Germline 657del5 mutation in the NBS1 gene in patients with malignant melanoma of the skin

Dębniak, Tadeusz; Górski, Bohdan; Cybulski, Cezary; Jakubowska, Anna; Kurzawski, Grzegorz; Lener, Marcin; Mierzejewski, Marek; Masojć, Bartosz; Mędrek, Krzysztof; Kładny, Józef; Załuga, Elzbieta; Maleszka, Romuald; Chosia, Maria; Lubiński, Jan

doi:10.1097/00008390-200308000-00005

Cited by 31 publications

(26 citation statements)

References 22 publications

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“…Although a number of published reports have suggested that mutations in NBS1, especially 657del5, is associated with elevated risk for some cancers, including ovarian (13), breast (7,8,10), melanoma (7,9), and lymphoid malignancies (7,11,12), such findings have not been replicated in other studies (21)(22)(23)(24). For prostate cancer, Cybulski et al (5) found that the 657del5 mutation was a risk factor.…”

Section: Discussionmentioning

confidence: 99%

“…This founder mutation has been found with a high frequency in the Slavic population, which includes individuals primarily from Poland, Ukraine, and the Czech Republic. A number of studies suggest that heterozygosity for a mutation in NBS1 may be associated with elevated risk for some cancers (7)(8)(9)(10)(11)(12)(13), including prostate cancer (5). Cybulski et al (5) showed an increased risk for prostate cancer among carriers of the 657del5 mutation in both familial and non-familial cases from Poland.…”

Section: Introductionmentioning

confidence: 99%

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Role of the Nijmegen Breakage Syndrome 1 Gene in Familial and Sporadic Prostate Cancer

Hebbring¹,

Fredriksson

White³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The Nijmegen breakage syndrome 1 (NBS1) gene, which participates in DNA double strand break repair, has been postulated to be a susceptibility factor for a number of cancers, including prostate cancer. Numerous mutations have been identified in NBS1, including the founder mutation 657del5. In this study, a number of analyses were done to determine whether mutations in NBS1 are associated with an increased risk for prostate cancer. The frequency of the 657del5 mutation in both familial prostate cancer cases (1,819 affected men among 909 families) and sporadic prostate cancer cases (1,218 affected men) collected from five centers participating in the International Consortium for Prostate Cancer Genetics were compared with that found in 697 normal controls. Seven individuals were identified to carry the mutation among the 3,037 cases screened: four in the familial group (three from one family and one from another) and three in the sporadic cases. The carrier frequency was 0.22% (2 of 909) for the probands and 0.25% (3 of 1,218) for the sporadic cases of prostate cancer. The 657del5 mutation was not detected in either the 293 unaffected members of the prostate cancer families or in the 697 control samples tested. The entire NBS1 gene was also sequenced in 20 of the youngest affected individuals from the Finnish group of familial cases to identify the presence of possible mutations in this high-risk group. One rare (D95N) and one common (E185Q) missense alteration was identified. More detailed analyses of the E185Q polymorphism, along with a third rare variant (R215W), failed to show an association with prostate cancer. Because the 657del5 mutation was absent from the control population, we are unable to determine if this alteration predisposes to prostate cancer. However, our data does suggest that mutations within NBS1, and in particular, 657del5, do not significantly contribute to the overall prostate cancer burden within our patient samples. (Cancer Epidemiol Biomarkers Prev 2006;15(5):935 -8)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of the Nijmegen Breakage Syndrome 1 Gene in Familial and Sporadic Prostate Cancer

Hebbring¹,

Fredriksson

White³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…It has been suggested that heterozygous carriers of the founder mutation of the NBS (657del5 allele) may be at increased risk of cancer, but prostate cancer specifically has not been studied to date (22)(23)(24)(25)(26)(27). In this study, we compared the frequency of the 657del5 mutation in unselected patients with sporadic and familial prostate cancer with that of a control group to determine whether NBS1 plays a role in the development of prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

NBS1 Is a Prostate Cancer Susceptibility Gene

et al. 2004

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To evaluate whether an inactivating mutation in the gene for the Nijmegen breakage syndrome (NBS1) plays a role in the etiology of prostate cancer, we compared the prevalence of the 657del5 NBS1 founder allele in 56 patients with familial prostate cancer, 305 patients with nonfamilial prostate cancer, and 1500 control subjects from Poland. Loss of heterozygosity analysis also was performed on DNA samples isolated from 17 microdissected prostate cancers, including 8 from carriers of the 657del5 mutation. The NBS1 founder mutation was present in 5 of 56 (9%) patients with familial prostate cancer (odds ratio, 16; P < 0.0001), 7 of 305 (2.2%) patients with nonfamilial prostate cancer (odds ratio, 3.9; P ‫؍‬ 0.01), and 9 of 1500 control subjects (0.6%). The wild-type NBS1 allele was lost in seven of eight prostate tumors from carriers of the 657del5 allele, but loss of heterozygosity was seen in only one of nine tumors from noncarriers (P ‫؍‬ 0.003). These findings suggest that heterozygous carriers of the NBS1 founder mutation exhibit increased susceptibility to prostate cancer and that the cancers that develop in the prostates of carriers are functionally homozygous for the mutation.

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“…(21) Recent studies strongly suggest that heterozygous 657del5 mutation carriers have an elevated risk of malignant tumor development, especially of melanoma, (22,23) colon and rectum cancer, (23) prostate cancer,…”

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confidence: 99%

“…(17) Heterozygous mutations in the NBS1 gene have been described in various groups of cancer patients, for example, patients with acute lymphoblastic leukemia (ALL), (18,19) non-Hodgkin's lymphoma (NHL), (20) and in cancer cell lines. (21) Recent studies strongly suggest that heterozygous 657del5 mutation carriers have an elevated risk of malignant tumor development, especially of melanoma, (22,23) colon and rectum cancer, (23) prostate cancer, (24) ovarian cancer, (25) breast cancer (26,27) and NHL. (28,29) The aim of our research was to assess whether mutations in the NBS1 gene may contribute to the development of larynx cancer (LC) and MPT of the head and neck.…”

mentioning

confidence: 99%

Increased risk of larynx cancer in heterozygous carriers of the I171V mutation of the NBS1 gene

Ziółkowska

Mosor

Wierzbicka³

et al. 2007

Cancer Science

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The high incidence of multiple primary tumors (MPT) is a significant problem in head and neck tumor treatment. Recent studies suggest that carriers of heterozygous mutations in the NBS1 gene have an increased risk of malignant tumor development. The aim of our research was to assess the frequency of NBS1 mutations in patients with larynx cancer only (LC) and with MPT. The MPT group consisted of patients with one cancer localized to the larynx (primary or second) and another at another site. DNA from 175 patients with LC and 93 patients with MPT was analyzed using the single-strand conformation polymorphism method and direct sequencing. We found nine carriers of the I171V mutation among these 268 cancer patients and only one carrier among 500 population controls (0.2%). Four carriers of the I171V mutation were detected among 175 LC patients (2.3%) and five among 93 patients with MPT (5.4%). The frequencies of the I171V mutation carriers in LC and MPT patients were significantly higher than in controls (odds ratio D espite recent advances in the diagnosis and treatment of head and neck squamous cell carcinoma (HNSCC), the survival rate of patients with these tumors is not improving. One of the reasons for this is the frequent development of second primary tumors (SPT). Among HNSCC patients, the frequency of SPT occurrence ranges from 12 to 30% with a constant rate of 2-3% per year for patients who survive for more than 10 years.[(1-3) The first tumor is responsible for 15% of patient deaths, whereas the second tumor is the cause of death in 71% of cases. Squamous cell carcinoma is the predominant histological type of the second tumor. (4) In the etiology of multiple primary tumors (MPT) of the head and neck, tobacco and alcohol abuse ('condemned mucosa theory') are essential but are not the only causal factors.(5) It is supposed that genetic factors play a great role in the occurrence of the first tumor and, in addition, predispose the patient to the development of a second primary tumor. Because of reduced DNA repair capacity in patients who had two or more independent malignancies, (6) it has been suggested that alterations in DNA repair genes may play a significant role in head and neck tumor development.The NBS1 gene belongs to a group of double-strand break repair genes and is located on chromosome band 8q21.3. (7)(8)(9) Biallelic mutations in the NBS1 gene are responsible for Nijmegen breakage syndrome (NBS, OMIM 251260), classified to a group of chromosomal instability syndromes. NBS is a rare autosomal recessive disorder, occurring mainly in central and eastern Europe.(10) The most common is the homozygous 657del5 mutation, observed in 90% of NBS patients. The protein product of the NBS1 gene, nibrin (p95, NBS1), is a member of the MRE11-RAD50-nibrin complex, (7) which is involved in DNA double-strand break repair by homologous recombination or non-homologous end joining, meiotic recombination and the DNA damage response. (7,11) The MRE11-RAD50-nibrin complex is also required for activation of the damage c...

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Germline 657del5 mutation in the NBS1 gene in patients with malignant melanoma of the skin

Cited by 31 publications

References 22 publications

Role of the Nijmegen Breakage Syndrome 1 Gene in Familial and Sporadic Prostate Cancer

Role of the Nijmegen Breakage Syndrome 1 Gene in Familial and Sporadic Prostate Cancer

NBS1 Is a Prostate Cancer Susceptibility Gene

Increased risk of larynx cancer in heterozygous carriers of the I171V mutation of the NBS1 gene

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