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Germline and somatic KLLN alterations in breast cancer dysregulate G2 arrest.

ABSTRACT: PTEN is a well-described predisposition gene for Cowden syndrome (CS), a familial cancer syndrome characterized by a high risk of breast and other cancers. KLLN, which shares a bidirectional promoter with PTEN, causes cell cycle arrest and apoptosis. We previously identified germline hypermethylation of the KLLN promoter in 37% of PTEN mutation-negative CS/CS-like (CSL) patients. Patients with germline KLLN hypermethylation have an increased prevalence of breast and renal cancers when compared with PTEN mutation carriers. We have consequently sought to identify and characterize germline KLLN variants/mutations in CS/CSL and in apparently sporadic breast cancer patients. KLLN variants in CS/CSL patients are rare (1 of 136, 0.007%). Interestingly, among 438 breast cancer patients, 13 (3%) have germline KLLN variants when compared with none in 128 controls (P = 0.049). Patients with KLLN variants have a family history of breast cancer when compared with those without (P = 0.02). We demonstrate that germline KLLN variants dysregulate the cell cycle at G2. Of 24 breast carcinomas analyzed, 3 (13%) have somatic KLLN hemizygous deletions, with somatic loss of the wild-type allele in a patient with germline KLLN p.Leu119Leu. Of 452 breast carcinomas in The Cancer Genome Atlas project, 93 (21%) have KLLN hemizygous or homozygous deletions. This is the first study to associate germline KLLN variants with sporadic breast cancer and to recognize somatic KLLN deletions in breast carcinomas. Our observations suggest that KLLN may be a low penetrance susceptibility factor for apparently sporadic breast cancer.

SUBMITTER: Nizialek EA

PROVIDER: S-EPMC3858115 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Germline and somatic KLLN alterations in breast cancer dysregulate G2 arrest.

Nizialek Emily A EA Peterson Charissa C Mester Jessica L JL Downes-Kelly Erinn E Eng Charis C

Human molecular genetics 20130227 12

PTEN is a well-described predisposition gene for Cowden syndrome (CS), a familial cancer syndrome characterized by a high risk of breast and other cancers. KLLN, which shares a bidirectional promoter with PTEN, causes cell cycle arrest and apoptosis. We previously identified germline hypermethylation of the KLLN promoter in 37% of PTEN mutation-negative CS/CS-like (CSL) patients. Patients with germline KLLN hypermethylation have an increased prevalence of breast and renal cancers when compared w ...[more]

PMID: 23446638

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Project description:ObjectivesIn breast cancer (BC) patients, the frequency of germline BRCA mutations (gBRCA) may vary according to the ethnic background, age, and family history of cancer. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the second most common somatic mutated gene in BC; however, the association of mutations in both genes with cancer has not been thoroughly investigated. Thus, our aims were to investigate gBRCA mutation frequency in a cohort of postmenopausal Brazilian BC patients and the association of gBRCA1/BRCA2 and PIK3CA somatic mutations.MethodsForty-nine postmenopausal (>55 years) and forty-one young (≤35 years) BC patients were included in this study. The postmenopausal group included patients who reported a positive family history of cancer. For these patients, gBRCA1/BRCA2 were sequenced using next-generation sequencing (NGS) or Sanger sequencing. Data for gBRCA in young patients were already available from a previous study. DNA from formalin-fixed, paraffin-embedded (FFPE) tumors was obtained from 27 postmenopausal and 41 young patients for analyzing exons 9 and 20 of PIK3CA. The association between gBRCA1/BRCA2 and somatic mutations in PIK3CA was investigated.ResultsThe overall frequency of gBRCA1/BRCA2 among the 49 postmenopausal patients was 10.2%. The frequencies of somatic mutations in PIK3CA in the postmenopausal and young patients were 37% and 17%, respectively (ns). The most common PIK3CA mutation was found to be E454A. Nonsense and frameshift mutations, which may counteract the oncogenic potential of PIK3CA were also detected. Regardless of age, 25% of BRCA1/BRCA2 mutation carriers and non-carriers , each, had PIK3CA somatic mutations.ConclusionsData obtained indicate that BRCA1/BRCA2 gene testing may be considered for postmenopausal patients with BC who have a family history of cancer. Although some of them are not considered pathogenic, somatic variants of PIK3CA are frequently observed in BC patients, especially in postmenopausal patients.

Project description:BACKGROUND:BRCA1 and BRCA2 mutations explain approximately one-fifth of the inherited susceptibility in high-risk Finnish hereditary breast and ovarian cancer (HBOC) families. EMSY is located in the breast cancer-associated chromosomal region 11q13. The EMSY gene encodes a BRCA2-interacting protein that has been implicated in DNA damage repair and genomic instability. We analysed the role of germline EMSY variation in breast/ovarian cancer predisposition. The present study describes the first EMSY screening in patients with high familial risk for this disease. METHODS:Index individuals from 71 high-risk, BRCA1/2-negative HBOC families were screened for germline EMSY sequence alterations in protein coding regions and exon-intron boundaries using Sanger sequencing and TaqMan assays. The identified variants were further screened in 36 Finnish HBOC patients and 904 controls. Moreover, one novel intronic deletion was screened in a cohort of 404 breast cancer patients unselected for family history. Haplotype block structure and the association of haplotypes with breast/ovarian cancer were analysed using Haploview. The functionality of the identified variants was predicted using Haploreg, RegulomeDB, Human Splicing Finder, and Pathogenic-or-Not-Pipeline 2. RESULTS:Altogether, 12 germline EMSY variants were observed. Two alterations were located in the coding region, five alterations were intronic, and five alterations were located in the 3'untranslated region (UTR). Variant frequencies did not significantly differ between cases and controls. The novel variant, c.2709 + 122delT, was detected in 1 out of 107 (0.9%) breast cancer patients, and the carrier showed a bilateral form of the disease. The deletion was absent in 897 controls (OR = 25.28; P = 0.1) and in 404 breast cancer patients unselected for family history. No haplotype was identified to increase the risk of breast/ovarian cancer. Functional analyses suggested that variants, particularly in the 3'UTR, were located within regulatory elements. The novel deletion was predicted to affect splicing regulatory elements. CONCLUSIONS:These results suggest that the identified EMSY variants are likely neutral at the population level. However, these variants may contribute to breast/ovarian cancer risk in single families. Additional analyses are warranted for rare novel intronic deletions and the 3'UTR variants predicted to have functional roles.

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Germline and somatic KLLN alterations in breast cancer dysregulate G2 arrest.

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Germline and somatic KLLN alterations in breast cancer dysregulate G2 arrest.

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