Analysis of PALB2 Gene in BRCA1/BRCA2 Negative Spanish Hereditary Breast/Ovarian Cancer Families with Pancreatic Cancer Cases

Blanco, Ana; Hoya, Miguel de la; Osorio, Ana; Díez, Orland; Miramar, María Dolores; Infante, Mar; Martínez-Bouzas, Cristina; Torres, Alexandra; Lasa, Adriana; Llort, Gemma; Brunet, Joan; Graña, Begoña; Segura, Pedro Pérez; García, María J.; Gutiérrez‐Enríquez, Sara; Carracedo, Ángel; Tejada, María-Isabel; Velasco, Eladio A.; Calvo, María Teresa; Balmañà, Judith; Benı́tez, Javier; Caldés, Trinidad; Vega, Ana

doi:10.1371/journal.pone.0067538

Cited by 46 publications

(29 citation statements)

References 38 publications

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“…The rate of MMR gene mutations in our cohort, comparable to that in colorectal cancer cohorts, warrants further investigation. Our cohort had no PALB2 or CDK2NA mutation carriers, which is consistent with previous studies that found very low rates of PALB2 and CDKN2A mutations in PC 12, 39, 49, 50, 54-56 . The lack of mutations in APC, PRSS1 , and STK11 does not eliminate the possibility that these genes cause a small proportion of PC.…”

Section: Discussionsupporting

confidence: 92%

Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients With Pancreatic Cancer

et al. 2015

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Background & Aims We investigated the prevalence of germline mutations in APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53 in patients with pancreatic cancer. Methods The Ontario Pancreas Cancer Study enrolls consenting participants with pancreatic cancer from a province-wide electronic pathology database; 708 probands were enrolled from April 2003 through August 2012. To improve precision of BRCA2 prevalence estimates, 290 probands were randomly selected from 3 strata, based on family history of breast and/or ovarian cancer, pancreatic cancer, or neither. Germline DNA was analyzed by next-generation sequencing using a custom multiple-gene panel. Mutation prevalence estimates were calculated from the sample for the entire cohort. Results Eleven pathogenic mutations were identified: 3 in ATM, 1 in BRCA1, 2 in BRCA2, 1 in MLH1, 2 in MSH2, 1 in MSH6, and 1 in TP53. The prevalence of mutations in all 13 genes was 3.8% (95% confidence interval, 2.1%–5.6%). Carrier status was significantly associated with breast cancer in the proband or first-degree relative (P<.01), and colorectal cancer in the proband or first-degree relative (P<.01), but not family history of pancreatic cancer, age of diagnosis, or stage at diagnosis. Of patients with a personal or family history of breast and colorectal cancer, 10.7% (4.4%–17.0%) and 11.1% (3.0%–19.1%) carried pathogenic mutations, respectively. Conclusions A small but clinically important proportion of pancreatic cancer is associated with mutations in known predisposition genes. The heterogeneity of mutations identified in this study demonstrates the value of using a multiple-gene panel in pancreatic cancer.

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Section: Discussionsupporting

confidence: 92%

Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients With Pancreatic Cancer

et al. 2015

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“…In the USA, Canada, and Europe, the frequency of PALB2 deleterious mutations was revealed to vary from 1.1 to 3.4% (8)(9)(10)(11)(12)(13)(14)(15). A total of 4 previous studies have arisen from Asia.…”

Section: Discussionmentioning

confidence: 99%

PALB2 mutation in a woman with bilateral breast cancer: A case report

Nakagomi

Hirotsu

Okimoto

et al. 2017

Molecular and Clinical Oncology

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Abstract. Partner and localizer of breast cancer 2 (PALB2) was identified as a moderate-risk gene of breast and pancreas cancer. The present authors previously reported that no PALB2 germline mutations with a deleterious frameshift or stop codons were identified in 155 Japanese patients with breast and/or ovarian cancer who were estimated to be at risk of hereditary cancer, according to the National Comprehensive Cancer Network (NCCN) criteria. In the present study, one patient with a deleterious mutation of PALB2 (c. 2834+2 T>C) has been identified from a study of an additional 128 cases. Therefore, the prevalence of PALB2 among Japanese patients is now estimated to be 0.35% (1/283). The proband was a 63-year-old woman with bilateral breast cancer, although she had experienced no other cancers. The proband had two elder sisters, the eldest of whom died from pancreatic cancer at 60 years of age. The proband's 40-year-old daughter was affected, but did not show any malignancies. There are only a few reports concerning PALB2 mutations in Japan. To the best of our knowledge, this is the first case study to reveal the significance of DNA-repair genes in the development of malignancies in Japanese patients with breast cancer. IntroductionThe significance of the breast cancer 1 (BRCA1) and BRCA2 mutations in familial breast and ovarian cancer has been well established (1,2). However, the mutations of these genes are estimated to cause, at most, 20-30% of cases of hereditary breast cancer (3). The present authors studied the BRCA1/2 mutations in 191 patients in a previous study, but the prevalence was shown to be unexpectedly low (4,5). In fact, it was only 7% among the analyzed patients who had a family history of breast cancers.Partner and localizer of BRCA2 (PALB2) was identified as a moderate-risk gene in breast and pancreas cancer (6). PALB2 is located on chromosome 16p12.2 containing 13 exons and 12 introns, and is involved in BRCA2-associated pathways (6). Recently, Antoniou et al (7) reported that PALB2 carriers have a high risk of developing breast cancer, and concluded that the cumulative risk of mutation carrier was 34% by the age of 70 in their prospective follow-up study on 154 families.The prevalence of the PALB2 mutation was reported to be 1.2-3.4% in European countries, whereas it is very rare in Asian countries (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). To the best of our knowledge, no study has been performed that has identified the PALB2 deleterious mutation in Japanese patients with breast cancer. From our first cohort data, no deleterious PALB2 mutations were identified in 155 patients with breast and/or ovarian cancer who were estimated to be at risk of hereditary cancer according to the National Comprehensive Cancer Network (NCCN) criteria (19). In the present case study, an additional 128 cases having breast and/or ovarian cancer were studied, and the case of a patient with bilateral breast cancer is presented who harbors the deleterious mutation in PALB2. Factoring in the first cohort of 155 c...

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“…However, the penetrance of mutations in PALB2 varied significantly in different populations, ranging in a 2-30-fold higher risk, as compared to that in non-carriers (Southey et al, 2010;Antoniou et al, 2014;Slavin et al, 2017). Several missense variants with an unknown significance have also reportedly been associated with breast cancer (Blanco et al, 2013;Damiola et al, 2015;Li et al, 2015;Nakagomi et al, 2016), among which L35P was identified as the pathogenic variant in a family with a strong history of breast cancer (Foo et al, 2017).…”

Section: Palb2/fancnmentioning

confidence: 99%

Fanconi Anemia Pathway: Mechanisms of Breast Cancer Predisposition Development and Potential Therapeutic Targets

Fang

Zhang

et al. 2020

Front. Cell Dev. Biol.

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The maintenance of genomic stability is crucial for species survival, and its failure is closely associated with tumorigenesis. The Fanconi anemia (FA) pathway, involving 22 identified genes, plays a central role in repairing DNA interstrand cross-links. Importantly, a germline defect in any of these genes can cause Fanconi's anemia, a heterogeneous genetic disorder, characterized by congenital growth abnormalities, bone marrow failure, and predisposition to cancer. On the other hand, the breast cancer susceptibility genes, BRCA1 and BRCA2, also known as FANCS and FANCD1, respectively, are involved in the FA pathway; hence, researchers have studied the association between the FA pathway and cancer predisposition. Here, we mainly focused on and systematically reviewed the clinical and mechanistic implications of the predisposition of individuals with abnormalities in the FA pathway to cancer, especially breast cancer.

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Analysis of PALB2 Gene in BRCA1/BRCA2 Negative Spanish Hereditary Breast/Ovarian Cancer Families with Pancreatic Cancer Cases

Cited by 46 publications

References 38 publications

Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients With Pancreatic Cancer

Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients With Pancreatic Cancer

PALB2 mutation in a woman with bilateral breast cancer: A case report

Fanconi Anemia Pathway: Mechanisms of Breast Cancer Predisposition Development and Potential Therapeutic Targets

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