Familial breast cancer is in most cases unexplained due to the lack of identifiable pathogenic variants in the BRCA1 and BRCA2 genes. The somatic mutational landscape and in particular the extent of ...BRCA-like tumour features (BRCAness) in these familial breast cancers where germline BRCA1 or BRCA2 mutations have not been identified is to a large extent unknown.
We performed whole-genome sequencing on matched tumour and normal samples from high-risk non-BRCA1/BRCA2 breast cancer families to understand the germline and somatic mutational landscape and mutational signatures. We measured BRCAness using HRDetect. As a comparator, we also analysed samples from BRCA1 and BRCA2 germline mutation carriers.
We noted for non-BRCA1/BRCA2 tumours, only a small proportion displayed high HRDetect scores and were characterized by concomitant promoter hypermethylation or in one case a RAD51D splice variant previously reported as having unknown significance to potentially explain their BRCAness. Another small proportion showed no features of BRCAness but had mutationally active tumours. The remaining tumours lacked features of BRCAness and were mutationally quiescent.
A limited fraction of high-risk familial non-BRCA1/BRCA2 breast cancer patients is expected to benefit from treatment strategies against homologue repair deficient cancer cells.
Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype.
We identified two families ...with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells.
Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability.
This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.
Accurate estimation of cancer risk in HBOC families often requires BRCA1/2 testing, but this may be impossible in deceased family members. Previous, testing archival formalin-fixed, paraffin-embedded ...(FFPE) tissue for germline BRCA1/2 variants was unsuccessful, except for the Jewish founder mutations. A high-throughput method to systematically test for variants in all coding regions of BRCA1/2 in archival FFPE samples of non-tumor tissue is described, using HaloPlex target enrichment and next-generation sequencing. In a validation study, correct identification of variants or wild-type was possible in 25 out of 30 (83%) FFPE samples (age range 1-14 years), with a known variant status in BRCA1/2. No false positive was found. Unsuccessful identification was due to highly degraded DNA or presence of large intragenic deletions. In clinical use, a total of 201 FFPE samples (aged 0-43 years) were processed. Thirty-six samples were rejected because of highly degraded DNA or failed library preparation. Fifteen samples were investigated to search for a known variant. In the remaining 150 samples (aged 0-38 years), three variants known to affect function and one variant likely to affect function in BRCA1, six variants known to affect function and one variant likely to affect function in BRCA2, as well as four variants of unknown significance (VUS) in BRCA1 and three VUS in BRCA2 were discovered. It is now possible to test for germline BRCA1/2 variants in deceased persons, using archival FFPE samples from non-tumor tissue. Accurate genetic counseling is achievable in families where variant testing would otherwise be impossible.
The risk of cancer in men from BRCA1 and BRCA2 families is relevant to define to motivate genetic testing and optimize recommendations for surveillance.
We assessed the risk of cancer in male ...mutation carriers and their first-degree relatives in 290 BRCA1 and BRCA2 families with comparison to matched controls with the aim to motivate genetic testing and optimize recommendations for surveillance.
Mutation carriers in BRCA1 families were not at increased risk of cancer, whereas mutation carriers in BRCA2 families were at increased risk of male breast cancer and prostate cancer with cumulative risks of 12.5% and 18.8%, respectively. Breast cancer developed at a mean age of 59 years, typically as ER/PR positive ductal carcinomas. Prostate cancer developed at a mean age of 68 years, with Gleason scores ≥ 8 in 40% of the tumors. The hazard ratio for BRCA2-associated prostate cancer was 3.7 (p < 0.001) in mutation carriers and 3.1 (p = 0.001) in first-degree relatives. Of the 37 prostate cancers, 19 were linked to four BRCA2 mutations within a region defined by c.6373-c.6492. Individuals with mutations herein had a HR of 3.7 for prostate cancer compared to individuals with mutations outside of this region.
Male mutation carriers and first-degree relatives in BRCA2 families are at an increased risk of breast cancer and prostate cancer with a potential prostate cancer cluster region within exon 11 of BRCA2.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Reply to V. Fallet et al Li, Shuai; Silvestri, Valentina; Rebbeck, Timothy R ...
Journal of clinical oncology,
08/2022, Letnik:
40, Številka:
22
Journal Article
In families screened for mutations in the
BRCA1
or
BRCA2
genes and found to have a segregating mutation the breast cancer risk for women shown not to carry the family-specific mutation might be at ...above “average” risk. We assessed the risk of breast cancer in a clinic based cohort of 725 female proven noncarriers in 239
BRCA1
and
BRCA2
families compared with birth-matched controls from the Danish Civil Registration System. Prospective analysis showed no significantly increased risk for breast cancer in noncarriers with a hazard ratio of 0.67 95 % confidence interval (CI) 0.32–1.42,
p
= 0.29 for all family members who tested negative and 0.87 (95 % CI 0.38–1.97,
p
= 0.73) for non-carries who were first-degree relatives of mutation carriers. Proven noncarriers from
BRCA1
and
BRCA2
families have no markedly increased risk for breast cancer compared to the general population, and our data do not suggest targeted breast cancer surveillance for noncarriers from
BRCA1
and
BRCA2
families.
Germline pathogenic variants in the
gene are associated with a cumulative high risk of breast/ovarian cancer. Several
variants result in complete loss of the exon-3 at the transcript level. The ...pathogenicity of these variants and the functional impact of loss of exon 3 have yet to be established. As a collaboration of the COVAR clinical trial group (France), and the ENIGMA consortium for investigating breast cancer gene variants, this study evaluated 8
variants resulting in complete deletion of exon 3. Clinical information for 39 families was gathered from Portugal, France, Denmark and Sweden. Multifactorial likelihood analyses were conducted using information from 293 patients, for 7 out of the 8 variants (including 6 intronic). For all variants combined the likelihood ratio in favor of causality was 4.39*10
. These results provide convincing evidence for the pathogenicity of all examined variants that lead to a total exon 3 skipping, and suggest that other variants that result in complete loss of exon 3 at the molecular level could be associated with a high risk of cancer comparable to that associated with classical pathogenic variants in
or
gene. In addition, our functional study shows, for the first time, that deletion of exon 3 impairs the ability of cells to survive upon Mitomycin-C treatment, supporting lack of function for the altered BRCA2 protein in these cells. Finally, this study demonstrates that any variant leading to expression of only
delta-exon 3 will be associated with an increased risk of breast and ovarian cancer.
Mutations in the
BRCA1
and
BRCA2
genes significantly contribute to hereditary breast cancer and ovarian cancer, but the phenotypic effect from different mutations is insufficiently recognized. We ...used a western Danish clinic-based cohort of 299
BRCA
families to study the female cancer risk in mutation carriers and their untested first-degree relatives. Founder mutations were characterized and the risk of cancer was assessed in relation to the specific mutations. In
BRCA1
, the cumulative cancer risk at age 70 was 35 % for breast cancer and 29 % for ovarian cancer. In
BRCA2
, the cumulative risk was 44 % for breast cancer and 15 % for ovarian cancer. We identified 47 distinct
BRCA1
mutations and 48 distinct mutations in
BRCA2
. Among these, 8 founder mutations
BRCA1
c.81-?_4986+?del, c.3319G>T (p.Glu1107*), c.3874delT and c.5213G>A (p.Gly1738Glu) and
BRCA2
c.6373delA, c.7008−1G>A, c.7617+1G>A and c.8474delC were found to account for 23 % of the
BRCA1
mutations and for 32 % of the
BRCA2
mutations. The
BRCA1
mutation c.3319G>T was, compared to other
BRCA1
mutations, associated with a higher risk for ovarian cancer. In conclusion, founder mutations in
BRCA1
and
BRCA2
contribute to up to one-third of the families in western Denmark and among these the
BRCA1
c.3319G>T mutation is potentially linked to an increased risk of ovarian cancer.
Hemolysis affects many biochemical analyses, and when pronounced the result is replaced by an autoreply pointing out the hemolysis present. However, for proper treatment it is crucial to know whether ...hemolysis is due to sampling (in vitro) or is taking place in the patient (in vivo). At present, no consensus exists on how to help clinicians differentiate between the two. Clinical surveillance is still necessary, and a future challenge will be improving the dialogue between clinicians and clinical biochemists. This article reviews the benefits of doing so and suggests procedures to help differentiate.
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