Germline pathogenic variants in  PALB2  and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without  CDH1  mutation: a whole-exome sequencing study

Fewings, Eleanor; Larionov, Alexey; Redman, James; Goldgraben, Mae A.; Scarth, James; Richardson, Susan; Brewer, Carole; Davidson, Rosemarie; Ellis, Ian O.; Evans, D. Gareth; Halliday, Dorothy; Izatt, Louise; Marks, Peter; McConnell, Vivienne; Verbist, Louis; Mayes, Rebecca; Clark, Graeme R.; Hadfield, James; Chin, Suet-Feung; Teixeira, Manuel R.; Giger, Olivier; Hardwick, Richard; Pietro, Massimiliano di; O’Donovan, Maria; Pharoah, Paul D.P.; Caldas, Carlos; Fitzgerald, Rebecca C.; Tischkowitz, Marc

doi:10.1016/s2468-1253(18)30079-7

Cited by 92 publications

(85 citation statements)

References 33 publications

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“…Although the mutation frequency was low, Norquist et al demonstrated that PALB2 mutation carriers had a significantly higher risk of ovarian cancer compared with the NHLBI Exome Sequencing Project (OR, 10.2; 95% CI, 2.2-47.0; p < 0.001) or the Exome Aggregation Consortium database (OR, 4.4; 95% CI, 2.1-9.1; p < 0.001) (8). Pathogenic PALB2 mutations have also been identified in patients with other cancers, such as gastric and prostate cancer; however, whether these mutations confer an increased cancer risk for these cancer types requires further research (91)(92)(93)(94).…”

Section: Palb2 and Other Cancersmentioning

confidence: 99%

Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management

Zhou

Zhang

et al. 2020

Front. Oncol.

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Partner and localizer of BRCA2 (PALB2) is vital for homologous recombination (HR) repair in response to DNA double-strand breaks (DSBs). PALB2 functions as a tumor suppressor and participates in the maintenance of genome integrity. In this review, we summarize the current knowledge of the biological roles of the multifaceted PALB2 protein and of its regulation. Moreover, we describe the link between PALB2 pathogenic variants (PVs) and breast cancer predisposition, aggressive clinicopathological features, and adverse clinical prognosis. We also refer to both the opportunities and challenges that the identification of PALB2 PVs provides in breast cancer genetic counseling and precision medicine.

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Section: Palb2 and Other Cancersmentioning

confidence: 99%

Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management

Zhou

Zhang

et al. 2020

Front. Oncol.

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“…Beyond BC, germline PVs in PALB2 have been associated with pancreatic cancer (PaC) 8,9 and gastric cancer. [10][11][12] Possible associations with ovarian (OC) 13 and colorectal cancer (CRC) 14 have been suggested, but the statistical evidence is weak. Guidelines for the management of PALB2-associated BC risk exist, 7,15 but risk estimates for other cancers are based on small numbers and have large imprecision.…”

Section: Introductionmentioning

confidence: 99%

Cancer Risks Associated With GermlinePALB2Pathogenic Variants: An International Study of 524 Families

Yang

Leslie

Doroszuk

et al. 2020

JCO

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316

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PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10−76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10−3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10−3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10−2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10−3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

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“…Germline mutations and deletions within the E-cadherin gene ( CDH1 ) are the main cause of HDGC and affect 14%–40% of families 10–12. Additionally, while α-E-catenin gene ( CTNNA1 ) mutations have been proven to cause HDGC, germline variants in homologous recombination DNA repair genes, such as PALB2 , await confirmation as potential causes of disease in mutation-negative HDGC families 13–15. Concerning GAPPS, APC promoter 1B point mutations are the underlying cause of this syndrome in several families 16.…”

Section: Introductionmentioning

confidence: 99%

Redefinition of familial intestinal gastric cancer: clinical and genetic perspectives

et al. 2020

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BackgroundFamilial intestinal gastric cancer (FIGC) remains genetically unexplained and without testing/clinical criteria. Herein, we characterised the age of onset and disease spectrum of 50 FIGC families and searched for genetic causes potentially underlying a monogenic or an oligogenic/polygenic inheritance pattern.MethodsNormal and tumour DNA from 50 FIGC probands were sequenced using Illumina custom panels on MiSeq, and their respective germline and somatic landscapes were compared with corresponding landscapes from sporadic intestinal gastric cancer (SIGC) and hereditary diffuse gastric cancer cohorts.ResultsThe most prevalent phenotype in FIGC families was gastric cancer, detected in 138 of 208 patients (50 intestinal gastric cancer probands and 88 unknown gastric cancer histology relatives), followed by colorectal and breast cancers. After excluding benign and intronic variants lacking impact in splicing, 12 rare high-quality variants were found exclusively in 11 FIGC probands. Only two probands carried potentially deleterious variants, but lacked somatic second-hits, weakly supporting the monogenic hypothesis for FIGC. However, FIGC probands developed gastric cancer at least 10 years earlier and carried more TP53 germline common variants than SIGC (p=4.5E-03); FIGC and SIGC could be distinguished by specific germline and somatic variant profiles; there was an excess of FIGC tumours presenting microsatellite instability (38%); and FIGC tumours displayed significantly more somatic common variants than SIGC tumours (p=4.2E-06).ConclusionThis study proposed the first data-driven testing criteria for FIGC families, and supported FIGC as a genetically determined, likely polygenic, gastric cancer-predisposing disease, with earlier onset and distinct from patients with SIGC at the germline and somatic levels.

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Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study

Cited by 92 publications

References 33 publications

Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management

Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management

Cancer Risks Associated With GermlinePALB2Pathogenic Variants: An International Study of 524 Families

Redefinition of familial intestinal gastric cancer: clinical and genetic perspectives

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