The University of Pennsylvania has discovered why the cancer recurs due to BRCA mutations

Researchers at the University of Pennsylvania's Basser BRCA Cancer Center have identified factors
that may make breast and ovarian cancers more likely to recur from cancers associated with mutations in the BRCA1/2 gene.

These mutations strongly predispose women to breast and ovarian cancer, which have a high risk
of recurrence after initial treatment.
In a new study published this week in Nature Communications, researchers compared a group of tumors from patients with primary and recurrent BRCA1/2 mutation-associated breast and ovarian cancers and found multiple features associated with recurrence, including those
that promise to improve the ability of tumor repair treatments to cause DNA damage.

Katherine Nathanson, M.
D.
, senior author of the study, said: "These results indicate key biological characteristics of drug resistance recurrence, which opens up new possibilities
for the treatment of BRCA1/2 mutant cancers.
" Katherine Nathanson is the Pearl Basser Professor of BRCA-related research at the University of Pennsylvania's Perreman School of Medicine, associate director of the Abramson Cancer Center, and director of
genetics at the Basser BRCA Center.

BRCA1 and BRCA2 proteins are key DNA repair proteins
.
Their loss of function makes some cells highly vulnerable to DNA damage, including damage that causes cancer
.
Women with inactivating mutations in the BRCA1 or BRCA2 genes have a very high lifetime risk of developing breast cancer and also have a high
risk of ovarian cancer.
Some women who learn they have a BRCA1/2 mutation opt for surgery to remove their breasts and ovaries to reduce their risk of cancer, while others are closely monitored to detect cancer
at an early stage.

Unfortunately, many women do not learn they have a BRCA1/2 mutation until after breast or ovarian cancer has developed, often when the disease progresses to the point where it cannot be cured
surgically.
These tumors associated with BRCA1/2 mutations can often be relieved with chemotherapy drugs and radiation therapy, which take advantage of the tumor's lower DNA repair capacity
.
But these tumors are at high risk of recurrence within years of a patient's completion of first-line therapy, and scientists know relatively little
about what causes them to recur.

For the study, Nathanson's team examined 67 groups of primary and recurrent breast and ovarian tumors from carriers of BRCA1/2 mutations
.
For each group, they compared the primary tumor's DNA mutations, gene activity patterns, and other tumor cell features to see how these characteristics differed from
the recurrent tumor.

"We hypothesized that differences between paired tumors may point to possible mechanisms by which tumor evolution allowed for recurrence," Nathanson said
.

A new observation found that, particularly in cancers where BRCA1 mutations recur, tumor cells typically convert to a specific subtype
of messenger RNA molecules expressing the BRCA2 protein.
This isoform is slightly shorter
than normal-length BRCA2 RNA.
It is translated to the usual BRCA2 protein but is more stable than normal BRCA2 messenger RNA, so it is expected to be associated with increased levels of the BRCA2 protein, which appears to be a way
to enhance repair.
In general, tumors treated with strong DNA-damaging drugs and/or radiation therapy may survive better and eventually recur when they enhance their ability to repair DNA damage
.
The researchers believe that the presence of short forms of BRCA2 RNA is associated not only with cancer recurrence, but also with significantly shorter patient survival times
.

Similarly, the researchers were surprised to find that whether a tumor lost a normal copy of the BRCA1 or BRCA2 gene (known as heterozygous loss), may change
as the tumor develops.
Loss of heterozygous sex is often considered necessary for BRCA1/2 germline mutation carriers to develop breast and ovarian cancer, but research by this team and others has shown that loss of heterozygous sex is not always necessary
.
Now, they found that in 25 percent of cases, heterozygous deletions were different between primary and recurrent tumors, a new finding that is only possible
in matched primary and recurrent tumors.
Some tumors develop to the point where they do not lose their heterozygous, which is part of
tumor development.
Other tumors go from losing heterozygotes to not having heterozygotes, which may be a mechanism
for treating drug resistance.
In all, the researchers have identified several new markers of therapeutic resistance, which they say underscores the importance of analyzing tumors at the time of
treatment.
Nathanson and her colleagues are continuing to evaluate multiple other factors
that influence treatment response and drug resistance in patients with BRCA1/2-related tumors.

Analysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers