Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients

Abstract

IntroductionGermline TP53 mutations cause an increased risk to early-onset breast cancer in Li-Fraumeni syndrome (LFS) families and the majority of carriers identified through breast cancer cohorts have LFS or Li-Fraumeni-like (LFL) features. However, in Asia and in many low resource settings, it is challenging to obtain accurate family history and we, therefore, sought to determine whether the presence of early-onset breast cancer is an appropriate selection criteria for germline TP53 testing.MethodsA total of 100 patients with early-onset breast cancer (≤ 35 years) treated at University Malaya Medical Centre between 2003 and 2009, were analyzed for germline mutations in BRCA1, BRCA2 and TP53 by full DNA sequencing. Of the mutations identified, we examined their likely pathogenicity on the basis of prevalence in a case-control cohort, co-segregation analyses and loss of heterozygosity (LOH) in tumor tissues.ResultsWe identified 11 BRCA1 (11%) and 6 BRCA2 (6%) germline carriers among early-onset breast cancer patients. Of the 83 BRCA-negative patients, we identified four exonic variants and three intronic variants in TP53. Of these, two exonic variants are clinically relevant (E346X and p. G334_R335dup6) and two novel missense mutations (A138V and E285K) are likely to be clinically relevant, on the basis of co-segregation and loss of heterozygosity (LOH). Notably, E285K was found in two unrelated individuals and haplotype analyses suggest a founder effect. Two of the three intronic variants are likely benign based on their prevalence in a control population. Clinically relevant TP53 germline mutations were identified in three of the four patients (75%) with a family history of at least two LFS-linked cancers (breast, bone or soft tissue sarcoma, brain tumors or adrenocortical cancer); 1 of the 17 patients (6%) with a family history of breast cancer only, and 1 of the 62 patients (< 2%) with no family history of breast or LFS-linked cancers.ConclusionsOur study reports germline BRCA1, BRCA2 and TP53 mutations are found in early-onset breast cancer patients at 11%, 6% and 5% respectively, suggesting that TP53 mutation screening should be considered for these patients. However, we find that even in low resource Asian settings where family history is poorly reported, germline TP53 mutations are found predominantly among breast cancer patients with a family history of LFS-linked cancers.

Risk of second primary cancer after breast cancer treatment

“…The high incidence of leukaemia among the younger age group could be linked either to treatment (radiotherapy or chemotherapy) or to genetic mutations in the tumour suppressor genes CHEK2 and TP53 known as Li-Fraumeni syndrome, with the affected women being susceptible to develop multiple primary tumours early in life, such as breast cancer, acute adult leukaemia and soft tissue sarcomas. Several recent reports confirm this genetic linkage (Lynch et al 2008;Ruijs et al 2010;Lee et al 2012;Silva et al 2012).…”

“…Several studies show that patients with a family history of breast cancer are at higher risks in developing SPCs (ovary, oesophagus, stomach, leukaemia, non-Hodgkin's lymphoma) due to genetic susceptibility (Welcsh & King 2001;Prochazka et al 2006;Lynch et al 2008;Ruijs et al 2010;Lee et al 2012;Silva et al 2012). It is well documented in the literature that women with BRCA1 and BRCA2 genes are more susceptible to develop breast cancers than women lacking these genes.…”

What Should a Gynecologist Know about Li-Fraumeni Syndrome? Lessons from a Patient Undergoing Hysterectomy for Benign Indications

“…A woman who is diagnosed with breast cancer before the age of 30 years and is not found to have a pathogenic BRCA mutation has an estimated 4-8% likelihood of having a TP53 mutation [3,[8][9]. Women with breast cancer diagnosed between ages 30 and 39 years may also have a small increased risk of having a TP53 mutation [10]. Gynecologists should refer patients with early pre-menopausal breast cancer for genetic testing for TP53 mutations.…”

Current review ofTP53pathogenic germline variants in breast cancer patients outside Li-Fraumeni syndrome

“…A single study found one pathogenic variant out of 67 Pakistani BRCAx women (1.5%) with negative family history diagnosed before 30 years (Rashid et al, 2012). When it comes to BRCAx early onset breast cancer patients unselected for family history, TP53 carrier frequencies were estimated at 7.7% for women diagnosed before the age of 30 years (McCuaig et al, 2012), or between 2.3% and 4.2% for women of different ancestries diagnosed before 36 years (Ang, Lim, Yong, & Lee, 2009;Carraro et al, 2013;Lee et al, 2012;Tinat et al, 2009). Ginsburg et al, 2009, however, found no carriers out of only 52 BRCAx women of varying ancestries, all diagnosed with breast cancer before 30 years.…”