To optimize genetic testing, it is necessary to establish the spectrum of breast cancer‐predisposing mutations in particular ethnic groups. We studied 1,018 women with a strong family history for ...breast cancer (families with hereditary breast cancer; HBC) from genetically homogenous population of Poland, which is populated by ethnic Slavs, for mutations in 14 cancer susceptibility genes. Additionally, we compared the frequency of candidate pathogenic variants in breast cancer cases and controls. Germline mutations were detected in 512 of 1,018 probands with breast cancer (50.3%), including BRCA1/2 mutations detected in 420 families and non‐BRCA mutations seen in 92 families. Thirteen BRCA1/2 founder mutations represented 84% of all BRCA1/2‐positive cases. Seven founder mutations of CHEK2, PALB2, NBN and RECQL represented 73% of all non‐BRCA‐positive cases. Odds ratios for hereditary breast cancer were 87.6 for BRCA1, 15.4 for PALB2, 7.2 for CHEK2, 2.8 for NBN and 15.8 for RECQL. Odds ratios for XRCC2, BLM and BARD1 were below 1.3. In summary, we found that 20 founder mutations in six genes (BRCA1/2, CHEK2, PALB2, NBN and RECQL) are responsible for 82% of Polish hereditary breast cancer families. A simple test for these 20 mutations will facilitate genetic testing for breast cancer susceptibility in Poland. It may also facilitate genetic testing for breast cancer susceptibility in other Slavic populations and women of Slavic descent worldwide.
What's new?
Poland is a genetically homogeneous population similar to Iceland, currently designing national policies for genetic testing. To define the range of pathogenic mutations, the authors conducted a large analysis of breast cancer susceptibility genes, defining pathogenic mutations in 50.3% families with hereditary breast cancer. They identified 20 distinct founder mutations in six genes that were responsible for more than 80% of all detected mutations; these 20 mutations could be combined in a single genetic test of breast cancer susceptibility in Polish women.
The objective of this study was to establish the contribution of PALB2 mutations to prostate cancer risk and to estimate survival among PALB2 carriers.
We genotyped 5472 unselected men with prostate ...cancer and 8016 controls for two Polish founder variants of PALB2 (c.509_510delGA and c.172_175delTTGT). In patients with prostate cancer, the survival of carriers of a PALB2 mutation was compared to that of non-carriers.
A PALB2 mutation was found in 0.29% of cases and 0.21% of controls (odds ratio (OR) = 1.38; 95% confidence interval (CI) 0.70-2.73; p = 0.45). PALB2 mutation carriers were more commonly diagnosed with aggressive cancers of high (8-10) Gleason score than non-carriers (64.3 vs 18.1%, p < 0.0001). The OR for high-grade prostate cancer was 8.05 (95% CI 3.57-18.15, p < 0.0001). After a median follow-up of 102 months, the age-adjusted hazard ratio for all-cause mortality associated with a PALB2 mutation was 2.52 (95% CI 1.40-4.54; p = 0.0023). The actuarial 5-year survival was 42% for PALB2 carriers and was 72% for non-carriers (p = 0.006).
In Poland, PALB2 mutations predispose to an aggressive and lethal form of prostate cancer.
•Serum Se level above 69 μg/L may be associated with improved outcomes of treatment for patients with I stage lung cancer.•The optimization of Se levels in patients with stage I disease may improve ...overall survival.•Serum Se levels in patients with stage I LuCa may be a valuable biomarker for the prognosis of lung cancer.
Although the results of studies in populations with low selenium status indicate an inverse correlation between body selenium levels and the risk of the lung cancer, the effect of this microelement on survival has not been studied.
We performed a prospective study of 302 patients diagnosed with lung cancer in Szczecin, Poland. Selenium concentration in serum was measured at the time of diagnosis and before treatment. All patients were followed for a maximum of 80 months or until death. Vital status was obtained from the Polish National Death Registry.
Using Cox proportional hazard analysis, performed for all individuals with lung cancer, the hazard ratio (HR) for death from all causes was 1.25 (95% CI: 0.86–1.83, P = 0.99) for patients in the lowest tertile compared to those in the highest tertile of serum selenium levels. Among the patients with stage I disease this relationship was significant (HR-2.73; P = 0.01) for selenium level in tertile 1 (<57 μg/L) compared to tertile 3 (>69 μg/L, reference). The 80 months crude survival after diagnosis was 79.5% (95% CI: 68.5–92.4%) for individuals in the highest tertile and 58.1% (95% CI: 45.1–74.9%) for individuals in the lowest tertile with stage I lung cancer.
These results suggest that in patients undergoing treatment for stage I lung cancer, serum selenium levels at the time of diagnosis (>69 μg/L) may be associated with improved overall survival.
Background
XRCC2
participates in homologous recombination and in DNA repair.
XRCC2
has been reported to be a breast cancer susceptibility gene and is now included in several breast cancer ...susceptibility gene panels.
Methods
We sequenced
XRCC2
in 617 Polish women with familial breast cancer and found a founder mutation. We then genotyped 12,617 women with breast cancer and 4599 controls for the
XRCC2
founder mutation.
Results
We identified a recurrent truncating mutation of
XRCC2
(c.96delT, p.Phe32fs) in 3 of 617 patients with familial breast cancer who were sequenced. The c.96delT mutation was then detected in 29 of 12,617 unselected breast cancer cases (0.23%) compared to 11 of 4599 cancer-free women (0.24%) (OR = 0.96; 95% CI 0.48–1.93). The mutation frequency in 1988 women with familial breast cancer was 0.2% (OR = 0.84, 95% CI 0.27–2.65). Breast cancers in
XRCC2
mutation carriers and non-carriers were similar with respect to age of diagnosis and clinical characteristics. Loss of the wild-type
XRCC2
allele was observed only in one of the eight breast cancers from patients who carried the
XRCC2
mutation. No cancer type was more common in first- or second-degree relatives of
XRCC2
mutation carriers than in relatives of the non-carriers.
Conclusion
XRCC2
c.96delT is a protein-truncating founder variant in Poland. There is no evidence that this mutation predisposes to breast cancer (and other cancers). It is premature to consider
XRCC2
as a breast cancer-predisposing gene.
Background
NBN
657del5 founder mutation predisposes to breast and prostate cancer. Recently, it has been reported that the pathogenicity of this mutation with regard to prostate cancer risk is ...modified by a missense variant of the same gene (E185Q).
Methods
To evaluate the interaction of the 657del5 and E185Q founder alleles of
NBN
on breast cancer risk in Poland, 4964 women with breast cancer and 6152 controls were genotyped for these two recurrent variants of
NBN
(657del5 truncating variant and E185Q missense variant).
Results
The
NBN
657del5 mutation was detected in 57 of 4964 unselected cases and in 35 of 6152 controls (OR = 2.0,
p
= 0.001). The E185Q GG genotype was detected in 2167 of 4964 unselected cases and in 2617 of 6152 controls (OR = 1.04,
p
= 0.3). In carriers of the 657del5 deletion, the elevated cancer risk was restricted to women with the GG genotype of the E185Q variant (OR = 3.6, 95% CI 1.9–6.6;
p
< 0.0001). Among women with other E185Q genotypes, the OR associated with 657del5 was 1.0 (95% CI 0.5–1.8;
p
= 0.9). The interaction between the two alleles was statistically significant (homogeneity
p
= 0.003).
Conclusion
In Poland, the pathogenicity of the
NBN
657del5 mutation is restricted to women with a homozygous GG genotype of missense variant of the same gene (E185Q). This is the first clear example whereby a moderate penetrance breast cancer gene is impacted by a genetic modifier.
The genetic basis of prostate cancer (PC) is complex and appears to involve multiple susceptibility genes. A number of studies have evaluated a possible correlation between several NER gene ...polymorphisms and PC risk, but most of them evaluated only single SNPs among XP genes and the results remain inconsistent. Out of 94 SNPs located in seven XP genes (XPA–XPG) a total of 15 SNPs were assayed in 720 unselected patients with PC and compared to 1121 healthy adults. An increased risk of disease was associated with the XPD SNP, rs1799793 (Asp312Asn) AG genotype (OR=2.60; p<0.001) and with the AA genotype (OR=531; p<0.0001) compared to the control population. Haplotype analysis of XPD revealed one protective haplotype and four associated with an increased disease risk, which showed that the A allele (XPD rs1799793) appeared to drive the main effect on promoting prostate cancer risk. Polymorphism in XPD gene appears to be associated with the risk of prostate cancer.
•We assessed 15 SNPs located in seven XP genes.•An increased risk of disease was associated with the XPD SNP.•Haplotype analysis of XPD revealed one protective haplotype and four associated with an increased disease risk.
Xeroderma pigmentosum (XP) is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. Genetic polymorphisms in XP genes may be associated with a ...change in DNA repair capacity, which could be associated with colorectal cancer development. We assessed the association between 94 single nucleotide polymorphisms (SNPs) within seven XP genes (
XPA
–
XPG
) and the colorectal cancer risk in the Polish population. We genotyped 758 unselected patients with colorectal cancer and 1,841 healthy adults. We found that a significantly decreased risk of colorectal cancer was associated with
XPC
polymorphism rs2228000_CT genotype (OR 0.59; p < 0.0001) and the rs2228000_TT genotype (OR 0.29; p < 0.0001) compared to the reference genotype (CC). And an increased disease risk was associated with the
XPD
SNP, rs1799793_AG genotype (OR 1.44, p = 0.018) and rs1799793_AA genotype (OR 3.31, p < 0.0001) compared to the reference genotype. Haplotype analysis within
XPC
,
XPD
and
XPG
revealed haplotypes associated with an altered colorectal cancer risk. Stratified analysis by gender showed differences between the association of three SNPs:
XPC
rs2228000,
XPD
rs1799793 and
XPD
rs238406 in females and males. Association analysis between age of disease onset and polymorphisms in
XPD
(rs1799793) and
XPC
(rs2228000) revealed differences in the prevalence of these variants in patients under and over 50 years of age. Our results confirmed that polymorphisms in
XPC
and
XPD
may be associated with the risk of colorectal cancer.
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