_000546.5:c.C523G RAD51D chr17:33434458 T TTA frameshift insertion NM_001142571:c.331_332insTA RAD51C, RAD51D, RET, SMAD4, STK11, TP53, VHL). RAD51D chr17:33434458 T TTA frameshift insertion NM_001142571:c.331_332insTA Printed by.