Georgia Chenevix-Trench

Mutational landscape of breast cancers from PALB2 germline mutation carriers

Background: The PALB2 gene encodes the partner and localizer of the BRCA2 protein, which participates in homologous recombination during DNA repair via an interaction with BRCA1 and BRCA2. Germline mutations in PALB2 are associated with an increased risk of breast cancer, with a cumulative risk of 35% by age 70 in female PALB2 mutant carriers. The aims of this project were to characterize the genomic landscape of PALB2 breast cancers and define the differences in the repertoire of somatic genetic alterations and mutational signatures between PALB2, BRCA1 and BRCA2 breast cancers. Methods: Representative samples from fourteen breast cancers from patients with known PALB2 germline mutations (seven frame-shift (2 H1170fs, 3 K346fs, 1 T841fs and 1 L531fs), five truncating (3 W1038* and 2 Q775*) and two missense (W1140G and L35P)) were microdissected to ensure a tumor cell content of >70%. DNA samples from microdissected tumors and their matched normal counterparts were subjected to whole exome sequencing on an Illumina HiSeq2000 to a median depth of 118x (range 33-193x). Somatic single nucleotide variations were detected using MuTect, and small insertions and deletions were identified using Strelka and Varscan2. Using ABSOLUTE and FACETS, we investigated the presence of loss of heterozygosity (LOH) of the PALB2 wild-type allele in these tumors. In addition, the mutational signatures and large scale state transitions (LSTs) were defined. The repertoire of somatic mutations identified in PALB2 breast cancers was compared to that of breast cancers from BRCA1 (n=11) and BRCA2 (n=10) germline mutation carriers from The Cancer Genome Atlas study. Results: PALB2 breast cancers were found to harbor a median of 80 somatic mutations (range 22-286) and one somatic mutation (range 0-13) affecting known cancer genes. Somatic loss of the PALB2 wild-type allele was found in five cases, and in three additional cases, a second PALB2 somatic mutation likely constituted the second 9hit9 (two with truncating mutations, Q479* and Q61*, and one with a Q921fs frameshift mutation). Six PALB2 breast cancers displayed the BRCA mutations signature; of these, five had PALB2 bi-allelic inactivation (three LOH of the wild-type allele and two a second PALB2 somatic mutation). 71% of the samples were found to have LSTs, including all cases with a BRCA mutational signature. A significant association between PALB2 bi-allelic inactivation and concurrent BRCA signature and high LST was observed (p=0.015). Breast cancers from PALB2 mutation carriers had fewer somatic TP53 mutations than BRCA1 breast cancers (3/14, 21% vs 9/11, 82%, p=0.004), but no difference in the repertoire of somatic mutations compared to that of BRCA2 breast cancers. Conclusions: PALB2 breast cancers were found to harbor pathogenic mutations in driver genes, including TP53, PIK3CA, NF1 and NCOR1, however lacked highly recurrent somatic mutations. Unlike BRCA1/2 breast cancers, the majority of breast cancers from PALB2 germline mutation carriers lacked LOH of the PALB2 wild-type allele. Importantly, however, an association between PALB2 bi-allelic inactivation and the BRCA mutational signature and LSTs was observed, providing additional evidence for a homologous recombination-deficient phenotype at least in a subset of PALB2 cancers. Citation Format: Burke KA, Berman S, Geyer FC, Piscuoglio S, Ng CK, Wen YH, Mannermaa A, Peterlongo P, Tondini C, Janatova M, Soo Hwang T, Ng P-S, Looi LM, Chenevix-Trench G, Southey MC, Weigelt B, Foulkes W, Tischkowitz M, Reis-Filho JS, PALB2 Interest Group. Mutational landscape of breast cancers from PALB2 germline mutation carriers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-03-01.

Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer (vol 313, pg 1347, 2015)

IMPORTANCEnLimited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.nnnOBJECTIVEnTo identify mutation-specific cancer risks for carriers of BRCA1/2.nnnDESIGN, SETTING, AND PARTICIPANTSnObservational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.nnnEXPOSURESnMutations of BRCA1 or BRCA2.nnnMAIN OUTCOMES AND MEASURESnBreast and ovarian cancer risks.nnnRESULTSnAmong BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHRu2009=u20091.46; 95% CI, 1.22-1.74; Pu2009=u20092u2009×u200910(-6)), c.4328 to c.4945 (BCCR2; RHRu2009=u20091.34; 95% CI, 1.01-1.78; Pu2009=u2009.04), and c. 5261 to c.5563 (BCCR2, RHRu2009=u20091.38; 95% CI, 1.22-1.55; Pu2009=u20096u2009×u200910(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHRu2009=u20090.62 (95% CI, 0.56-0.70; Pu2009=u20099u2009×u200910(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHRu2009=u20091.71; 95% CI, 1.06-2.78; Pu2009=u2009.03), c.772 to c.1806 (BCCR1; RHRu2009=u20091.63; 95% CI, 1.10-2.40; Pu2009=u2009.01), and c.7394 to c.8904 (BCCR2; RHRu2009=u20092.31; 95% CI, 1.69-3.16; Pu2009=u2009.00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHRu2009=u20090.51; 95% CI, 0.44-0.60; Pu2009=u20096u2009×u200910(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHRu2009=u20090.57; 95% CI, 0.41-0.80; Pu2009=u2009.001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.nnnCONCLUSIONS AND RELEVANCEnBreast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer - eScholarship

IMPORTANCEnLimited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.nnnOBJECTIVEnTo identify mutation-specific cancer risks for carriers of BRCA1/2.nnnDESIGN, SETTING, AND PARTICIPANTSnObservational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.nnnEXPOSURESnMutations of BRCA1 or BRCA2.nnnMAIN OUTCOMES AND MEASURESnBreast and ovarian cancer risks.nnnRESULTSnAmong BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHRu2009=u20091.46; 95% CI, 1.22-1.74; Pu2009=u20092u2009×u200910(-6)), c.4328 to c.4945 (BCCR2; RHRu2009=u20091.34; 95% CI, 1.01-1.78; Pu2009=u2009.04), and c. 5261 to c.5563 (BCCR2, RHRu2009=u20091.38; 95% CI, 1.22-1.55; Pu2009=u20096u2009×u200910(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHRu2009=u20090.62 (95% CI, 0.56-0.70; Pu2009=u20099u2009×u200910(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHRu2009=u20091.71; 95% CI, 1.06-2.78; Pu2009=u2009.03), c.772 to c.1806 (BCCR1; RHRu2009=u20091.63; 95% CI, 1.10-2.40; Pu2009=u2009.01), and c.7394 to c.8904 (BCCR2; RHRu2009=u20092.31; 95% CI, 1.69-3.16; Pu2009=u2009.00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHRu2009=u20090.51; 95% CI, 0.44-0.60; Pu2009=u20096u2009×u200910(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHRu2009=u20090.57; 95% CI, 0.41-0.80; Pu2009=u2009.001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.nnnCONCLUSIONS AND RELEVANCEnBreast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Genetic Modifiers of Risk of BRCA1- and BRCA2-Related Breast and Ovarian Cancers

Mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancers as well as other cancers [1,2]. Several studies have estimated the breast and ovarian cancer risks associated with BRCA1 and BRCA2 mutations [3–11]. Initial studies, based on families with multiple affected individuals, estimated that the risk of breast cancer by age 70 is 85% in BRCA1 and 84% in BRCA2 mutation carriers