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Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility.

ABSTRACT: Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish breast cancer cases (n?=?578-1565) and controls (n?=?337-1228). Mutations showing potential cancer association were analyzed in additional Finnish cohorts. c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p?=?0.018) and likely represents a Northern Finnish founder mutation. A deleterious c.2715?+?1G?>?A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640_644del5) in RNF168, causative for recessive RIDDLE syndrome, had high prevalence in majority of the analyzed cohorts, but did not associate with breast cancer. In conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warranting further investigations in other populations. Furthermore, high frequency of RNF168 c.640_644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms.

SUBMITTER: Mantere T

PROVIDER: S-EPMC5429682 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility.

Mantere Tuomo T Tervasmäki Anna A Nurmi Anna A Rapakko Katrin K Kauppila Saila S Tang Jiangbo J Schleutker Johanna J Kallioniemi Anne A Hartikainen Jaana M JM Mannermaa Arto A Nieminen Pentti P Hanhisalo Riitta R Lehto Sini S Suvanto Maija M Grip Mervi M Jukkola-Vuorinen Arja A Tengström Maria M Auvinen Päivi P Kvist Anders A Borg Åke Å Blomqvist Carl C Aittomäki Kristiina K Greenberg Roger A RA Winqvist Robert R Nevanlinna Heli H Pylkäs Katri K

Scientific reports 20170406 1

Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish brea ...[more]

PMID: 28386063

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Project description:BackgroundGermline variations may contribute to lung cancer susceptibility besides environmental factors. The influence of germline mutations on lung cancer susceptibility and their correlation with somatic mutations has not been systematically investigated.MethodsIn this study, germline mutations from 1,026 non-small cell lung cancer (NSCLC) patients were analyzed with a 58-gene next-generation sequencing (NGS) panel containing known hereditary cancer-related genes, and were categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines in pathogenicity, and the corresponding somatic mutations were analyzed using a 605-gene NGS panel containing known cancer-related genes.ResultsPlausible genetic susceptibility was found in 4.7% of lung cancer patients, in which 14 patients with pathogenic mutations (P group) and 34 patients with likely-pathogenic mutations (LP group) were identified. The ratio of the first degree relatives with lung cancer history of the P groups was significantly higher than the Non-P group (P=0.009). The ratio of lung cancer patients with history of other cancers was higher in P (P=0.0007) or LP (P=0.017) group than the Non-P group. Pathogenic mutations fell most commonly in BRCA2, followed by CHEK2 and ATM. Likely-pathogenic mutations fell most commonly in NTRK1 and EXT2, followed by BRIP1 and PALB2. These genes are involved in DNA repair, cell cycle regulation and tumor suppression. By comparing the germline mutation frequency from this study with that from the whole population or East Asian population (gnomAD database), we found that the overall odds ratio (OR) for P or LP group was 17.93 and 15.86, respectively, when compared with the whole population, and was 2.88 and 3.80, respectively, when compared with the East Asian population, suggesting the germline mutations of the P and LP groups were risk factors for lung cancer. Somatic mutation analysis revealed no significant difference in tumor mutation burden (TMB) among the groups, although a trend of lower TMB in the pathogenic group was found. The SNV/INDEL mutation frequency of TP53 in the P group was significantly lower than the other two groups, and the copy number variation (CNV) mutation frequency of PIK3CA and MET was significantly higher than the Non-P group. Pathway enrichment analysis found no significant difference in aberrant pathways among the three groups.ConclusionsA proportion of 4.7% of patients carrying germline variants may be potentially linked to increased susceptibility to lung cancer. Patients with pathogenic germline mutations exhibited stronger family history and higher lung cancer risk.

Dataset Information

Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility.

Publications

Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility.

Similar Datasets

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