Systemic pathology

Assignment
Topic-Article review of inherited DNA-repair gene mutations in
men with metastatic prostate cancer.
Professor-Dr.J.Antonio
Submitted by-Zakaria Ahmed (MD-4)

1. Title of the article

Inherited DNA-Repair Gene Mutations in Men with Metastatic
Prostate Cancer
2. Website URL
https://www.ncbi.nlm.nih.gov/pubmed/27433846
3. Journal name
Associate Professor, Genetics
Associate Director, Genetics and Solid Tumors Laborator
4. Impact Factor if any
16.265
5. Indexed by
Nelson PS
6.Publication year
July 6, 2016
7. Principle Author name
Mateo J
8. Co-authors name
Van Allen EM
9. Abstract
Acquired transformations in DNA-repair qualities, for example,
BRCA2 are related with expanded dangers of deadly prostate tumor.
In spite of the fact that the predominance of germline transformations
in DNA-repair qualities among men with restricted prostate disease
who are unselected for family inclination is lacking to warrant routine
testing, the recurrence of such changes in patients with metastatic
prostate growth has not been built up

We enrolled 692 men with reported metastatic prostate tumor who

were unselected for family history of malignancy or age at finding.
We segregated germline DNA and utilized multiplex sequencing
examines to evaluate changes in 20 DNA-repair qualities related with
autosomal overwhelming tumor inclination disorders

An aggregate of 84 germline DNA-repair quality transformations that

were attempted to be harmful were distinguished in 82 men (11.8%);
changes were found in 16 qualities, including BRCA2 (37 men
[5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]),
BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Change
frequencies did not vary as indicated by whether a family history of
prostate tumor was available or as per age at analysis. Generally
speaking, the recurrence of germline changes in DNA-repair qualities
among men with metastatic prostate malignancy essentially
surpassed the commonness of 4.6% among 499 men with restricted
prostate growth (P<0.001), incorporating men with high-chance
ailment, and the pervasiveness of 2.7% in the Exome Aggregation
Consortium, which incorporates 53,105 people without a known tumor
determination (P<0.001).
In our multicenter ponder, the occurrence of germline
transformations in qualities interceding DNA-repair forms among men
with metastatic prostate disease was 11.8%, which was altogether
higher than the frequency among men with confined prostate tumor.
The frequencies of germline transformations in DNA-repair qualities
among men with metastatic infection did not contrast altogether as
per age at determination or family history of prostate disease.
10. Are the key words given as per norms
DNA, Metastatic Prostate Cancer
11. Introduction
Inherited mutations in DNA-repair genes such as BRCA2 are
associated with increased risks of lethal prostate cancer. Although the
prevalence of germline mutations in DNA-repair genes among men
with localized prostate cancer who are unselected for family
predisposition is insufficient to warrant routine testing, the frequency
of such mutations in patients with metastatic prostate cancer has not
been established
12. Hypothesis
The authors state that they did not correct for the number of
hypotheses tested, and it is unclear whether they applied any
adjustments because of the winners curse. In addition, if no
Bonferroni correction was applied to the P values, this would further
exacerbate the winners curse and result in an even higher false
positive rate. Future studies should validate the intriguing findings in
this initial study

13. Research methodology

We recruited 692 men with documented metastatic prostate cancer
who were unselected for family history of cancer or age at diagnosis.
We isolated germline DNA and used multiplex sequencing assays to
assess mutations in 20 DNA-repair genes associated with autosomal
dominant cancer-predisposition syndromes
14. Sampling
For the analysis of Case Series 3, germline DNA was extracted from
saliva or buccal swab samples with the use of the Oragene kit (DNA
Genotek). Libraries for targeted sequencing were constructed with a
customized GeneRead DNaseq Panel (Qiagen) covering 53 genes and
run on the Illumina MiSeq sequencer, as described previously.16
15. Statistical analysis
Associations between DNA-repair gene mutation status and age, race,
or Gleason score strata were evaluated with the use of two-sided
Fishers exact tests. The frequencies of DNA-repair gene mutations
among the 692 patients with metastatic prostate cancer were
evaluated relative to the expected frequencies from the Exome
Aggregation Consortium (53,105 persons) or the Cancer Genome
Atlas cohort (499 persons) with the use of two-sided exact binomial
tests. We also performed analyses in which the 150 men from the
previously reported Case Series 1 were excluded18 (Table S5 in the
Supplementary Appendix). No adjustments were made for multiple
comparisons; P values of less than 0.05 were considered to indicate
statistical significance.

16. Conclusion/Summary
In our multicenter study, the incidence of germline mutations in genes
mediating DNA-repair processes among men with metastatic prostate
cancer was 11.8%, which was significantly higher than the incidence
among men with localized prostate cancer. The frequencies of
germline mutations in DNA-repair genes among men with metastatic
disease did not differ significantly according to age at diagnosis or
family history of prostate cancer.

17. Reference
APA(American Psychological Association)
18. Other research related to the above research
DNA-repair defects and olaparib in metastatic prostate
cancer
DNA Repair Gene XRCC1 and XPD Polymorphisms and Risk of Prostate
Cancer
19. Your Perspective
The study was sparked by an unexpected result of an earlier study. As
the researchers were profiling genomic changes in metastatic
prostate cancers, they sequenced DNA from normal tissues in the
same patients for comparison purposes. They found that 8% of men
with metastatic prostate cancer in that study had inherited a mutation
in a DNA-repair gene.

The proportion of inherited, or germline, mutations was so

unexpectedly high that the researchers conducted the current study
in part to see whether the high frequency of mutations was
reproducible when we were looking at a large population of men,

20.What else could have been included (Example, Future study)?

The researchers noted that, in the future, men who have prostate
cancer with these inherited mutations may be candidates for
particular treatments, such as drugs that target molecular changes
associated with defects in DNA repair.