Study: Inherited breast cancer in Nigerian women

IN-DEPTH REVIEW OF RESEARCH

Study background:

Among Nigerian women, breast cancer is frequently diagnosed at later stages and is often triple negative. Breast cancer in Nigerian women is far more frequently fatal than in Europe or the United States. Historically, breast cancer incidence in this population has been low, but recently it has been increasing.

Identification of women who are at particularly high risk of breast cancer would better target use of limited Nigerian breast cancer screening resources.  

Researchers of this study wanted to know:

1.  Among Nigerian women, what proportion of breast cancer is due to an inherited mutation in a breast cancer gene?

2. What breast cancer genes most frequently harbor deleterious mutations in Nigerian women?

3. What is the increased risk associated with inherited mutations in known breast cancer genes in this population?

Study design:

Participants were part of the Nigerian Breast Cancer Study.  This case-control study enrolled Nigerian patients with invasive breast cancer between March 1998 and March 2014. All participants were at least 18 years old and were included regardless of age at diagnosis, family history of breast cancer, or previous genetic testing.  Controls were recruited from hospital outpatient clinics. The study enrolled 1,136 breast cancer patients and 997 controls.

Although some participants were age 70 and older, most ranged in age from 30-59 years.  Most did not have or did not know if they had a family history of breast cancer.  Most cases were diagnosed with late-stage breast cancer (stage III: 241; stage IV: 256; unknown: 559).  Among the patients, 133 had triple-negative breast cancer (TNBC) and 157 did not; 846 patients did not know the hormone receptor status of their breast cancer.

Participants agreed to genetic testing using the BROCA panel of cancer genes (http://tests.labmed.washington.edu/BROCA). This panel includes both high-risk and moderate-risk breast cancer genes.  Breast cancer genes included were BRCA1, BRCA2, ATM, ATR, BAP1, BARD1, BRIP1, CDH1, CHEK1, CHEK2, FAM175A, FANCM, GEN1, MRE11A, NBN1, PALB2, PTWEN, RAD51B, RAD51C, RAD51D, RECQL, RINT1, SLX4, TP53 and XRCC2.

Study findings:

Among 1,136 Nigerian women with breast cancer who were tested for mutations in 25 breast cancer genes:

• 167 (14.7%) had a mutation
  • 80 (7%) in BRCA1
  • 47 (4.1%) in BRCA2
  • 11 (1.0%) in PALB2
  • 5 (0.4%) in TP53
  • 24 (2.1%) in any of 10 other breast cancer genes

Among 997 controls (Nigerian women without breast cancer):

• 18 (1.8%) had a mutation
  • 3 (1.6%) in BRCA1
  • 4 (2.2%) in BRCA2
  • 1 each (0.5%) in ATM, BARD1, BRIP1, CHEK1, and GEN1
  • 5 in SLX4 and 1 in FAM175A (total of 3.3%) neither of which has been associated with an increased risk of breast cancer.
     
• The BRCA1 gene contributed most risk, because 7.0% of patients had a deleterious BRCA1 mutation and the increased risk associated with a BRCA1 mutation was extremely high (among 80 cases and 3 controls there was a 23.4-fold increase in breast cancer risk).
• The BRCA2 gene contributed the second highest risk (among 47 cases and 4 controls there was a 10.3-fold increase in breast cancer risk).
• Increased breast cancer risks were also associated with mutations in PALB2 (11 cases: 0 controls) and TP53 (5 cases: 0 controls).
• Compared with other patients, participants with BRCA1 mutations were significantly younger and more likely to have TNBC.
• Compared to European women, CHEK2 in Nigerian women played a far more minor role in breast cancer.
• Mutations in the FAM175A and SLX4 genes were only found in controls, which supports prior observations that mutations in these genes do not predispose to breast cancer.
• Age at diagnosis was significantly younger for BRCA1 mutation carriers (42.63 years + 10.14 years) and for TP53 mutation carriers (32.8 years + 9.26 years) than for other patients.
• The most common mutation among Nigerian breast cancer cases was BRCA1 pM1175R.  This is of particular historical interest because this was the first BRCA1 mutation identified in an African American family.

Limitations:

The primary limitation of this study was that tumor stage and ER/PR status was only available for a small number of participants.  This hindered the ability to document the high prevalence of TNBC in the study population. This is most likely due to the resource-limited setting of Nigeria. 

Conclusions:

Results of this study support four important conclusions: 1) Inherited BRCA1 and BRCA2 mutations have a major effect on breast cancer incidence in Nigerian women; 11% of breast cancer patients in Nigeria carry a deleterious mutation in BRCA1 or BRCA2. 2) Most of the well-documented prevalence of TNBC in Nigerian women remains unexplained. 3) Genetic testing in Nigerian women with breast cancer is useful only if it is comprehensive with full sequencing of all known breast cancer genes. 4) This study was an opportunity to evaluate the mutation status of breast cancer patients regardless of age at diagnosis and family history of disease or previous genetic testing.  It was designed to minimize ascertainment bias (enrolling   disproportional segments of the intended study population) to include controls from the same geographic areas as patients.  Importantly, these results revealed a very high risk for BRCA1 and BRCA2 mutation carriers with a high prevalence of mutation carriers among Nigerian breast cancer patients.