# 614320

PANCREATIC CANCER, SUSCEPTIBILITY TO, 4; PNCA4


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
17q21.31 {Pancreatic cancer, susceptibility to, 4} 614320 3 BRCA1 113705

TEXT

A number sign (#) is used with this entry because this form of susceptibility to pancreatic cancer is caused by heterozygous mutation in the BRCA1 gene (113705).

For background, phenotypic description, and a discussion of genetic heterogeneity of pancreatic cancer, see 260350.


Mapping

This form of susceptibility to pancreatic cancer is caused by mutations in the BRCA1 gene, which Miki et al. (1994) mapped to chromosome 17q21.


Molecular Genetics

Al-Sukhni et al. (2008) found loss of heterozygosity at the BRCA1 locus in pancreatic tumor DNA from 5 (71%) of 7 patients with pancreatic cancer who carried a heterozygous germline BRCA1 mutation (see, e.g., 113705.0003 and 113705.0018). Pancreatic tumor DNA was available for sequencing in 4 cases, and 3 demonstrated loss of the wildtype allele. In contrast, only 1 (11%) of 9 patients with sporadic pancreatic cancer and no germline BRCA1 mutations showed LOH at the BRCA1 locus. Al-Sukhni et al. (2008) concluded that BRCA1 germline mutations likely predispose to the development of pancreatic cancer and suggested that individuals with these mutations be considered for pancreatic cancer-screening programs.

Zhen et al. (2015) tested germline DNA from 727 unrelated probands with pancreatic cancer and a positive family history for mutations in BRCA1 and BRCA2 (600185) (including deletions and rearrangements), PALB2 (610355), and CDKN2A (600160). Among these probands, 521 met criteria for familial pancreatic cancer (FPC; at least 2 affected first-degree relatives). The prevalence of deleterious mutations, excluding variants of unknown significance, among FPC probands was BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. Four novel deleterious mutations were detected. FPC probands carried more mutations in the 4 genes (8.0%) than nonfamilial pancreatic cancer probands (3.5%; OR = 2.40, 95% CI 1.06-5.44, p = 0.03). The probability of testing positive for deleterious mutations in any of the 4 genes ranged up to 10.4%, depending on family history of cancers.


Clinical Management

Golan et al. (2019) conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib, a PARP (see 173870) inhibitor, as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. The primary end point was progression-free survival, which was assessed by blinded independent central review. Of the 3,315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 received olaparib and 62 received placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval (CI), 0.35 to 0.82; p = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups. There was no significant between-group difference in health-related quality of life. The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group. Golan et al. (2019) concluded that among patients with germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo.


REFERENCES

  1. Al-Sukhni, W., Rothenmund, H., Eppel Borgida, A., Zogopoulos, G., O'Shea, A.-M., Pollett, A., Gallinger, S. Germline BRCA1 mutations predispose to pancreatic adenocarcinoma. Hum. Genet. 124: 271-278, 2008. [PubMed: 18762988, related citations] [Full Text]

  2. Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J., Park, J.-O., Hochhauser, D., Arnold, D., Oh, D.-Y., Reinacher-Schick, A., Tortora, G., Algul, H., O'Reilly, E. M., McGuinness, D., Cui, K. Y., Schlienger, K., Locker, G. Y., Kindler, H. L. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. New Eng. J. Med. 381: 317-327, 2019. [PubMed: 31157963, related citations] [Full Text]

  3. Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P. A., Harshman, K., Tavtigian, S., Liu, Q., Cochran, C., Bennett, L. M., Ding, W., Bell, R., Rosenthal, J., and 33 others. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66-71, 1994. [PubMed: 7545954, related citations] [Full Text]

  4. Zhen, D. B., Rabe, K. G., Gallinger, S., Syngal, S., Schwartz, A. G., Goggins, M. G., Hruban, R. H., Cote, M. L., McWilliams, R. R., Roberts, N. J., Cannon-Albright, L. A., Li, D., Moyes, K., Wenstrup, R. J., Hartman, A.-R., Seminara, D., Klein, A. P., Petersen, G. M. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet. Med. 17: 569-577, 2015. [PubMed: 25356972, related citations] [Full Text]


Ada Hamosh - updated : 08/12/2019
Ada Hamosh - updated : 10/19/2015
Creation Date:
Matthew B. Gross : 10/31/2011
alopez : 08/12/2019
alopez : 10/19/2015
alopez : 10/19/2015
mgross : 10/31/2011

# 614320

PANCREATIC CANCER, SUSCEPTIBILITY TO, 4; PNCA4


ORPHA: 1333;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
17q21.31 {Pancreatic cancer, susceptibility to, 4} 614320 3 BRCA1 113705

TEXT

A number sign (#) is used with this entry because this form of susceptibility to pancreatic cancer is caused by heterozygous mutation in the BRCA1 gene (113705).

For background, phenotypic description, and a discussion of genetic heterogeneity of pancreatic cancer, see 260350.


Mapping

This form of susceptibility to pancreatic cancer is caused by mutations in the BRCA1 gene, which Miki et al. (1994) mapped to chromosome 17q21.


Molecular Genetics

Al-Sukhni et al. (2008) found loss of heterozygosity at the BRCA1 locus in pancreatic tumor DNA from 5 (71%) of 7 patients with pancreatic cancer who carried a heterozygous germline BRCA1 mutation (see, e.g., 113705.0003 and 113705.0018). Pancreatic tumor DNA was available for sequencing in 4 cases, and 3 demonstrated loss of the wildtype allele. In contrast, only 1 (11%) of 9 patients with sporadic pancreatic cancer and no germline BRCA1 mutations showed LOH at the BRCA1 locus. Al-Sukhni et al. (2008) concluded that BRCA1 germline mutations likely predispose to the development of pancreatic cancer and suggested that individuals with these mutations be considered for pancreatic cancer-screening programs.

Zhen et al. (2015) tested germline DNA from 727 unrelated probands with pancreatic cancer and a positive family history for mutations in BRCA1 and BRCA2 (600185) (including deletions and rearrangements), PALB2 (610355), and CDKN2A (600160). Among these probands, 521 met criteria for familial pancreatic cancer (FPC; at least 2 affected first-degree relatives). The prevalence of deleterious mutations, excluding variants of unknown significance, among FPC probands was BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. Four novel deleterious mutations were detected. FPC probands carried more mutations in the 4 genes (8.0%) than nonfamilial pancreatic cancer probands (3.5%; OR = 2.40, 95% CI 1.06-5.44, p = 0.03). The probability of testing positive for deleterious mutations in any of the 4 genes ranged up to 10.4%, depending on family history of cancers.


Clinical Management

Golan et al. (2019) conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib, a PARP (see 173870) inhibitor, as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. The primary end point was progression-free survival, which was assessed by blinded independent central review. Of the 3,315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 received olaparib and 62 received placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval (CI), 0.35 to 0.82; p = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups. There was no significant between-group difference in health-related quality of life. The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group. Golan et al. (2019) concluded that among patients with germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo.


REFERENCES

  1. Al-Sukhni, W., Rothenmund, H., Eppel Borgida, A., Zogopoulos, G., O'Shea, A.-M., Pollett, A., Gallinger, S. Germline BRCA1 mutations predispose to pancreatic adenocarcinoma. Hum. Genet. 124: 271-278, 2008. [PubMed: 18762988] [Full Text: https://doi.org/10.1007/s00439-008-0554-0]

  2. Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J., Park, J.-O., Hochhauser, D., Arnold, D., Oh, D.-Y., Reinacher-Schick, A., Tortora, G., Algul, H., O'Reilly, E. M., McGuinness, D., Cui, K. Y., Schlienger, K., Locker, G. Y., Kindler, H. L. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. New Eng. J. Med. 381: 317-327, 2019. [PubMed: 31157963] [Full Text: https://doi.org/10.1056/NEJMoa1903387]

  3. Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P. A., Harshman, K., Tavtigian, S., Liu, Q., Cochran, C., Bennett, L. M., Ding, W., Bell, R., Rosenthal, J., and 33 others. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66-71, 1994. [PubMed: 7545954] [Full Text: https://doi.org/10.1126/science.7545954]

  4. Zhen, D. B., Rabe, K. G., Gallinger, S., Syngal, S., Schwartz, A. G., Goggins, M. G., Hruban, R. H., Cote, M. L., McWilliams, R. R., Roberts, N. J., Cannon-Albright, L. A., Li, D., Moyes, K., Wenstrup, R. J., Hartman, A.-R., Seminara, D., Klein, A. P., Petersen, G. M. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet. Med. 17: 569-577, 2015. [PubMed: 25356972] [Full Text: https://doi.org/10.1038/gim.2014.153]


Contributors:
Ada Hamosh - updated : 08/12/2019
Ada Hamosh - updated : 10/19/2015

Creation Date:
Matthew B. Gross : 10/31/2011

Edit History:
alopez : 08/12/2019
alopez : 10/19/2015
alopez : 10/19/2015
mgross : 10/31/2011