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

Akçay, İzzet Mehmet; Çelik, Elifnaz; Ağaoğlu, Nihat Buğra; Alkurt, Gizem; Akgun, Tugba Kizilboga; Yildiz, Jale; Enç, Feruze Yılmaz; Kır, Gözde; Canbek, Sezin; Kılıç, Ali; Zemheri, Ebru; Ezbercı, Fikret; Özçelik, Melike; Doğanay, Gizem Dinler; Doğanay, Levent

doi:10.1002/ijc.33199

Cited by 30 publications

(30 citation statements)

References 33 publications

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“…The rate of pathogenic variants (PVs) identified with multigene NGS panel testing in Turkish patients with BC was 15.8% in our study. Most of these PVs were BRCA1 and BRCA2 genes (~39%), which is consistent with previous literature ( 16 , 19 ). Furthermore, the prevalence of BRCA1/2 mutations in the CG was 6.7% and in those with FH of BC was 14.1%, which was similar to the literature in which the prevalence ranges from 9 to 21% ( 20 – 22 ).…”

Section: Discussionsupporting

confidence: 92%

“…In Turkey, Large Genomic Rearrangements (LGRs). rates are between 1-4% (19,24,25) comparable with different populations around the world (0.1-12.7%) (16,(26)(27)(28)(29)(30).…”

Section: Positive In Gene Categoriesmentioning

confidence: 68%

“…The first was a multinational study, and the pathogenic/likely pathogenic mutation rate was found to be similar (15.8%) to our study ( 16 ). In the second study conducted by Akcay et al ( 19 ), cancer susceptibility genes were analyzed in breast and colorectal cancer patients. High BC risk genes were found in 17.2% of patients and, a low BC risk gene in 3.9%.…”

Section: Discussionmentioning

confidence: 99%

“…In the second study conducted by Akcay et al (19), cancer susceptibility genes were analyzed in breast and colorectal cancer patients. High BC risk genes were found in 17.2% of patients and, a low BC risk gene in 3.9%.…”

Section: Positive In Gene Categoriesmentioning

confidence: 99%

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Importance of multigene panel test in patients with consanguineous marriage and family history of breast cancer

et al. 2022

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Next-generation sequencing (NGS) technology is used to evaluate hereditary cancer risks of patients worldwide; however, information concerning the germline multigene mutational spectrum among patients with breast cancer (BC) with consanguineous marriage (CM) is limited. Therefore, this prospective study aimed to determine the molecular characteristics of patients with BC who were tested with multigene hereditary cancer predisposition NGS panel and to show the effect of CM on cancer-related genes. Patients with BC with or without CM and family history (FH) of BC treated in our breast center were selected according to The National Comprehensive Cancer Network (NCCN) criteria for hereditary BC. In these patients, the analysis of a panel of 33 genes involved in hereditary cancer predisposition was performed after genetic counseling by using NGS. The pathogenic variant (PV) and the variant of uncertain significance (VUS) were found to be 15.8 and 47.4%, respectively. PVs were identified in 10/33 genes in 34 patients; 38.2% in BRCA1/2 genes; 6, 24, and 14% in other high, moderate and low-risk genes, respectively. The CM rate was 17.7% among the 215 patients with BC. The PV rate was 13.2% in patients with CM and 16.4% in patients without CM (P=0.80). When PV and VUS were evaluated together, the PV+VUS ratio was significantly higher in patients with CM and FH of BC than patients without CM and FH of BC (88.2 vs. 63.3%, P=0.045). Analysis of multigene panel provided 9.76% additional PVs in moderate/low-risk genes. The PV rate was similar in patients with BC with or without CM. A high PV+VUS ratio in patients with CM and FH of BC suggests that genes whose importance are unknown are likely to be pathogenic genes later.

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Section: Discussionsupporting

confidence: 92%

“…In Turkey, Large Genomic Rearrangements (LGRs). rates are between 1-4% (19,24,25) comparable with different populations around the world (0.1-12.7%) (16,(26)(27)(28)(29)(30).…”

Section: Positive In Gene Categoriesmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Positive In Gene Categoriesmentioning

confidence: 99%

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Importance of multigene panel test in patients with consanguineous marriage and family history of breast cancer

et al. 2022

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“…As summarized in Table 1 , among 22 FANC genes, FANCS/BRCA1 and FANCD2/BRCA2 , high-risk hereditary breast-ovarian cancer syndrome susceptibility genes, are the most investigated as CRC susceptibility genes beyond its well-known predispositions [ 27 , 28 , 29 , 30 , 31 , 44 , 73 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ]. Recent findings revealed that the prevalence of BRCA1/2 PVs among early-onset (1.3%) [ 30 ] and unselected patients with CRC (3.9%) [ 88 ] is more frequent than would be happening by chance.…”

Section: Potential Role Of Fanc Gene Mutations In ...mentioning

confidence: 99%

Fanconi Anemia Pathway in Colorectal Cancer: A Novel Opportunity for Diagnosis, Prognosis and Therapy

Parsa

Nobili

Karimpour

et al. 2022

JPM

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Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and has the second highest mortality rate globally. Thanks to the advent of next-generation sequencing technologies, several novel candidate genes have been proposed for CRC susceptibility. Germline biallelic mutations in one or more of the 22 currently recognized Fanconi anemia (FA) genes have been associated with Fanconi anemia disease, while germline monoallelic mutations, somatic mutations, or the promoter hypermethylation of some FANC genes increases the risk of cancer development, including CRC. The FA pathway is a substantial part of the DNA damage response system that participates in the repair of DNA inter-strand crosslinks through homologous recombination (HR) and protects genome stability via replication fork stabilization, respectively. Recent studies revealed associations between FA gene/protein tumor expression levels (i.e., FANC genes) and CRC progression and drug resistance. Moreover, the FA pathway represents a potential target in the CRC treatment. In fact, FANC gene characteristics may contribute to chemosensitize tumor cells to DNA crosslinking agents such as oxaliplatin and cisplatin besides exploiting the synthetic lethal approach for selective targeting of tumor cells. Hence, this review summarizes the current knowledge on the function of the FA pathway in DNA repair and genomic integrity with a focus on the FANC genes as potential predisposition factors to CRC. We then introduce recent literature that highlights the importance of FANC genes in CRC as promising prognostic and predictive biomarkers for disease management and treatment. Finally, we represent a brief overview of the current knowledge around the FANC genes as synthetic lethal therapeutic targets for precision cancer medicine.

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Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care—Checking CHEK2

et al. 2022

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ImportanceGermline CHEK2 pathogenic variants (PVs) are frequently detected by multigene cancer panel testing (MGPT), but our understanding of PVs beyond c.1100del has been limited.ObjectiveTo compare cancer phenotypes of frequent CHEK2 PVs individually and collectively by variant type.Design, Setting, and ParticipantsThis retrospective cohort study was carried out in a single diagnostic testing laboratory from 2012 to 2019. Overall, 3783 participants with CHEK2 PVs identified via MGPT were included. Medical histories of cancer in participants with frequent PVs, negative MGPT (wild type), loss-of-function (LOF), and missense were compared.Main Outcomes and MeasuresParticipants were stratified by CHEK2 PV type. Descriptive statistics were summarized including median (IQR) for continuous variables and proportions for categorical characteristics. Differences in age and proportions were assessed with Wilcoxon rank sum and Fisher exact tests, respectively. Frequencies, odds ratios (ORs), 95% confidence intervals were calculated, and P values were corrected for multiple comparisons where appropriate.ResultsOf the 3783 participants with CHEK2 PVs, 3473 (92%) were female and most reported White race. Breast cancer was less frequent in participants with p.I157T (OR, 0.66; 95% CI, 0.56-0.78; P<.001), p.S428F (OR, 0.59; 95% CI. 0.46-0.76; P<.001), and p.T476M (OR, 0.74; 95% CI, 0.56-0.98; P = .04) PVs compared with other PVs and an association with nonbreast cancers was not found. Following the exclusion of p.I157T, p.S428F, and p.T476M, participants with monoallelic CHEK2 PV had a younger age at first cancer diagnosis (P < .001) and were more likely to have breast (OR, 1.83; 95% CI, 1.66-2.02; P < .001), thyroid (OR, 1.63; 95% CI, 1.26-2.08; P < .001), and kidney cancer (OR, 2.57; 95% CI, 1.75-3.68; P < .001) than the wild-type cohort. Participants with a CHEK2 PV were less likely to have a diagnosis of colorectal cancer (OR, 0.62; 95% CI, 0.51-0.76; P < .001) compared with those in the wild-type cohort. There were no significant differences between frequent CHEK2 PVs and c.1100del and no differences between CHEK2 missense and LOF PVs.Conclusions and RelevanceCHEK2 PVs, with few exceptions (p.I157T, p.S428F, and p.T476M), were associated with similar cancer phenotypes irrespective of variant type. CHEK2 PVs were not associated with colorectal cancer, but were associated with breast, kidney, and thyroid cancers. Compared with other CHEK2 PVs, the frequent p.I157T, p.S428F, and p.T476M alleles have an attenuated association with breast cancer and were not associated with nonbreast cancers. These data may inform the genetic counseling and care of individuals with CHEK2 PVs.

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

Cited by 30 publications

References 33 publications

Importance of multigene panel test in patients with consanguineous marriage and family history of breast cancer

Importance of multigene panel test in patients with consanguineous marriage and family history of breast cancer

Fanconi Anemia Pathway in Colorectal Cancer: A Novel Opportunity for Diagnosis, Prognosis and Therapy

Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care—Checking CHEK2

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