What Is an Inherited PALB2 Mutation? How Should Carriers Manage Their Risk?

What are the function and mutation of the PALB2 gene?

The PALB2 gene takes its name from "BRCA2 Partner and Localizer (Partner and Localizer of BRCA2)." This gene is located on chromosome 16 and encodes a protein involved in tumor suppression. This protein, in the cell nucleus, binds to the BRCA2 (BReast CAncer gene 2–Breast Cancer gene 2) early-onset protein , colocalizes with it, and allows BRCA2 accumulation. In other words, PALB2 works with BRCA2 to repair damaged DNA. BRCA2 is a gene that produces proteins that help repair damaged DNA. When the BRCA2 gene, which acts as a tumor suppressor, or genes that work with it have a mutation, cancer can develop.

PALB2 has an important and versatile role in genome integrity. Biallelic mutations in PALB2 (mutations inherited from both the mother and father) cause Fanconi anemia (FA), while monoallelic mutations (involving a single allele) predispose individuals to inherited breast, ovarian, and pancreatic cancers.

• Related topic: What does heredity mean in cancer? Which cancers are inherited?

General information for people with inherited PALB2 mutations

• Both men and women can carry a mutation in the PALB2 gene.
• People with an inherited PALB2 mutation have an increased risk of certain cancers. For people with a PALB2 mutation, guidelines exist for screening and preventing certain cancers. In addition, genetic testing may identify PALB2 mutation-positive people for whom clinical trials may also be available.
• People with a PALB2 mutation who have been diagnosed with cancer may qualify for specific targeted cancer drugs or clinical trials.
• Inheriting a PALB2 mutation from both parents can cause Fanconi anemia.

Which cancer risks are increased by an inherited PALB2 mutation?

• Women with a PALB2 mutation are at high risk of breast cancer. The estimated lifetime risk is between 33-58%.
• Women with a PALB2 mutation may have an increased risk of ovarian cancer.
• Men and women with a PALB2 mutation have a slightly increased risk of pancreatic cancer.
• For other cancers, risk in people with a PALB2 mutation is unknown or supported by insufficient evidence.

RELATED TOPICS

• Who should have genetic testing for inherited breast cancer?
• How should people at risk of inherited ovarian cancer be monitored?

What are inherited cancer genes and mutations?

What can we do to screen for and prevent inherited breast, ovarian, and pancreatic cancers?

Breast cancer

For individuals at high risk of breast cancer because they carry a mutation in inherited cancer genes:

Screening and prevention of inherited breast cancer

• Clinical breast examinations every 6-12 months from age 30.
• Annual mammography (using 3D mammography if available) and contrast-enhanced breast imaging from age 30 with MRI
• Women should discuss the advantages and disadvantages of risk-reducing mastectomy with their doctors.
  • Studies have shown that risk-reducing mastectomy (precautionary removal of both breasts) can effectively reduce breast cancer risk by approximately 90% in high-risk women. Nevertheless, mastectomy has not been shown to improve overall survival in high-risk women. Even after mastectomies, some breast tissue and therefore some breast cancer risk remain.
• Consider participating in studies investigating other cancer screening methods or medications to reduce risk.

There are different options for managing breast cancer risk:

• Breast screening
  • Breast cancer screening uses tests to try to detect cancer at an early stage, when it is most treatable. The earlier cancer is found, the greater the person’s chance of surviving it. The most common types of breast screening include:
    • Breast examinations
    • Mammograms
    • 3D mammograms (tomosynthesis)
    • Ultrasound
    • Magnetic resonance imaging (MRI)
• Medications (to reduce risk)
  • Healthy women at high risk may benefit from medications to reduce breast cancer risk. Two types of medication can be used to reduce breast cancer risk in women: selective estrogen receptor modulators (tamoxifen) and aromatase inhibitors.
• Surgery (to reduce risk)
  • The US National Comprehensive Cancer Network (NCCN) guidelines discuss the benefits and limitations of risk-reducing mastectomy in women with an inherited mutation linked to breast cancer, and which women may benefit most from surgery. NCCN guidelines recommend "considering risk-reducing mastectomy" for women with inherited mutations in the following genes:
    • BRCA1
    • BRCA2
    • PALB2
    • PTEN
    • TP53
  • For women with mutations in other genes, NCCN recommends basing the mastectomy decision on their personal and family cancer history.
  • NCCN recommends enhanced screening for high-risk women who choose not to undergo risk-reducing mastectomy.
  • For high-risk men, guidelines do not recommend risk-reducing mastectomy. For men diagnosed with breast cancer, treatment usually includes a mastectomy on the affected side. Although some men diagnosed with cancer in one breast choose to have both breasts removed, very little research shows that the benefits of removing the other breast outweigh the risks.

- Related topic: Why did Angelina Jolie have both breasts removed? 

The option you choose to manage your breast cancer risk will depend on several factors, including:

• Your age
• Your sex
• The presence of an inherited gene mutation
• Your personal and family cancer history
• Other risk factors
• Personal preferences

Genes linked to breast cancer risk (inherited mutations in the following genes have been associated with increased breast cancer risk in women):

• ATM
• BARD1
• BRCA1 (often linked to triple-negative breast cancer)
• BRCA2
• CDH1 (often linked to lobular breast cancer)
• CHEK2
• NBN (only in people with the 657del5 mutation)
• NF1
• PALB2
• PTEN
• STK11
• TP53

More research is needed to confirm a link between the following gene mutations and breast cancer, and to develop risk management guidelines for people with mutations in these genes:

• BRIP1
• RAD51C
• RAD51D

Men with inherited mutations in the following genes have an increased risk of breast cancer:

• BRCA1
• BRCA2
• CHEK2
• PALB2

Other factors linked to breast cancer risk:

Factors such as diet, weight, exercise, smoking, alcohol consumption, hormone use, and environmental exposures can affect breast cancer risk in the general population and in people at high risk of cancer.

Ovarian cancer

For individuals at high risk of ovarian cancer because they carry a mutation in inherited cancer genes:

Preventing ovarian cancer

• National Comprehensive Cancer Network (NCCN) guidelines recommend managing ovarian cancer risk based on family history. If there is no family history of ovarian cancer, NCCN does not recommend risk-reducing salpingo-oophorectomy (removal of the ovaries and fallopian tubes).
• Consider enrolling in clinical trials investigating methods for early detection or medications to lower risk.

Ovarian cancer screening and risk reduction

Fallopian tube, ovarian, and primary peritoneal cancers are related and are often grouped as "ovarian cancer" because the risk factors and medical options are similar for all three. Every woman is at risk of these cancers, and the risk increases with age. In the general population, a woman’s lifetime risk of developing ovarian cancer is less than 2 percent. This means that 1 in every 50 women will encounter ovarian cancer during her lifetime.

Approaches used to manage ovarian cancer risk include:

• Screening (usually involving a combination of the following):
  • A pelvic examination is an internal vaginal examination, usually performed by a gynecologist, to look for abnormalities in the reproductive system.
  • Transvaginal ultrasound involves an ultrasound device inserted into the vagina, using sound waves to look for abnormal changes in the ovaries.
  • CA125 is a protein found in the blood that is sometimes elevated in women with ovarian cancer. The test is considered neither sensitive nor specific for finding ovarian cancer in high-risk women.
  • Screening for average-risk individuals: Experts do not recommend routine screening for women at average risk of fallopian tube, primary peritoneal, or ovarian cancer.
• Medications (to reduce risk)
  • Progesterone, commonly used as birth control medication, has been shown to reduce ovarian cancer risk in both high-risk and average-risk women. Progesterone can have side effects that vary greatly depending on how the medication is taken. These side effects may include increased risks of breast cancer and blood clots, as well as weight gain. Young women under age 25 may be particularly susceptible to the increased breast cancer risk caused by progesterone in birth control.
  • High-risk women considering medication to reduce ovarian cancer risk should talk with their doctors to decide whether chemoprevention (reducing cancer risk with medication) is the best option for managing their risks.
• Surgery (to reduce risk)
  • Salpingo-oophorectomy is surgery to remove the fallopian tubes and ovaries to treat or prevent disease. "Risk-reducing salpingo-oophorectomy" (RRSO) means removing healthy ovaries and fallopian tubes to reduce a person’s risk of cancer. Research on RRSO in high-risk women has shown the following:
    • It is an effective way to reduce the risk of ovarian and fallopian tube cancer. Even after the ovaries and tubes are removed, a residual risk of primary peritoneal cancer remains.
    • It may reduce the risk of death in high-risk women.
    • It may also reduce breast cancer risk in some high-risk women.
    • It does not eliminate cancer risk completely. After RRSO, there is still a risk of primary peritoneal cancer. However, this risk is very low and varies by gene mutation.
  • Salpingectomy involves removing only the fallopian tubes. Emerging research suggests that the fallopian tubes may be the origin of many inherited ovarian cancers. This has led researchers to investigate whether premenopausal women can have their fallopian tubes removed and delay removal of the ovaries until after menopause. Studies examining salpingectomy to reduce risk are currently enrolling high-risk women. Until these studies are completed, experts cannot say definitively that salpingectomy reduces ovarian cancer risk in high-risk women.
  • Open surgery (also known as laparotomy) involves an incision in the lower abdomen to remove the ovaries, fallopian tubes, and (in women undergoing hysterectomy) the uterus.
  • Laparoscopic surgery involves a small abdominal incision to insert a flexible scope with a camera used to view the ovaries and tubes. Additional small incisions are made to insert the surgical instruments needed for salpingo-oophorectomy. People undergoing laparoscopy can generally recover faster and spend less time in hospital than those undergoing open surgery. Most RRSO procedures can be performed laparoscopically.

Surgery can have risks and side effects. It is important to speak with specialists to learn as much as possible about your ovarian cancer risk and make an informed decision about the best option for reducing it.

The option you choose to manage your ovarian cancer risk will depend on several factors, including:

• Your age
• The presence of an inherited gene mutation
• Your personal and family cancer history
• Other risk factors
• Personal preferences

Genes linked to fallopian tube, ovarian, and primary peritoneal cancer risk (inherited mutations in the following genes have been associated with increased ovarian cancer risk):

• ATM
• BRCA1
• BRCA2
• BRIP1
• EPCAM
• MLH1
• MSH2
• PMS2
• RAD51C
• RAD51D
• MSH6
• PALB2
• STK11**

*More research is needed to confirm the link between ovarian cancer and an inherited mutation in this gene.

**Most tumors in people with this mutation are benign.

Other factors linked to fallopian tube, ovarian, and primary peritoneal cancer risk:

Research is mixed on how other factors affect fallopian tube, ovarian, and primary peritoneal cancer risk. More research is needed to understand whether other factors affect risk in people with inherited mutations.

Pancreatic cancer

Pancreatic cancer screening for people with a family history:

• For PALB2 mutation carriers who have a first- or second-degree relative with pancreatic cancer, screening starts at age 50 or 10 years younger than the relative’s age at diagnosis.
• For mutation carriers who choose pancreatic cancer screening, NCCN recommends screening at an experienced facility under ideal research conditions. Before screening, people should discuss its potential benefits, risks, costs, and limitations with their doctors.
• Annual screening with contrast-enhanced MRI / MRCP (magnetic resonance cholangiopancreatography) and / or EUS (endoscopic ultrasound) is considered.
• Consider enrolling in a clinical trial looking at methods to screen for cancer or medications to reduce risk.

Factors affecting pancreatic cancer risk

Everyone is at risk of pancreatic cancer, and risk increases with age. A person’s lifetime risk of developing pancreatic cancer in the general population is approximately 1 percent. This means that 1 in every 100 people will develop pancreatic cancer during their lifetime.

Genes linked to pancreatic cancer risk (inherited mutations in the following genes have been associated with increased pancreatic cancer risk):

• ATM
• BRCA1
• BRCA2
• CDKN2A
• EPCAM*
• MLH1
• MSH2*
• PALB2
• STK11
• TP53

* Lynch syndrome studies linking the genes MSH2, MSH6, and EPCAM to pancreatic cancer are inconclusive.

Inherited mutations in the following genes are linked to pancreatic cancer risk:

• CDKN1
• MEN1
• NF1
• RET
• VHL

Types of pancreatic cancer screening

• Contrast-enhanced magnetic resonance cholangiopancreatography (MRCP) is a special type of MRI that closely examines the pancreas, liver, gallbladder, bile duct, and pancreatic duct to find abnormalities such as cancer. People undergoing MRCP should fast for four hours before the procedure. An injection of a contrast agent called gadolinium is given before the test to help radiologists find abnormalities more easily.
• Endoscopic ultrasound (EUS) involves passing a small tube with an attached ultrasound probe through the esophagus into the stomach. This allows doctors to look closely at the pancreas. EUS is performed as an outpatient procedure under anesthesia.

How should people with inherited mutations undergo pancreatic cancer screening?

• NCCN recommends that people undergoing pancreatic screening have the procedure at an experienced facility and ideally as part of a research study. Before screening, people should discuss its potential benefits, risks, costs, and limitations with their doctors.
• NCCN recommends that people with inherited mutations in the following genes (with or without a family history of cancer) "consider pancreatic cancer screening" with MRCP or EUS:
  • STK11: (Peutz-Jeghers syndrome): Consider pancreatic cancer screening with MRCP or EUS every 1-2 years, starting at age 30-35 or 10 years before the earliest pancreatic cancer in the family.
  • CDKN2A: Consider pancreatic cancer screening starting at age 40 or 10 years before the earliest pancreatic cancer diagnosis in the family.
• NCCN guidelines recommend that people with an inherited mutation in one of the following genes and a family history of cancer"consider pancreatic cancer screening" with MRCP or EUS starting at age 50 or 10 years before the earliest pancreatic cancer diagnosis in the family:
  • ATM
  • BRCA1
  • BRCA2
  • MLH1
  • MSH2
  • MSH6
  • EPCAM
  • PALB2
  • TP53

NCCN does not currently recommend pancreatic cancer screening for those without a family history, who have the mutations listed above.

Other factors linked to pancreatic cancer risk:

Factors such as diet, weight, exercise, smoking, alcohol consumption, and type 2 diabetes can affect pancreatic cancer risk in the general population.

Other medical concerns for people with inherited PALB2 mutations

Children who inherit PALB2 mutations from both their mother and father can develop a rare and serious childhood disease called Fanconi Anemia (FA). Children with FA have blood problems, physical and developmental problems, and an increased risk of cancers such as leukemia and lymphoma. Children with FA may also develop cancers of the head, neck, skin, gastrointestinal tract, or genital tract.

Both parents must carry a PALB2 mutation for a child to have Fanconi anemia. Couples in which one partner has a known PALB2 mutation may wish to speak with a genetic counselor about testing the other partner before having children.

Parents have the options of assisted reproductive technology and preimplantation genetic diagnosis to select embryos without inherited PALB2 mutations.

What cancer treatment options are available for people with PALB2 mutations?

People with an inherited PALB2 mutation who have been diagnosed with cancer may have different treatment options from those without the mutation. If you have an inherited PALB2 mutation, have been diagnosed with cancer, and any of the following situations apply to you, you may wish to discuss your medical options with your doctor. You may also consider enrolling in a clinical trial investigating which treatments work best for people with an inherited PALB2 mutation:

• If you have metastatic prostate cancer
• If you have advanced ovarian cancer
• If you are deciding on breast cancer surgery

PARP inhibitors

PARP inhibitors are a type of targeted therapy that works by blocking a protein used to repair damaged DNA. They were initially developed to treat cancers in people with an inherited BRCA1 or BRCA2 mutation. Since then, research and additional FDA approvals have expanded the use of PARP inhibitors to more situations.

Metastatic prostate cancer

The PARP inhibitor Lynparza (olaparib) has FDA approval to treat men with metastatic, castration-resistant prostate cancer who have a PALB2 mutation or a mutation in another gene linked to certain DNA damage repair. Lynparza may be used to treat men whose prostate cancer has progressed while taking enzalutamide (Xtandi) or abiraterone (Zytiga).

PARP inhibitors for advanced ovarian, fallopian tube, or primary peritoneal cancer

Several PARP inhibitors have been approved to treat ovarian cancers at different stages of the disease. In some cases, a tumor biomarker test known as HRD (homologous recombination deficiency) testing may help women with an inherited PALB2 mutation and advanced ovarian cancer find out whether they could benefit from a PARP inhibitor.

• Related topic: Use of PARP inhibitors in ovarian cancer (detailed)

Breast cancer surgical decisions

Second Because of the high risk of a second breast cancer diagnosis, women diagnosed with breast cancer who test positive for an inherited PALB2 mutation may choose bilateral mastectomy (removal of both breasts) rather than lumpectomy (breast-conserving surgery) and radiotherapy. Mutation carriers who undergo mastectomy are less likely to develop a second breast cancer.

There has not been enough research to show the benefit of screening and prevention for cancers other than breast, ovarian, and pancreatic cancer in people with a PALB2 mutation. Experts therefore recommend managing these risks based on family history. Research studies on cancer screening and prevention may be available for people with PALB2 mutations.