Spectrum of germline pathogenic variants using a targeted next generation sequencing panel and genotype-phenotype correlations in patients with suspected hereditary breast cancer at an academic medical centre in Pakistan

Abstract

Background Breast cancer is the most common malignancy in women, affecting over 1.5 million women every year, which accounts for the highest number of cancer-related deaths in women globally. Hereditary breast cancer (HBC), an important subset of breast cancer, accounts for 5–10% of total cases. However, in Low Middle-Income Countries (LMICs), the population-specific risk of HBC in different ethnicities and the correlation with certain clinical characteristics remain unexplored. Methods Retrospective chart review of patients who visited the HBC clinic and proceeded with multi-gene panel testing from May 2017 to April 2020. Descriptive and inferential statistics were used to analyze clinical characteristics of patients. Fisher’s exact, Pearson’s chi-squared tests and Logistic regression analysis were used for categorical variables and Wilcoxon rank-sum test were used for quantitative variables. For comparison between two independent groups, Mann-Whitney test was performed. Results were considered significant at a p value of < 0.05. Results Out of 273 patients, 22% tested positive, 37% had a VUS and 41% had a negative genetic test result. Fifty-five percent of the positive patients had pathogenic variants in either BRCA1 or BRCA2, while the remaining positive results were attributed to other genes. Patients with a positive result had a younger age at diagnosis compared to those having a VUS and a negative result; median age 37.5 years, IQR (Interquartile range) (31.5–48). Additionally, patients with triple negative breast cancer (TNBC) were almost 3 times more likely to have a positive result (OR = 2.79, CI = 1.42–5.48 p = 0.003). Of all patients with positive results, 25% of patients had a negative family history of breast and/or related cancers. Conclusions In our HBC clinic, we observed that our rate of positive results is comparable, yet at the higher end of the range which is reported in other populations. The importance of expanded, multi-gene panel testing is highlighted by the fact that almost half of the patients had pathogenic or likely pathogenic variants in genes other than BRCA1/2, and that our test positivity rate would have only been 12.8% if only BRCA1/2 testing was done. As the database expands and protocol-driven referrals are made across the country, our insight about the genetic architecture of HBC in our population will continue to increase.

Prophylactic Risk‐Reducing Mastectomy (PRRM): A Set Practice or Catch‐22 Situation in LMIC. A Single‐Centre Prospective Cohort Study

“…Consistent with results from other countries in our region, we found that 60% had a positive family history of BRCA1/2-related cancers, with the majority having firstdegree affected relatives (70.2%); also, predominant cancer identified among them was BC, followed by gynaecological malignancies [8,16,19,21]. Iranian study also concurs with our results of positive family history and early age at BC diagnosis and correlates it to an increased mutation detection rate [19].…”

“…We found that the overall positivity of high penetrance BC genes ( BRCA1/2 and P /LP) was 20.12%; however, a study from this region showed an overall positivity as 22% [8]. Also, 73.7% were BRCA1 /2 positive and 25.2% had P /LP variants, which in contrast to the same study was 55% and 45% for BRCA1 /2 and P /LP variants, respectively [8].…”

“…We found that the overall positivity of high penetrance BC genes ( BRCA1/2 and P /LP) was 20.12%; however, a study from this region showed an overall positivity as 22% [8]. Also, 73.7% were BRCA1 /2 positive and 25.2% had P /LP variants, which in contrast to the same study was 55% and 45% for BRCA1 /2 and P /LP variants, respectively [8]. Our overall BRCA1 /2 positivity rate is 14.6%, while the same study showed this rate to be 12.8%; however, both results showed a higher‐than‐average prevalence rate of mutations than other countries [8].…”

“…Pakistani females are at the top of the list in terms of incidence, prevalence and mortality for BC [7]. Similarly, the bulk of BRCA1/2 positivity is around 12.8% in a patient's cohort who were eligible for genetic testing according to the NCCN criteria, which is higher than in neighbouring countries [6, 8]. This BRCA1/2 positivity makes the affected susceptible to the risk of developing BC by 40–80%, making genetic testing even more crucial; because by offering bilateral risk‐reducing mastectomy (BRRM), this risk is reduced to ≥ 90% [9, 10].…”

Breast cancer in a teenage girl with BRCA mutation: A case report from a low middle-income country

“…Germ-line mutations in the BRCA1/2 genes predispose women to HOBC. HBOC patients in the Pakistani population have a higher positivity rate of BRCA1/2 variants in their gene pool [24] with BRCA 1 mutations being a significant contributor to the high prevalence of BC in Pakistan (found in approximately 12 % of women with early-onset BC) [24] , [25] , [26] , [27] , [28] , [29] . A BRCA 1 mutation was seen in our patient as well.…”