The PALB2 Gene Is a Strong Candidate for Clinical Testing in BRCA1- and BRCA2-Negative Hereditary Breast Cancer

Janatová, Markéta; Kleibl, Zdeněk; Stříbrná, Jana; Panczak, A; Veselá, Kamila; Zimovjanová, Martina; Kleiblová, Petra; Dundr, Pavel; Soukupová, Jana; Pohlreich, Petr

doi:10.1158/1055-9965.epi-13-0745-t

Cited by 48 publications

(37 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The PALB2 mutation frequency in our larger series was highly significant compared to population rates and was associated with similar odds ratios for OC as were RAD51C, RAD51D , and BRIP1 (Table 2). The corrected frequency of PALB2 mutations in the ESP is consistent with PALB2 mutation rates from other previously published control sets in which full sequencing of PALB2 was performed 30,32 , supporting the use of the ESP as a comparison population.…”

Section: Discussionsupporting

confidence: 84%

See 1 more Smart Citation

Inherited Mutations in Women With Ovarian Carcinoma

et al. 2016

View full text Add to dashboard Cite

Importance Germline mutations in BRCA1 and BRCA2 are relatively common in women with ovarian, fallopian tube, and peritoneal carcinoma (OC) causing a greatly increased lifetime risk of these cancers, but the frequency and relevance of inherited mutations in other genes is less well characterized. Objective To determine the frequency and importance of germline mutations in cancer-associated genes in OC. Design Subjects were ascertained from two phase III clinical trials in newly diagnosed advanced stage OC (GOG 218 and GOG 262), and a university-based gynecologic oncology tissue bank. Germline DNA was sequenced from women with OC using the targeted capture and multiplex sequencing assay BROCA. Setting Referral centers participating in NRG Oncology studies, and a University-based gynecologic oncology practice (UW). Participants The study population was 1915 women with OC with available germline DNA, unselected for age or family history, enrolled at the time of OC diagnosis (GOG 218, N=788; GOG 262, N=557; UW, N=570). Main Outcomes and Measures Mutation frequencies in OC were compared to the NHLBI GO Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC). Clinical characteristics and survival were assessed by mutation status. Results Of 1915 subjects, 280 (15%) had mutations in BRCA1 (182), or BRCA2 (98) and 8 (0.4%) had mutations in DNA mismatch repair (MMR) genes. Mutations in BRIP1 (26), RAD51C (11), RAD51D (11), PALB2 (12) and BARD1 (4), were significantly more common in OC patients than in the ESP or ExAC, and in total were present in 3.3% of patients. Race, histologic subtype, and disease site were not predictive of mutation frequency. Mutation status affected survival, in particular for BRCA2 mutation carriers with HR 0.60 (95% CI 0.45 – 0.79, p<0.001) for progression-free survival, and HR 0.39 (95% CI 0.25 – 0.60, p<0.001) for overall survival in the GOG patients. Conclusions and Relevance In total, 347/1915 (18%) OC patients carried pathogenic germline mutations in genes associated with OC risk. PALB2 and BARD1 are suspected OC genes and together with established OC genes (BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH2, MLH1, PMS2, and MSH6) bring the total number of genes suspected to cause hereditary OC to 11.

show abstract

Section: Discussionsupporting

confidence: 84%

“…However, it is reassuring that mutation frequencies in the ESP for these genes were similar to previously published controls. 8,9,30,32,41 Further research is needed to clarify the roles of inherited mutations in PALB2 and BARD1 in ovarian cancer risk.…”

Section: Discussionmentioning

confidence: 99%

Inherited Mutations in Women With Ovarian Carcinoma

et al. 2016

View full text Add to dashboard Cite

show abstract

“…This mutation has been detected in 0.6–1.4% of breast cancer patients in three independent studies in Poland [5, 16, 26]. The other recurrent PALB2 mutation, c.172_175delTTGT, was identified in breast cancer patients from the Czech Republic and Poland [5, 18, 26]. …”

Section: Discussionmentioning

confidence: 99%

PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland

et al. 2017

View full text Add to dashboard Cite

BackgroundThe PALB2 gene encodes a protein that plays a crucial role in maintaining genomic integrity. Germline inactivating mutations in PALB2 are associated with an increased risk of breast and ovarian cancer. The prevalence and spectrum of recurrent PALB2 germline mutations in breast and ovarian cancer patients from Poland is not clearly defined.Methods PALB2 exons were amplified from 460 BRCA1/2-mutation negative women with familial breast and/or ovarian cancer and early-onset breast cancer using AmpliSeq technology and sequenced on an Ion Torrent PGM sequencer. In addition, eight selected variants were genotyped using TaqMan assays in 807 BRCA1/2-mutation negative breast cancer patients and 1690 healthy women.ResultsTwo recurrent PALB2 mutations, c.172_175delTTGT and c.509_510delGA, were identified, along with one novel mutation, c.347insT. In total, PALB2 pathogenic mutations were detected in 7/460 (1.5%) patients. Furthermore, in breast and/or ovarian cancer patients, several single nucleotide variants (SNVs) were detected in the PALB2 coding region. In an additional group of 807 patients, eight (1%) carriers of two pathogenic mutations, c.172_175delTTGT (0.5%) and c.509_510delGA (0.5%), were identified. The c.509_510delGA mutation was not identified in healthy controls, while c.172_175delTTGT was identified in 4/1690 (0.24%) of control women.ConclusionsGermline mutations in the PALB2 gene were observed at a frequency of approximately 1.5% in Polish breast and/or ovarian cancer patients. Our study confirms two recurrent PALB2 mutations; c.172_175delGA and c.509_510delGA.

show abstract

“…For carriers of BRCA1 or BRCA2 , genome sequencing can be beneficial for surveillance and surgical decisions (Heemskerk-Gerritsen et al 2015; Ingham et al 2013; Riedl et al 2014; Sieh et al 2014; Trujillano et al 2015). Moreover, even for BRCA1 or BRCA2 -negative patients, genome sequencing may be beneficial in identifying other genes, such as PALB2 , CHEK2 , and ATM , that may confer an increased risk of familial breast cancer (Cybulski et al 2011; Desmond et al 2015; Janatova et al 2013; Renwick et al 2006). Genome sequencing can be used to identify and choose targeted therapeutic agents for some cancer patients (Ellis et al 2012; Yauch and Settleman 2012; Zardavas et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Information Topics of Greatest Interest for Return of Genome Sequencing Results among Women Diagnosed with Breast Cancer at a Young Age

Seo

Ivanovich

Goodman

et al. 2016

Journal of Genetic Counseling

View full text Add to dashboard Cite

We investigated what information women diagnosed with breast cancer at a young age would want to learn when genome sequencing results are returned. We conducted 60 semi-structured interviews with women diagnosed with breast cancer at age 40 or younger. We examined what specific information participants would want to learn across result types and for each type of result, as well as how much information they would want. Genome sequencing was not offered to participants as part of the study. Two coders independently coded interview transcripts; analysis was conducted using NVivo10. Across result types, participants wanted to learn about health implications, risk and prevalence in quantitative terms, causes of variants, and causes of diseases. Participants wanted to learn actionable information for variants affecting risk of preventable or treatable disease, medication response, and carrier status. The amount of desired information differed for variants affecting risk of unpreventable or untreatable disease, with uncertain significance, and not health-related. Women diagnosed with breast cancer at a young age recognize the value of genome sequencing results in identifying potential causes and effective treatments and expressed interest in using the information to help relatives and to further understand their other health risks. Our findings can inform the development of effective feedback strategies for genome sequencing that meet patients’ information needs and preferences.

show abstract

The PALB2 Gene Is a Strong Candidate for Clinical Testing in BRCA1- and BRCA2-Negative Hereditary Breast Cancer

Cited by 48 publications

References 50 publications

Inherited Mutations in Women With Ovarian Carcinoma

Inherited Mutations in Women With Ovarian Carcinoma

PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland

Information Topics of Greatest Interest for Return of Genome Sequencing Results among Women Diagnosed with Breast Cancer at a Young Age

Contact Info

Product

Resources

About