Mutation status of RAD51C,PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations

Abstract

In addition to BRCA1 and BRCA2, RAD51C,PALB2 and BRIP1 are known as breast cancer susceptibility genes. However, the mutation status of these genes in Japanese familial breast cancer cases has not yet been evaluated. To this end, we analyzed the exon sequence and genomic rearrangement of RAD51C,PALB2 and BRIP1 in 100 Japanese patients diagnosed with familial breast and ovarian cancer and without BRCA1 and BRCA2 mutations. We detected a large deletion from exons 6 to 9 in RAD51C, 4 novel BRIP1 missense variants containing 3 novel non‐synonymous variants, c.89A>C, c.736A>G and c.2131A>G, and a splice donor site variant c.918+2T>C. No deleterious variant of PALB2 was detected. The results of pedigree analysis showed that the proband with a large deletion on RAD51C had a family history of both breast and ovarian cancer, and the families of probands with novel BRIP1 missense variants included a male patient with breast cancer or many patients with breast cancer within the second‐degree relatives. We showed that the mutation frequency of RAD51C in Japanese familial breast cancer cases was similar to that in Western countries and that the prevalence of deleterious mutation of PALB2 was possibly lower. Furthermore, our results suggested that BRIP1 mutation frequency in Japan might differ from that in Western countries.

Olaparib Monotherapy for BRIP1-Mutated High-Grade Serous Endometrial Cancer

“…Accumulating evidence indicates that patients with BRIP1 mutations have HRR deficiency and are consequently hypersensitive to PARP inhibition. 14 BRIP1 is a BRCA1-interacting protein (the BRIP1-BRCA1 interaction is important for HRR) and associates with BRCA1 as cells progress through the S phase of the cell cycle. 15 , 16 BRIP1 is a DNA helicase that interacts with the COOH-terminal BRCT repeat of BRCA1.…”

Germline breast cancer susceptibility gene mutations and breast cancer outcomes

“…Also mutations in RAD51C have not been found to increase the risk of breast cancer [ 18 – 20 ] and mutations in RAD51D have been associated with high risk of ovarian cancer but not with breast cancer [ 21 ]. Nevertheless, other studies have indicated that mutations in RAD51C [ 22 ] and RAD51D [ 17 , 23 , 24 ] contribute to the risk of both breast and ovarian cancer, and that RAD50 is an intermediate-risk breast cancer susceptibility gene [ 25 ]. Although germline mutations in the DNA mismatch repair genes ( MLH1, MSH2, MSH6, PMS2 ) have been mostly associated with Lynch syndrome, evidence has been established to support the connections between the mutations in the DNA mismatch repair genes and the risk or survival of breast cancer [ 26 – 29 ].…”

“…Although germline mutations in the DNA mismatch repair genes ( MLH1, MSH2, MSH6, PMS2 ) have been mostly associated with Lynch syndrome, evidence has been established to support the connections between the mutations in the DNA mismatch repair genes and the risk or survival of breast cancer [ 26 – 29 ]. Similarly, whether BRIP1 is a breast cancer susceptibility gene remains controversial [ 30 ], and perhaps is dependent on the ethnicity of the cohort studied [ 22 ]. NF1 mutations have been known to associate with increased risk of breast cancer in younger population [ 31 ] and poor breast cancer survival [ 32 ].…”

Risks of Solid Tumors in Heterozygous Carriers of Recessive Syndromes

“…U nosiček mutace genu RAD51C by ale měla být zvážena preventivní adnexektomie ve 45-50 le tech (event. dříve, věk posuzovat podle nejčasnějšího výskytu karcinomu ovaria v rodině, podobně jako u nosiček mu tace genu BRIP1) [18,20,22,23].…”

“…Souvislost mutací genu BRIP1 se zvýšeným rizikem karci nomu prsu nebyla jednoznačně proká zána, i když je v ně kte rých publikacích možná souvislost uváděna vč. databází OMIM a ClinVar [21][22][23].…”