Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls

2020 ◽  
Vol 148 (2) ◽  
pp. 285-295
Author(s):  
Izzet Mehmet Akcay ◽  
Elifnaz Celik ◽  
Nihat Bugra Agaoglu ◽  
Gizem Alkurt ◽  
Tugba Kizilboga Akgun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Pathogenic Variant ◽  
Cancer Susceptibility Genes ◽  
Colorectal Cancer Patients

scholarly journals Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes

2017 ◽  
Vol 5 (5) ◽  
pp. 553-569 ◽  
Author(s):  
Melissa S. DeRycke ◽  
Shanaka Gunawardena ◽  
Jessica R. Balcom ◽  
Angela M. Pickart ◽  
Lindsey A. Waltman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Targeted Sequencing ◽  
Cancer Susceptibility Genes

Colorectal cancer susceptibility variants and clinical outcome in adjuvant and metastatic colorectal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4051-4051
Author(s):  
H. Lenz ◽  
G. Lurje ◽  
C. A. Haiman ◽  
D. Yang ◽  
A. Pohl ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Risk ◽  
Clinical Outcome ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Tumor Recurrence ◽  
Cancer Susceptibility ◽  
Locally Advanced ◽  
Germline Variants ◽  
Colorectal Cancer Patients

4051 Background: Recent genome-wide association studies had identified colorectal cancer susceptibility loci on chromosomes 8q24 (rs6983267), 15q13(rs4779584), 18q21(rs4939827, rs12953717 and rs4464148), 10p14(rs10795668) and 8q23.3(rs16892766). Although the function role of these germline variants are unclear, given the importance of these variants and colorectal cancer risk, we have carried out the first pilot study to explore the association of these variants and clinical outcome. We used pooled data from two CRC-cohorts (locally advanced and metastatic CRC), and investigated the hypothesis that these germline variants may be associated with clinical outcome in adjuvant and metastatic colorectal cancer patients. Methods: Whole blood was collected from 515 patients with locally advanced (n=197) and metastatic CRC (n=318). After extraction of genomic-DNA, germline variants were genotyped as previously described (Haiman et al, Nat Genet, 2007). The genotype success rate was 98%. Blinded repeat samples (5%) were included for quality control purposes; genotype concordance was ≥ 99%. Results: Our results suggest that rs10795668 at 10p14 and rs719725 are significantly associated with time to tumor recurrence in adjuvant colorectal cancer patients, patients with rs10795668 AA genotype had significantly increased risk of time to tumor recurrence compared with those harboring G allele (TG+GG) patients(p=0.05, log-rank test). In metastatic cancer patients, we found rs4939827 at 18q21.1 were significantly associated with overall survival in female patients and rs10795668 at 10p14 were significantly associated with OS in male patients, respectively (p<0.05). Conclusions: Our preliminary results suggest cancer risk alleles may also associated with clinical outcome in adjuvant and metastatic colorectal cancer. Moreover, this correlation is sex-specific in metastatic colorectal cancer. Further comprehensive trials warranted to confirm our pilot findings. [Table: see text]

scholarly journals Li-Fraumeni syndrome: not a straightforward diagnosis anymore—the interpretation of pathogenic variants of low allele frequency and the differences between germline PVs, mosaicism, and clonal hematopoiesis

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Felipe Batalini ◽  
Ellie G. Peacock ◽  
Lindsey Stobie ◽  
Alison Robertson ◽  
Judy Garber ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cancer Susceptibility ◽  
Somatic Mosaicism ◽  
Susceptibility Genes ◽  
Breast Cancer Patients ◽  
Li Fraumeni Syndrome ◽  
Clonal Hematopoiesis ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

Abstract The introduction of next-generation sequencing has resulted in testing multiple genes simultaneously to identify inherited pathogenic variants (PVs) in cancer susceptibility genes. PVs with low minor allele frequencies (MAFs) (< 25–35%) are highlighted on germline genetic test reports. In this review, we focus on the challenges of interpreting PVs with low MAF in breast cancer patients undergoing germline testing and the implications for management. The clinical implications of a germline PV are substantial. For PV carriers in high-penetrance genes like BRCA1, BRCA2, and TP53, prophylactic mastectomy is often recommended and radiation therapy avoided when possible for those with Li-Fraumeni syndrome (LFS). For germline PV carriers in more moderate-risk genes such as PALB2, ATM, and CHEK2, annual breast MRI is recommended and prophylactic mastectomies considered for those with significant family histories. Detection of PVs in cancer susceptibility genes can also lead to recommendations for other prophylactic surgeries (e.g., salpingo-oophorectomy) and increased surveillance for other cancers. Therefore, recognizing when a PV is somatic rather than germline and distinguishing somatic mosaicism from clonal hematopoiesis (CH) is essential. Mutational events that occur at a post-zygotic stage are somatic and will only be present in tissues derived from the mutated cell, characterizing classic mosaicism. Clonal hematopoiesis is a form of mosaicism restricted to the hematopoietic compartment. Among the genes in multi-gene panels used for germline testing of breast cancer patients, the detection of a PV with low MAF occurs most often in TP53, though has been reported in other breast cancer susceptibility genes. Distinguishing a germline TP53 PV (LFS) from a somatic PV (TP53 mosaicism or CH) has enormous implications for breast cancer patients and their relatives. We review how to evaluate a PV with low MAF. The identification of the PV in another tissue confirms mosaicism. Older age, exposure to chemotherapy, radiation, and tobacco are known risk factors for CH, as is the absence of a LFS-related cancer in the setting of a TP53 PV with low MAF. The ability to recognize and understand the implications of somatic PVs, including somatic mosaicism and CH, enables optimal personalized care of breast cancer patients.

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