Study: Inherited gene mutations found in pancreatic cancer families in Spain

IN-DEPTH REVIEW OF RESEARCH

Study background

Pancreatic ductal adenocarcinoma (PDAC) accounts for 95 percent of all pancreatic cancer diagnoses. Only ten percent of people with PDAC are expected to live more than five years after diagnosis. This is, in part, because most pancreatic cancers are diagnosed at advanced stages when they are difficult to treat.

While the exact cause of pancreatic cancer is often not known, research shows that a family history of pancreatic cancer can increase a person’s risk for the illness. In fact, 10 to 13 percent of all pancreatic cancer cases are hereditary.

In some high-risk pancreatic cancer families, increased risk is linked to inherited mutations in BRCA1, BRCA2, PALB2 and other genes that are associated with hereditary cancers. Some people with inherited pancreatic cancer have “familial pancreatic cancer”—defined as having at least two immediate relatives (e.g., parent, sibling or child) with pancreatic cancer. Inherited pancreatic cancer can also occur in people who have a family history ovarian cancer, breast cancer, prostate cancer, melanoma and other cancers, and familial cancer syndromes like Lynch or Peutz-Jeghers syndromes. Although inherited mutations in BRCA1, BRCA2, PALB2 and other hereditary cancer genes are known to increase risk of pancreatic cancer, information is still lacking about inherited mutations in other genes that put families at high risk for pancreatic cancer.

If confirmed by future studies, conclusions from the current study could lead to genetic testing that detects more gene mutations that put people at risk for inherited pancreatic cancer. This would benefit pancreatic cancer patients and their families, and people without pancreatic cancer who have a family history of the disease.

Researchers of this study wanted to know:

Which hereditary cancer genes are mutated among patients with a family history of pancreatic cancer.

Populations looked at in this study

This study included 43 patients from different families with a family history of pancreatic cancer. They were recruited from Pan-Gen-FAM, a Spanish national registry that was developed to study hereditary pancreatic cancer.

Participants were required to provide information about pancreatic and other hereditary cancers within at least three generations of their families. Patients were then categorized into the following family groups:

• Familial pancreatic cancer (FPC): Patients with at least two immediate relatives (e.g., parent, sibling, or child) with pancreatic cancer (26 participants).
• Hereditary Breast and Ovarian Cancer Syndrome (HBOCS + PC): Patients at high risk of inherited breast, ovarian and other cancers who had at least one relative with pancreatic cancer (8 participants).
• Familial Atypical Multiple Mole Melanoma (FAMMM + PC): Patients at high risk of inherited melanoma and had at least one relative with pancreatic cancer (1 participant).
• Hereditary Non-Polyposis Colorectal Cancer /Lynch Syndrome (HNPCC + PC < 50 years): Patients at high risk of inherited colon cancer and had at least one relative diagnosed with pancreatic cancer at age 50 or younger (8 participants).

Study design:

The study was carried out in 10 hospitals throughout Spain. Researchers searched through previously published medical literature to identify genes associated with hereditary cancer—35 genes were identified. Blood samples were collected from participants and tested for mutations in each of the 35 genes.

Mutated genes were described as:

• Pathogenic and likely pathogenic: Mutations that increase cancer risk.
• Variants of uncertain significance: Mutations for which cancer risk cannot be determined.

Study findings:  

Researchers identified mutations in known hereditary cancer genes among participants with a family history of pancreatic cancer. 

• In FPC families, mutations known to increase cancer risk were found in 19 percent of patients (5 of 26) in MLH1, CDKN2A, POLQ and FANCM.
• In FPC families, possibly pathogenic mutations were found in 35 percent of patients (9 of 26) in FANCC, MLH1, PMS2, CFTR, APC and MUTYH. Whether these variants are associated with increased risk of pancreatic cancer is unknown.
• Genes containing variants of uncertain significance (VUS) were found in 53 percent of patients (23 of 43 patients). These included VUSs in APC, BRCA2, BUB1, CFTR, FANCC, MSH2, MSH4, MUTYH, PALB2, PMS2 and POLN. Whether these variants are associated with increased risk of pancreatic cancer is unknown.

Strengths and limitations

Strengths

• Patients were tested for inherited mutations in genes known to increase risk of pancreatic cancer from previous studies.
• Participants were from different family types that are known to be at high risk for hereditary pancreatic cancer.

Limitations

• Study researchers highlighted the following limitations:
  • The study had a small number of participants.
  • Testing included only inherited mutations in 35 genes that are known to be associated with hereditary pancreatic cancer. It is possible that more, as yet unidentified genes are associated with hereditary pancreatic cancer.
• Limitations that were not mentioned by study researchers included:
  • There were an unequal numbers of participants from the four types of hereditary cancer families. For example, the FPC group consisted of 26 participants, compared with HBOC + PC group which included just eight participants.   
  • The study did not include participants from families with other familial cancer syndromes, such as Peutz-Jeghers syndrome, that put them at risk for pancreatic cancer.  
  • The study did not mention race/ethnicity of families. Only Spanish families were tested. Inherited mutations in hereditary cancer genes may differ in families from other parts of the world.
  • The study did not mention gender.

Context

Previous research links pancreatic cancer risk to inherited mutations in genes that are associated with hereditary cancers. Similarly, results of the current study showed that inherited mutations in the MLH1, CDKN2A, CHEK2, FANCM and PTEN genes increase the risk of pancreatic cancer. Results of the current study also indicate that inherited mutations in TET2 and POLQ may play a role in hereditary pancreatic cancer. If more research confirms the role of these two genes, they may be elevated as a hallmark for hereditary pancreatic cancer risk.

Conclusions:

The current study identified inherited mutations in multiple genes that are associated with hereditary cancer. These genes may increase pancreatic cancer risk in patients with a family history of pancreatic cancer. Most harmful mutations (pathogenic or likely pathogenic) were seen in 21 percent of the study’s participants who had a history of pancreatic cancer alone or in combination with other hereditary cancers, including breast and ovarian cancer, melanoma, prostate cancer and Lynch syndrome cancers. These findings can help develop gene testing panels that comprehensively screen individuals who are at high-risk for pancreatic cancer and those who are already diagnosed. Genetic screening of high-risk populations could help detect pancreatic cancer earlier and improve outcomes for patients.

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Posted 10/28/2020