New Gene Tied to Major Breast Cancer Risk

Clinical testing for genes that confer a predisposition to breast cancer has been revolutionized by next-generation sequencing and multigene panels that allow relatively inexpensive and rapid genetic profiling are now in widespread use.

However, the usefulness of this sequencing technology for medical follow-up is limited by incomplete information on breast-cancer risk, even for well-documented genes such as Breast cancer early onset 1 (BRAC1) and BRAC2.


An international team of scientists led by those at the University of Cambridge (UK) identified families through 14 participating medical centers. Families were eligible for inclusion if at least one family member with breast cancer who tested negative for BRCA1 and BRCA2 mutations had a loss-of-function mutation in a gene called Partner and Localizer of BRCA2 (PALB2).

The inheritance patterns of disease and genotypes in families were used to estimate the cancer risk conferred by PALB2 loss-of-function mutations, with the use of modified complex-segregation-analysis methods. Included in the final analysis were 154 families including 311 women with PALB2 mutations, of whom 229 had breast cancer and 51 men with PALB2 mutations, of whom seven had breast cancer. Among the 154 families, there were 48 different loss-of-function mutations in PALB2.

The risk of breast cancer for PALB2 mutation carriers was increased by a factor of 9.47 as compared with the breast-cancer incidence in the general population of the UK between 1993 and 1997, under a single-gene model of constant relative risk across all ages. The corresponding mean cumulative risk of breast cancer by 70 years of age was estimated to be 47.5%. Breast-cancer estrogen-receptor status was available for 129 affected PALB2 mutation carriers, and the tumors in 95 of the 129 (74%) were estrogen-receptor–positive. This frequency is similar to that seen among patients with BRCA2 mutations or with sporadic breast cancer. Men with a faulty PALB2 gene also have a risk for breast cancer that is eight times greater than men in the general population.

Jeffrey N. Weitzel, MD, a coauthor and genetics expert at City of Hope Cancer Center (Duarte, CA, USA), said, “Testing for PALB2 often is included in more comprehensive genetic testing, and the new study should give people with the mutation better information on their risk. Doctors say that people with faulty cancer genes should be offered genetic counseling and may want to consider more frequent screening and prevention options, which can range from hormone-blocking pills to breast removal.”

The authors concluded that women with loss-of-function mutations in PALB2 should be studied to determine whether enhanced surveillance for breast cancer, in line with that offered to women with mutations in BRCA2 can influence outcomes. Risk-reducing surgical options could also be tested. The team also noted a nonsignificant increase, by a factor of 2.3, in the risk of ovarian cancer for PALB2 carriers. The study was published on August 7, 2014, in the New England Journal of Medicine.

Related Links:
University of Cambridge
City of Hope Cancer Center