To establish the contribution of four founder alleles of NBN to prostate cancer risk and cancer survival.
Five thousand one hundred eighty-nine men with prostate cancer and 6,152 controls were ...genotyped for four recurrent variants of NBN (657del5, R215W, I171V, and E185Q).
The NBN 657del5 mutation was detected in 74 of 5,189 unselected cases and in 35 of 6,152 controls (odds ratio OR, 2.5; p < 0.001). In carriers of 657del5 deletion, the cancer risk was restricted to men with the GG genotype of the E185Q variant of the same gene. Among men with the GG genotype, the OR associated with 657del5 was 4.4 (95% confidence interval CI, 2.4 to 8.0). Among men with other E185Q genotypes, the OR associated with 657del5 was 1.4 (95% CI, 0.8 to 2.4) and the interaction was significant (homogeneity p=0.006). After a median follow-up of 109 months, mortality was worse for 657del5 mutation carriers than for non-carriers (hazard ratio HR, 1.6; p=0.001). The adverse effect of 657del5 on survival was only seen on the background of the GG genotype of E185Q (HR, 1.9; p=0.0004).
The NBN 657del5 mutation predisposes to poor prognosis prostate cancer. The pathogenicity of this mutation, with regards to both prostate cancer risk and survival, is modified by a missense variant of the same gene (E185Q).
Bloom Syndrome is a rare recessive disease which includes a susceptibility to various cancers. It is caused by homozygous mutations of the BLM gene. To investigate whether heterozygous carriers of a ...BLM mutation are predisposed to breast cancer, we sequenced BLM in 617 patients from Polish families with a strong family history of breast cancer. We detected a founder mutation (c.1642C>T, p.Gln548Ter) in 3 of the 617 breast cancer patients (0.49%) who were sequenced. Then, we genotyped 14,804 unselected breast cancer cases and 4698 cancer-free women for the founder mutation. It was identified in 82 of 14,804 (0.55%) unselected cases and in 26 of 4698 (0.55%) controls (OR = 1.0; 95%CI 0.6–1.6). Clinical characteristics of breast cancers in the BLM mutation carriers and non-carriers were similar. Loss of the wild-type BLM allele was not detected in cancers from the BLM mutation carriers. No cancer type was more common in the relatives of mutation carriers compared to relatives of non-carriers. The BLM founder mutation p.Gln548Ter, which in a homozygous state is a cause of Bloom syndrome, does not appear to predispose to breast cancer in a heterozygous state. The finding casts doubt on the designation of BLM as an autosomal dominant breast cancer susceptibility gene.
In designing national strategies for genetic testing, it is important to define the full spectrum of pathogenic mutations in prostate cancer (PCa) susceptibility genes. To investigate the frequency ...of mutations in PCa susceptibility genes in Polish familial PCa cases and to estimate gene‐related PCa risks and probability of aggressive disease, we analyzed the coding regions of 14 genes by exome sequencing in 390 men with familial prostate cancer and 308 cancer‐free controls. We compared the mutation frequencies between PCa cases and controls. We also compared clinical characteristics of prostate cancers between mutation carriers and noncarriers. Of the 390 PCa cases, 76 men (19.5%) carried a mutation in BRCA1, BRCA2, NBN, ATM, CHEK2, HOXB13, MSH2 or MSH6 genes. No mutations were found in BRIP1, PTEN, TP53, MLH1, PMS2 and SPOP. Significant associations with familial PCa risk were observed for CHEK2, NBN, ATM, and HOXB13. High‐grade (Gleason 8‐10) tumors were seen in 56% of BRCA2, NBN or ATM carriers, compared to 21% of patients who tested negative for mutations in these genes (OR = 4.7, 95% CI 2.0‐10.7, P = .0003). In summary, approximately 20% of familial prostate cancer cases in Poland can be attributed to mutations in eight susceptibility genes. Carriers of mutations in BRCA2, NBN and ATM develop aggressive disease and may benefit from intensified screening and/or chemotherapy.
What's new?
Genetic susceptibility plays an important role in prostate cancer (PCa). In designing genetic‐testing strategies for PCa screening, it is important to define the full spectrum of pathogenic mutations that increase PCa risk. In this study, the authors found that approximately 20% of familial prostate cancer cases in Poland can be attributed to mutations in eight susceptibility genes. In addition, carriers of mutations in BRCA2, NBN and ATM are more likely to develop aggressive disease. These patients may benefit from intensified screening and/or chemotherapy.
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.
, in addition to other members of the
gene family, has recently been intensively studied due to its identification as a gene whose activation in cancer is responsible for a specific pattern of ...massively occurring somatic mutations. It was recently shown that a common large deletion in the
cluster (the
deletion) may increase the risk of breast cancer. However, conflicting evidence regarding this association was also reported. In the first step of our study, using different approaches, including an in-house designed multiplex ligation-dependent probe amplification assay, we analyzed the structure of the deletion and showed that although the breakpoints are located in highly homologous regions, which may generate recurrent occurrence of similar but not identical deletions, there is no sign of deletion heterogeneity. This knowledge allowed us to distinguish transcripts of all affected genes, including the highly homologous canonical
and
, and the hybrid
gene. We unambiguously confirmed the presence of the hybrid transcript and showed that the
deletion negatively correlates with
and
expression and positively correlates with
expression, whose mRNA level is >10-fold and >1500-fold lower than the level of
and
, respectively. In the next step, we performed a large-scale association study in three different cohorts (2972 cases and 3682 controls) and showed no association of the deletion with breast cancer, familial breast cancer or ovarian cancer. Further, we conducted a meta-analysis that confirmed the lack of the association of the deletion with breast cancer in non-Asian populations.
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.
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
p.K3326* variant is considered a low-penetrance variant for breast cancer. Aldehydes that accumulate in cells under insufficient aldehyde oxidation were most recently shown to trigger ...carcinogenesis by promoting depletion of BRCA2 protein. Allele T of the common variant rs10744777 in the
gene was associated with reduced expression of aldehyde dehydrogenase, the main enzyme in aldehyde oxidation. We hypothesized that this allele could modify breast cancer risk in women with the
p.K3326* low-penetrance variant through reduced function of ALDH2, increased accumulation of cellular aldehydes, and depletion of BRCA2 protein.
We genotyped 11,873 Polish women diagnosed with breast cancer and 7,615 ethnically matched controls for these two variants. Next, we extended our analysis of rs10744777 to 231 carriers of pathogenic
mutations.
p.K3326* variant was associated with significant increase in breast cancer risk only in those who were homozygous for the T allele of the
rs10744777 variant (odds ratio = 1.72; 95% CI, 1.19 to 2.48;
= .003). The
p.K3326* variant did not increase the risk of breast cancer among those who were heterozygous or homozygous for the C allele of the
rs10744777 variant (odds ratio = 1.05; 95% CI, 0.73 to 1.51;
= .81). In the carriers of high-risk
mutations, the TT genotype of rs10744777 conferred a modest (18%) and not significant increase in breast cancer risk.
Our results suggest that
p.K3326* variant, which is low-penetrance by itself, confers increased breast cancer risk on the background of the TT genotype of the
rs10744777 variant in the Polish population.
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