open access
Advances in sequencing technology have made multigene testing, or “panel
testing,” a practical option when looking for
genetic variants that may
be associated with a risk of breast cancer. In June 2013, the U.S.
Supreme Court
1 invalidated specific claims made by Myriad Genetics with respect to the patenting of the genomic DNA sequence of
BRCA1 and
BRCA2. Other companies immediately began to offer panel tests for breast cancer genes that included
BRCA1 and
BRCA2. The subsequent flourishing of gene-panel testing services (
Table 1Table 1Examples of Multigene Testing Panels for Breast Cancer., and Table S1 in the
Supplementary Appendix,
available with the full text of this article at NEJM.org) has generated
much interest both within the clinical genetics community and in the
popular press.
2
These panels cover a total of more than 100 genes, and breast cancer is
specifically mentioned as an indication for 21 of these genes. However,
the fact that the technology is available does not necessarily mean
that such tests are appropriate or desirable........
.... Mutations in three other DNA repair genes,
RAD51C,
RAD51D, and
BRIP1, have shown clear evidence of an association with
ovarian cancer.
49-53
However, in each case, the evidence for association with breast cancer
is limited. Recent exome studies and targeted sequencing studies have
suggested that breast cancer is associated with deleterious variants in
FANCC,54 FANCM,55 and
XRCC2.56
I
n none of these instances, however, does the evidence reach the
threshold level (P<0.0001) that we propose for DNA-repair genes. The
recent findings of deleterious mutations in
RECQL in women with
a strong family history of breast cancer, however, suggests that this
gene confers susceptibility to breast cancer.
57,58.....
Other Genes
The
panels currently marketed for the prediction of risk of cancer contain
many other genes, most of which have been included by virtue of their
relevance to rare mendelian cancer syndromes. Variants in some of these
genes may also be associated with breast cancer. Mutations in DNA
mismatch-repair genes
(MLH1, MSH2, MSH6, and PMS2) may be associated with breast cancer, but in a recent review, Win et al.
59 concluded that the evidence was
equivocal. It has also been suggested that
MUTYH
variants that confer a predisposition to polyposis colorectal cancer
may confer a predisposition to breast cancer, but a recent case–control
study reported no association.
60 Another recent study suggested that carriers of
MEN1 mutations may be at increased risk for breast cancer.
61 A recent case–control study has reported an association between rare variants in
PPM1D and breast cancer.
62
However, this association does not reach our proposed significance
threshold, and, in addition, the sequence variants are observed as
mosaics in lymphocytes and are not inherited.
There is currently no
clear evidence of an association between breast cancer and any other
gene.........
choices?
"Overwhelmingly Canadian patients have voiced their support for assisted-dying and yet 'we' are still not listening but using many excuses why not. It is about choice - the patients' choice as they are truly and ultimately the ones affected by the decision, that which is being made by others. Many high profile physicians (and other healthcare providers) - prior to dying - have made their opinions on the role of assisted-dying clear. We all know the names - Dr Donald Low is one. It is to understand that medicine today, as we know it, is unable, in selected cases, to resolve extreme pain and agony and yet - we wish to prolong this suffering at any cost? As a cancer survivor (3 times so far) I have personally witnessed (non- medical background) cancer friends begging to die. Begging. They have begged their 'god' to die. For anyone who has witnessed these intimate experiences - they leave terrible emotional scars. Ultimately the question remains as to why we would continue to witness these events knowing that no medical intervention is available to ease these sufferings. This is where the choice - the patients' choice - demands compassion, integrity and 'to do no further harm'."