The Genetics of Pancreatic Cancer

In the second part of this series on pancreatic cancer, we’ll look at the changes in our understanding of the role of familial genetics in pancreatic cancer, and how that new understanding holds promise for new therapeutics.

In the mid-1970s doctors began reporting cases of familial pancreatic cancer, where multiple first-degree relatives had presented with pancreatic cancer. Epidemiological studies could give us estimates of risk, but not the source of the risk or a mechanistic understanding of it. It wasn’t until the the earliest days of the genomic era; however, that researchers had the tools necessary to understand the genetic components of these cancers.

Estimates vary depending on the study size, but approximately 10% of pancreatic cancer patients have one of the following syndromes which predispose them to pancreatic cancer:

BRCA2 – a DNA repair gene that predisposes family members to breast, ovarian, pancreatic and prostate cancer.
Other DNA Repair Genes (PALB2 & ATM)
Peutz-Jeghers Syndrome (STK11/LKB1)
Fanconi Anemia Syndrome (FANCC)
Lynch Syndrome (MLH1, MSH2, MSH6, and PMS2)
Von Hippel-Lindau Syndrome (VHL)
Hereditary pancreatitis (PRSS1, SPINK1)
FAMMM – Familial Atypical Multiple Mole Melanoma (CDKN2A)
Palladin (PALLD)

The chart below shows the relative prevalence of these syndromes within the pancreatic cancer patient population.

Source: [1]

Of these syndromes, BRCA2 and CDKN2A account for the majority of mutations found in familial pancreatic cancer. For the most part, the genes associated with these syndromes have been well-established. One exception to this is Palladin, a gene first reported by Pogue-Geile, etc al[2], to be mutated in a family known as Family X. Subsequent papers [3] however, failed to recapitulate the findings.

Pooling Resources

In 2002, PACGENE, a consortium of 7 cancer centers, was formed to help centralize the collection of genetic information about pancreatic cancer within the US and Canada. The institutions involved include MD Anderson, the Mayo Clinic, Dana-Farber Cancer Institute, and Johns Hopkins. The goal of the consortium is to collect data from the broadest pool of pancreatic cancer patients and to eventually create a means of surveillance and early detection amongst families which were likely to see an increased rate in pancreatic cancer diagnosis.

Some of the participating institutions, like Johns Hopkins, had previously established pancreatic cancer tumor registries. Their tumor registry, known as National Familial Pancreas Tumor Registry (NFPTR) was established in 1994, by Ralph Hruban, one of the leading researchers in pancreatic cancer.

The NCI formed the Early Detection Research Network to help collect, curate and standardize available information on cancer-related biomarkers. The website also helps identify potential collaborators, and funding opportunities for biomarker development.

In 2015, David Zhen of the Mayo Clinic published a study[4] of the prevalence of mutations found in the families of pancreatic cancer patients using PACGENE data. The dataset confirmed that BRCA2 (3.7%) mutations were most prevalent in the patient population, followed by CDKN2A (2.5%), BRCA1 (1.2%) and PALB2 (0.6%).

In 2010, McWilliams et al[5], reported a modest association between mutations in the CFTR gene (cystic fibrosis transmembrane conductance regulator), and an increased risk in pancreatic cancer. Over the past 20 years, we’ve seen the association between breast, ovarian, and pancreatic cancer become more clearly defined. Along with that effort, we’ve seen additional associations being made with stomach cancer [6], prostate cancer and colon cancer [6,7].

Perhaps one of the most valuable datasets for familial pancreatic cancer (FPC) has been the Australian Pancreatic Cancer Genome Initiative. The data set of over 760 patients has yielded a new axon guidance pathway [8], a novel set of subtypes (more about that in a later blog post), and the discovery [9] that more that nearly 78% of FPC families had 2 affected first degree relatives (FDRs). The study also revealed that if a parent was diagnosed with pancreatic cancer, that a child would be likely to be diagnosed on average 12 years earlier; thus indicating the importance of awareness in early detection of the disease.

On a side note, most of these studies showed that smoking accelerated the course of the disease, often resulting in an earlier age of presentation than one would normally get with non-smokers. And while, we’ve known for some time that smoking increases the risk of pancreatic cancer, the mechanism of action hadn’t (until recently [10]) been investigated. Their findings concluded that the mutation rate of critical driver genes in pancreatic cancer was higher in smokers than in non-smokers, resulting in faster progression, earlier-onset, and increased aggressiveness of the disease. The mechanism by which smoking alters signalling in pancreatic cancer was also studied [11], and smoking was also linked to changes in the axon guidance pathway [11,12].

The Real Challenge Is In The Data

By far, the biggest challenge in assessing the impact of these syndromes on the patient population, is our lack of a comprehensive dataset.

PACGENE in North America, NFPTR, EUROPAC, FaPaCa in Germany, Japanese Familial Pancreatic Cancer Registry and similar efforts in other countries, have thus far provided the most comprehensive datasets, but there are always holes in the data, leading to more questions.

Efforts[4,13] to assess risk using self-reported questionnaires vs genetic counselor driven questionnaires, have found that self-reporting actually failed to identify a number of high-risk family members. Thus indicating that comprehensive efforts involving not only questionnaires, but also genomic screening are necessary to accurately determine risk within families.

Given that 53,000 patients will be diagnosed with pancreatic cancer in the United States this year, these numbers represent such a small fraction of the patient population making it difficult to assess the real prevalence of these syndromes. Many of the studies found new candidate gene variants of unknown significance. Of these, we don’t know which of them may be “driver” mutations for specific processes within pancreatic cancer, or “passenger” mutations. Without that mechanistic understanding of the roles of these genes, it’s difficult to identify plausible new drug targets, and difficult to understand how pervasive these variants may be in the population as a whole.

Putting The Data To Work In The Clinic

One of the primary goals for collecting the data, is to develop early screening and surveillance programs for families where pancreatic cancer is a known risk.

The efforts thus far have been to try and answer two basic questions: who is most at risk for pancreatic cancer, and how can we cost-effectively identify them at an early enough stage for treatment to be effective.

Who to Test

Using the information gleaned from PACGENE and similar efforts, the risk population has become easier to identify. Many of the efforts; however, have been hampered by small sample sizes, and a narrow focus on families that report 2 or more cases of pancreatic cancer in first-degree relatives. The problem with this narrowed approach to identifying high-risk kindreds is that you will miss families where first degree relatives have cancers other than pancreatic cancer. The narrow definition means that we miss relatives with breast, ovarian, and prostate cancers which have been shown to be linked to BRCA1/2 mutations. But it also means that we are less likely to uncover novel new biomarkers. It also means that the 10% number of FPC families quoted earlier, may actually be larger than we suspect.

The temporal nature of cancer also means that as patients age into that “magic window” of cancer susceptibility, bounded by age, familial risk, diabetes onset, smoking and other risk factors; we still aren’t acting quickly enough to identify other family members who may be at risk. We still treat each cancer patient as though their disease was a sporadic case of bad luck, rather than something that may have arisen out of an inherited syndrome, and requires assessment. If clinicians were to assess familial risk at the time of diagnosis of a single member of a family, we would be more likely to intercept cancer at an early stage. That one family member would in-effect play the role of “canary in the mine” to the other family members.

How to Test Them More Cost-Effectively

While studies have shown that Endoscopic Ultrasonography (EUS) can be used as a cost-effective surveillance tool for high risk families. It is still too expensive and too invasive to be made widely available beyond families that fit into these predefined high-risk categories. What’s needed is a low-cost screening mechanism that could be made part of a yearly checkup, perhaps a test that could be added to the existing blood panel. A test that can be made broadly available, and is likely to identify a wider risk pool.

Traditionally molecular diagnostics for pancreatic cancer have been rather limited. CA19-9, CA-50 and CEA over-expression has been used as biomarker for pancreatic cancer diagnosis, and treatment efficacy. As genomic technologies have made their way into clinical practice, there has been a renewed focus on identifying new multi-biomarker signatures [14], [15], [16] capable of identifying pancreatic cancer earlier, providing staging and prognostic information, as well as guiding precision medicine. These newer technologies are less invasive, and more economic to implement in a clinical setting, thus making them more likely to be used.

Recently we’ve begun to see a number of emergent diagnostic platforms applied to detecting pancreatic cancer including circulating tumor cell (CTC) based diagnostics [1,17], and microRNA-based diagnostics [18], [19]. This month, the Economist reported that Cancer Research UK was investigating the potential use of a breathalyzer-type technology capable of detecting different types of cancers based on the presence of volatile organic compounds (VOCs) found in the breath.

The Illumina spinoff company GRAIL, has been working on a new cell-free DNA diagnostic for pancreatic cancer. Because the signals are often low for early stage disease, GRAIL sequences the genomic regions thousands of times to improve the signal-to-noise ratio and sequences a larger panel of genes making it more likely to detect rare tumor DNA molecules.

GRAIL is also working on a study called the Circulating Cell-Free Genome Atlas which will include 7000 cancer patients, at various stages of disease progression, various ages, genders and smoking history.

Immunovia, the Swedish molecular diagnostics company, has developed a multiplex antibody array, known as IMMARAY PANCAN-D capable of detecting 98% of pancreatic cancers [20] [21].

Trends

Over the next 10 years we will see the continuing translation of bench-top ‘omic technologies to the bedside to help diagnose patients, and guide their treatment. As the cost of these technologies continue to decline, we will see greater use amongst family members. Beyond the clinic, the consumer genomic testing services such as 23andMe continue to proliferate in the marketplace; increasing awareness amongst family members of the potential risk of pancreatic cancer. We’re also seeing cancer diagnosis as a canary in a mine, helping bring awareness of the potential of cancer risk to be passed down through the germline.

In the past 5 years, we’ve seen a growing realization of the genetic nature of cancer which has changed the way the clinical community views and treats cancer. Rather than seeing cancer in terms of its tissue of origin; we’re seeing greater emphasis placed on the genetic commonalities between a variety of different types of cancer. This has resulted in the application of treatments from other cancers, and even other diseases, to pancreatic cancer.

References

1. Petersen GM. Familial Pancreatic Adenocarcinoma. Hematol Oncol Clin North Am. 2015;29: 641–653.

2. Pogue-Geile KL, Chen R, Bronner MP, Crnogorac-Jurcevic T, Moyes KW, Dowen S, et al. Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism. PLoS Med. 2006;3: e516.

3. Klein AP, Borges M, Griffith M, Brune K, Hong S-M, Omura N, et al. Absence of deleterious palladin mutations in patients with familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2009;18: 1328–1330.

4. Zhen DB, Rabe KG, Gallinger S, Syngal S, Schwartz AG, Goggins MG, et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med. 2015;17: 569–577.

5. McWilliams RR, Petersen GM, Rabe KG, Holtegaard LM, Lynch PJ, Bishop MD, et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma. Cancer. 2010;116: 203–209.

6. Jakubowska A E al. BRCA2 gene mutations in families with aggregations of breast and stomach cancers. – PubMed – NCBI [Internet]. [cited 2 Dec 2017]. Available: https://www.ncbi.nlm.nih.gov/pubmed/12373604

7. Lee MV, Katabathina VS, Bowerson ML, Mityul MI, Shetty AS, Elsayes KM, et al. BRCA-associated Cancers: Role of Imaging in Screening, Diagnosis, and Management. Radiographics. 2017;37: 1005–1023.

8. Biankin AV, Waddell N, Kassahn KS, Gingras M-C, Muthuswamy LB, Johns AL, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491: 399–405.

9. Humphris JL, Johns AL, Simpson SH, Cowley MJ, Pajic M, Chang DK, et al. Clinical and pathologic features of familial pancreatic cancer. Cancer. 2014;120: 3669–3675.

10. Matsubayashi H, Takaori K, Morizane C, Maguchi H, Mizuma M, Takahashi H, et al. Familial pancreatic cancer: Concept, management and issues. World J Gastroenterol. 2017;23: 935–948.

11. Momi N, Kaur S, Ponnusamy MP, Kumar S, Wittel UA, Batra SK. Interplay between smoking-induced genotoxicity and altered signaling in pancreatic carcinogenesis. Carcinogenesis. 2012;33: 1617–1628.