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Is there any disease in adult human, other-than cancer, which-is resulted from mutation?

Is there any disease in adult human, other-than cancer, which-is resulted from mutation?


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On all environmental articles I read about 3 impacts of mutagens (say Cigarette/ Naphthalene/ EtBr/ Colchicine/ ionizing radiation/ whatever )…

1. direct effect on tissues, other than mutation, such-as burns, choke, cirrhosis of liver, Lesion in lungs etc. (no direct relation with mutation)

2. Mutation affecting development of organs and intelligence, in youngs; and hidden mutation not affecting adults but showing expression (birth-defects) in future progeny.

and

3. Tumor and Cancer.

Now, my question is, if an adult become exposed to some mutagen; the only visible effect of mutation (not about burns etc, talking about genetic-mutation)… on that affected-individual; whether cancer is the only-possible disease? or it is possible to occur some-other sort of genetic disease (not about future but only to that particular affected-one)


anything else should happen… say exact opposite thing… uncontrolled apoptosis that gradually kills whole affected person (for say).

or for say due to a genetic-damage a person became unable to perform cell-division, so no wound healing. If once part of body become cut, and it remain open forever, never seals. (I never heard or read anywhere).

instead of cell-death, they could perform some-other malfunctions, too. Like turning-off certain normal function, say stopped transport of certain molecule, or say stopped a function like color-vision, or start to secrete / accumulate some metabolites same-way as inborn error of metabolism?

But could anything such happen other-than cancer?


Before answering your question, an important note. Not all neoplastic growth is malignant. A mutation may result in a benign growth, which is an outcome different from cancer. Not all of these change to cancers. Moreover, almost all genetic diseases may arise de novo as a germline mutation, and this mutation may be caused due to the environmental mutagen, and hence will be a non-neoplastic outcome of environmental mutation. The list of such genetic diseases is impossible to replicate here.

Assuming you are asking non-malignant diseases involving somatic (acquired) mutation as a pathogenetic event, here's a subset.

Some diseases with proven somatic mutation are:

Neurofibromatosis 1 & 2
McCune-Albright
Paroxysmal Nocturnal Hemoglobinuria
Incontinentia Pigmenti

For more details, have a look at this paper here.
Erickson RP. Somatic gene mutation and human disease other than cancer. Mutation Research/Reviews in Mutation Research. 2003 Mar 31;543(2):125-36.


The senescent methylome and its relationship with cancer, ageing and germline genetic variation in humans

Cellular senescence is a stable arrest of proliferation and is considered a key component of processes associated with carcinogenesis and other ageing-related phenotypes. Here, we perform methylome analysis of actively dividing and deeply senescent normal human epithelial cells.

Results

We identify senescence-associated differentially methylated positions (senDMPs) from multiple experiments using cells from one donor. We find that human senDMP epigenetic signatures are positively and significantly correlated with both cancer and ageing-associated methylation dynamics. We also identify germline genetic variants, including those associated with the p16INK4A locus, which are associated with the presence of in vivo senDMP signatures. Importantly, we also demonstrate that a single senDMP signature can be effectively reversed in a newly-developed protocol of transient senescence reversal.

Conclusions

The senDMP signature has significant potential for understanding some of the key (epi)genetic etiological factors that may lead to cancer and age-related diseases in humans.


Disease Overview

The proposed revised World Health Organization criteria for the diagnosis of polycythemia vera (p. vera) requires two major criteria and one minor criterion or the first major criterion together with two minor criteria.[1]

  1. Hemoglobin of more than 18.5 g/dL in men, 16.5 g/dL in women, or elevated red cell mass greater than 25% above mean normal predicted value.
  2. Presence of JAK2 V617F or other functionally similar mutations, such as the exon 12 mutation of JAK2.
  1. Bone marrow biopsy showing hypercellularity with prominent erythroid, granulocytic, and megakaryocytic proliferation.
  2. Serum erythropoietin level below normal range.
  3. Endogenous erythroid colony formation in vitro.

Other confirmatory findings no longer required for diagnosis include the following:[2-4]

  • Oxygen saturation with arterial blood gas greater than 92%.
  • Splenomegaly.
  • Thrombocytosis (>400,000 platelets/mm 3 ).
  • Leukocytosis (>12,000/mm 3 ).
  • Leukocyte alkaline phosphatase (>100 units in the absence of fever or infection).

There is no staging system for this disease.

Patients have an increased risk of cardiovascular and thrombotic events [5] and transformation to acute myelogenous leukemia or primary myelofibrosis.[6-8] Age older than 65 years, leukocytosis, and a history of vascular events (bleeding or thrombosis) are associated with a poor prognosis.[6,9,10] Patients younger than 40 years have a more indolent course, with fewer thrombotic events or transformation to acute leukemia.[11]

Treatment Overview

The primary therapy for p. vera includes intermittent, chronic phlebotomy to maintain the hematocrit below 45% this recommendation was confirmed in a randomized, prospective trial, which demonstrated lower rates of cardiovascular death and major thrombosis using this hematocrit target.[12,13] The target level for women may need to be lower (e.g., hematocrit <40%), but there are no empiric data to confirm this recommendation.[14]

Complications of phlebotomy include the following:

  • Progressive and sometimes extreme thrombocytosis and symptomatology related to chronic iron deficiency, including pica, angular stomatitis, and glossitis.
  • Dysphagia that is the result of esophageal webs (very rare).
  • Possibly muscle weakness.

In addition, progressive splenomegaly or pruritus not controllable by antihistamines may persist despite control of the hematocrit by phlebotomy. (Refer to the PDQ summary on Pruritus for more information.) If phlebotomy becomes impractical, hydroxyurea or interferon-alpha can be added to control the disease.

The Polycythemia Vera Study Group randomly assigned more than 400 patients to phlebotomy (target hematocrit <45), radioisotope phosphorous 32 (32P) (2.7 mg/m 2 administered intravenously every 12 weeks as needed), or chlorambucil (10 mg administered by mouth daily for 6 weeks, then given daily on alternate months).[15] The median survival for the phlebotomy group (13.9 years) and the radioisotope 32P group (11.8 years) was significantly better than that of the chlorambucil group (8.9 years), primarily because of excessive late deaths from leukemia or other hematologic malignancies.[15][Level of evidence: 1iiA] Because of these concerns, many clinicians use hydroxyurea for patients who require cytoreductive therapy that is caused by massive splenomegaly, a high phlebotomy requirement, or excessive thrombocytosis.[15]

In a pooled analysis of 16 different trials, interferon-alpha therapy resulted in avoidance of phlebotomy in 50% of patients, with 80% of patients experiencing marked reduction of splenomegaly.[16][Level of evidence: 3iiiDiv] Interferon posed problems of cost, side effects, and parenteral route of administration, but no cases of acute leukemia were seen in this analysis. In a phase II study (NCT01259856), 50 patients with p. vera who required therapy with hydroxyurea and had either an inadequate response or unacceptable side effects received pegylated interferon alpha-2a. The complete response rate was 22% and the partial response rate was 38%, with only a 14% discontinuation rate from side effects.[17][Level of evidence: 3iiiDiv]

Patients who required therapy with hydroxyurea but had either an inadequate response or unacceptable side effects were randomly assigned to receive ruxolitinib or standard therapy (interferon, chlorambucil, or busulfan). Ruxolitinib provided better control of hematocrit (60% vs. 20% P < .001), reduction of spleen volume (38% vs. 1% P < .001) and reduction of symptom score by 50% (49% vs. 5% P < .001).[18][Level of evidence: 1iiDiv]

In patients previously treated with hydroxyurea, ruxolitinib and interferon have not been compared in a randomized trial.

Patients with p. vera and no splenomegaly in whom hydroxyurea failed were studied in a randomized prospective trial of 173 participants.[19] Patients were randomly assigned to receive ruxolitinib (the JAK2 inhibitor) versus best available therapy (such as interferon, higher doses of hydroxyurea, or no treatment). Hematocrit control was achieved in 62% of ruxolitinib-treated patients versus 19% of controls (hazard ratio, 7.28 95% confidence interval [CI], 3.43󈜗.45 P < .001).[19][Level of evidence: 1iiDiv]

In a Cochrane review of two randomized studies of 630 patients with no clear indication or contraindication for aspirin, those receiving 100 mg of aspirin versus placebo had reduction of fatal thrombotic events, but this benefit was not statistically significant (odds ratio, 0.20 95% CI, 0.03𔂿.14).[20] A retrospective review of 105 patients who underwent surgery documented that 8% of them had thromboembolisms and 7% of them had major hemorrhages with previous cytoreduction by phlebotomy and postoperative subcutaneous heparin in one half of the patients.[21]

Guidelines based on anecdotal reports have been developed for the management of pregnant patients with p. vera.[3]

Treatment options include the following:

  1. Phlebotomy.[12]
  2. Hydroxyurea (alone or with phlebotomy).[14,15]
  3. Interferon-alpha [16,22-24] and pegylated interferon-alpha.[17,25,26]
  4. Ruxolitinib.[19]
  5. Rarely, chlorambucil or busulfan may be required, especially if interferon or hydroxyurea are not tolerated, as is often seen in patients older than 70 years.[2]
  6. Low-dose aspirin (� mg) daily, unless contraindicated by major bleeding or gastric intolerance.[9,20]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Tefferi A, Thiele J, Vardiman JW: The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer 115 (17): 3842-7, 2009. [PUBMED Abstract]
  2. Streiff MB, Smith B, Spivak JL: The diagnosis and management of polycythemia vera in the era since the Polycythemia Vera Study Group: a survey of American Society of Hematology members' practice patterns. Blood 99 (4): 1144-9, 2002. [PUBMED Abstract]
  3. McMullin MF, Bareford D, Campbell P, et al.: Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol 130 (2): 174-95, 2005. [PUBMED Abstract]
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  8. Chait Y, Condat B, Cazals-Hatem D, et al.: Relevance of the criteria commonly used to diagnose myeloproliferative disorder in patients with splanchnic vein thrombosis. Br J Haematol 129 (4): 553-60, 2005. [PUBMED Abstract]
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  10. Bonicelli G, Abdulkarim K, Mounier M, et al.: Leucocytosis and thrombosis at diagnosis are associated with poor survival in polycythaemia vera: a population-based study of 327 patients. Br J Haematol 160 (2): 251-4, 2013. [PUBMED Abstract]
  11. Boddu P, Masarova L, Verstovsek S, et al.: Patient characteristics and outcomes in adolescents and young adults with classical Philadelphia chromosome-negative myeloproliferative neoplasms. Ann Hematol 97 (1): 109-121, 2018. [PUBMED Abstract]
  12. Berk PD, Goldberg JD, Donovan PB, et al.: Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol 23 (2): 132-43, 1986. [PUBMED Abstract]
  13. Marchioli R, Finazzi G, Specchia G, et al.: Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 368 (1): 22-33, 2013. [PUBMED Abstract]
  14. Lamy T, Devillers A, Bernard M, et al.: Inapparent polycythemia vera: an unrecognized diagnosis. Am J Med 102 (1): 14-20, 1997. [PUBMED Abstract]
  15. Kaplan ME, Mack K, Goldberg JD, et al.: Long-term management of polycythemia vera with hydroxyurea: a progress report. Semin Hematol 23 (3): 167-71, 1986. [PUBMED Abstract]
  16. Lengfelder E, Berger U, Hehlmann R: Interferon alpha in the treatment of polycythemia vera. Ann Hematol 79 (3): 103-9, 2000. [PUBMED Abstract]
  17. Yacoub A, Mascarenhas J, Kosiorek H, et al.: Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea. Blood 134 (18): 1498-1509, 2019. [PUBMED Abstract]
  18. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al.: Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 372 (5): 426-35, 2015. [PUBMED Abstract]
  19. Passamonti F, Griesshammer M, Palandri F, et al.: Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol 18 (1): 88-99, 2017. [PUBMED Abstract]
  20. Squizzato A, Romualdi E, Passamonti F, et al.: Antiplatelet drugs for polycythaemia vera and essential thrombocythaemia. Cochrane Database Syst Rev 4: CD006503, 2013. [PUBMED Abstract]
  21. Ruggeri M, Rodeghiero F, Tosetto A, et al.: Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey. Blood 111 (2): 666-71, 2008. [PUBMED Abstract]
  22. Silver RT: Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. Cancer 107 (3): 451-8, 2006. [PUBMED Abstract]
  23. Quintás-Cardama A, Kantarjian HM, Giles F, et al.: Pegylated interferon therapy for patients with Philadelphia chromosome-negative myeloproliferative disorders. Semin Thromb Hemost 32 (4 Pt 2): 409-16, 2006. [PUBMED Abstract]
  24. Huang BT, Zeng QC, Zhao WH, et al.: Interferon α-2b gains high sustained response therapy for advanced essential thrombocythemia and polycythemia vera with JAK2V617F positive mutation. Leuk Res 38 (10): 1177-83, 2014. [PUBMED Abstract]
  25. Quintás-Cardama A, Kantarjian H, Manshouri T, et al.: Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol 27 (32): 5418-24, 2009. [PUBMED Abstract]
  26. Quintás-Cardama A, Abdel-Wahab O, Manshouri T, et al.: Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood 122 (6): 893-901, 2013. [PUBMED Abstract]

Naked mole rats and cancer

The naked mole rat may be hard on the eye, but this burrowing rodent is of great interest to scientists because it doesn’t get cancer. Naked mole rats could also teach us something about longevity. Given their size, they should live a similar length of time as their relative the dormouse (about four years), yet they often live seven times longer.

Looks aren’t everything in the world of biology. Neil Bromhall/Shutterstock

These ugly rodents are slowly giving up their secrets to scientists and one day might help us develop new therapies to beat cancer and age-related diseases.


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About PDQ

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This PDQ cancer information summary has current information about the treatment of gestational trophoblastic disease. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

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Novel genetic patterns may make us rethink biology and individuality

Professor of Genetics Scott Williams, PhD, of the Institute for Quantitative Biomedical Sciences (iQBS) at Dartmouth's Geisel School of Medicine, has made two novel discoveries: first, a person can have several DNA mutations in parts of their body, with their original DNA in the rest -- resulting in several different genotypes in one individual -- and second, some of the same genetic mutations occur in unrelated people. We think of each person's DNA as unique, so if an individual can have more than one genotype, this may alter our very concept of what it means to be a human, and impact how we think about using forensic or criminal DNA analysis, paternity testing, prenatal testing, or genetic screening for breast cancer risk, for example. Williams' surprising results indicate that genetic mutations do not always happen purely at random, as scientists have previously thought.

His work, done in collaboration with Professor of Genetics Jason Moore, PhD, and colleagues at Vanderbilt University, was published in PLOS Genetics journal on November 7, 2013.

Genetic mutations can occur in the cells that are passed on from parent to child and may cause birth defects. Other genetic mutations occur after an egg is fertilized, throughout childhood or adult life, after people are exposed to sunlight, radiation, carcinogenic chemicals, viruses, or other items that can damage DNA. These later or "somatic" mutations do not affect sperm or egg cells, so they are not inherited from parents or passed down to children. Somatic mutations can cause cancer or other diseases, but do not always do so. However, if the mutated cell continues to divide, the person can develop tissue, or a part thereof, with a different DNA sequence from the rest of his or her body.

"We are in reality diverse beings in that a single person is genetically not a single entity -- to be philosophical in ways I do not yet understand -- what does it mean to be a person if we are variable within?" says Williams, the study's senior author, and founding Director of the Center for Integrative Biomedical Sciences in iQBS. "What makes you a person? Is it your memory? Your genes?" He continues, "We have always thought, 'your genome is your genome.' The data suggest that it is not completely true."

In the past, it was always thought that each person contains only one DNA sequence (genetic constitution). Only recently, with the computational power of advanced genetic analysis tools that examine all the genes in one individual, have scientists been able to systematically look for this somatic variation. "This study is an example of the type of biomedical research project that is made possible by bringing together interdisciplinary teams of scientists with expertise in the biological, computational and statistical sciences." says Jason Moore, Director of the iQBS, who is also Associate Director for Bioinformatics at the Cancer Center, Third Century Professor, and Professor of Community and Family Medicine at Geisel.

Having multiple genotypes from mutations within one's own body is somewhat analogous to chimerism, a condition in which one person has cells inside his or her body that originated from another person (i.e., following an organ or blood donation or sometimes a mother and child -- or twins -- exchange DNA during pregnancy. Also, occasionally a person finds out that, prior to birth, he or she had a twin who did not survive, whose genetic material is still contained within their own body). Chimerism has resulted in some famous DNA cases: one in which a mother had genetic testing that "proved" that she was unrelated to two of her three biological sons.

Williams says that, although this was a small study, "there is a lot more going on than we thought, and the results are, in some ways, astoundingly weird."

Because somatic changes are thought to happen at random, scientists do not expect unrelated people to exhibit the same mutations. Williams and colleagues analyzed the same 10 tissue samples in two unrelated people. They found several identical mutations, and detected these repeated mutations only in kidney, liver and skeletal body tissues. Their research examined "mitochondrial DNA" (mtDNA) -- a part of DNA that is only inherited from the mother. Technically all women would share mtDNA from one common female ancestor, but mutations have resulted in differences. The importance of Williams' finding is that these tissue-specific, recurrent, common mutations in mtDNA among unrelated study subjects -- only detected in three body tissues -- are "not likely being developed and maintained through purely random processes," according to Williams. They indicate "a completely different model &hellip. a decidedly non-random process that results in particular mutations, but only in specific tissues."

If our human DNA changes, or mutates, in patterns, rather than randomly if such mutations "match" among unrelated people or if genetic changes happen only in part of the body of one individual, what does this mean for our understanding of what it means to be human? How may it impact our medical care, cancer screening, or treatment of disease? We don't yet know, but ongoing research may help reveal the answers.

Christopher Amos, PhD, Director of the Center for Genomic Medicine and Associate Director for Population Sciences at the Cancer Center, says, "This paper identifies mutations that develop in multiple tissues, and provides novel insights that are relevant to aging. Mutations are noticed in several tissues in common across individuals, and the aging process is the most likely contributor. The theory would be that selected mutations confer a selective advantage to mitochondria, and these accumulate as we age." Amos, who is also a Professor of Community and Family Medicine at Geisel, says, "To confirm whether aging is to blame, we would need to study tissues from multiple individuals at different ages." Williams concurs, saying, "Clearly these do accumulate with age, but how and why is unknown -- and needs to be determined."

As more and better data become available from high-throughput genetic analyses and high-powered computers, researchers are identifying an increasing number of medical conditions that result from somatic mutations, including neurological, hematological, and immune-related disorders. Williams and colleagues are conducting further research to examine how diseases, other than cancer or even benign conditions, may result from somatic changes. Williams, Moore and Amos will employ iQBS's Discovery supercomputer for next-generation sequencing to process subjects' DNA data. Future analyses will include large, whole-genome sequencing of the data for the two individuals studied in the current report.

Williams explains, "We know that cancer is caused by mutations that cause a tumor. But in this work, we chose to study mutations in people without any cancer. Knowing how we accumulate mutations may make it easier to separate genetic signals that may cause cancer from those that accumulate normally without affecting disease. It may also allow us to see that many changes that we thought caused cancer do not in many situations, if we find the same mutations in normal tissues."

Just as our bodies' immune systems have evolved to fight disease, interestingly, they can also stave off the effects of some genetic mutations. Williams states that, "Most genetic changes don't cause disease, and if they did, we'd be in big trouble. Fortunately, it appears our systems filter a lot of that out."

Mark Israel, MD, Director of Norris Cotton Cancer Center and Professor of Pediatrics and Genetics at Geisel, says, "The fact that somatic mutation occurs in mitochondrial DNA apparently non-randomly provides a new working hypothesis for the rest of the genome. If this non-randomness is general, it may affect cancer risks in ways we could not have previously predicted. This can have real impact in understanding and changing disease susceptibility."


Causes in non-smokers

Not all people who get lung cancer are smokers. Many people with lung cancer are former smokers, but many others never smoked at all. And it is rare for someone who has never smoked to be diagnosed with small cell lung cancer (SCLC), but it can happen.

Lung cancer in non-smokers can be caused by exposure to radon, secondhand smoke, air pollution, or other factors. Workplace exposures to asbestos, diesel exhaust or certain other chemicals can also cause lung cancers in some people who don’t smoke.

A small portion of lung cancers occur in people with no known risk factors for the disease. Some of these might just be random events that don’t have an outside cause, but others might be due to factors that we don’t yet know about.

Lung cancers in non-smokers are often different from those that occur in smokers. They tend to occur in younger people and often have certain gene changes that are different from those in tumors found in smokers. In some cases, these gene changes can be used to guide treatment.


Treatment for familial adenomatous polyposis

Researchers from Tel Aviv University and Tel Aviv Sourasky Medical Center (Ichilov Hospital) have developed an innovative drug treatment for familial adenomatous polyposis (FAP), a rare, inherited condition that affects adolescents and young adults and often leads to colorectal cancer.

The novel drug, based on antibiotics, inhibits the development of intestinal polyps that, left untreated, become cancerous. In a preliminary clinical trial, the condition of seven out of eight patients who completed the full treatment improved dramatically.

The research was jointly led by Prof. Rina Rosin-Arbesfeld of the Department of Microbiology and Clinical Immunology at TAU's Sackler School of Medicine and Prof. Revital Kariv of the Sackler School and the Department of Gastroenterology at Tel Aviv Sourasky Medical Center. It was published on July 8 in the International Journal of Cancer.

FAP, which is characterized by multiple polyps along the gastrointestinal tract, especially in the large bowel, is caused by a mutation in the adenomatous polyposis coli (APC) gene. These mutations are also crucial for colorectal cancer development.

"To prevent the development of colorectal cancer, FAP patients are closely monitored via frequent colonoscopies to locate and remove their polyps," Prof. Rosin-Arbesfeld says. "However, some patients must have their colons removed at a very young age, which dramatically affects their quality of life."

In its normal state, APC promotes the production of a protein that inhibits cancer development. But mutations to the APC gene produce an inactive protein that is unable to prevent the development of the polyps. In some FAP patients, the mutations in the APC gene are what are called "nonsense mutations."

"Each sequence of three nucleotides in the DNA is a code that tells the cell to produce a certain amino acid, which are the building blocks of the proteins produced in the body's cells," Prof. Rosin-Arbesfeld explains. "At the end of the protein coding sequence, there is usually a 'stop codon' to stop the protein production. But in FAP patients with a nonsense mutation, the APC's stop codon appears prematurely, so the protein production stops prematurely, creating an inactive protein."

Previous experiments on cell cultures and mouse models in Prof. Rosin-Arbesfeld's laboratory revealed that certain types of antibiotics caused cells to "ignore" the mutation stop codon and a normal protein resulted. These trials yielded promising results that led to the clinical trial at Tel Aviv Sourasky Medical Center.

"Since the relevant antibiotics were already approved for human use, we decided to move directly from the laboratory to the clinic and to examine the treatment of FAP patients," says Prof. Rosin-Arbesfeld.

In the clinical study carried out by Prof. Kariv and Dr. Shlomi Cohen, director of the Pediatric Gastroenterology Unit at Dana-Dwek Children's Hospital, 10 FAP patients received the novel antibiotic therapy. Eight of them completed the treatment, which lasted four months. Colonoscopies performed during and after the treatment showed that in seven patients the polyps significantly decreased in number. Moreover, the positive effects of the treatment were evident a year after it began.

"Our goal as therapists, in addition to preventing cancer, is to improve the quality of life of our patients and their families and to enable them to live as full and normal lives as possible," Prof. Kariv concludes. "The new therapeutic approach we are developing may allow patients to delay surgical intervention or even prevent it entirely."

The researchers recently won Tel Aviv University's SPARK grant, which supports the development of applied research.


Discussion

FAMMM syndrome has long been suspected to be associated with additional cancers, outside of the syndromic FAMMM-related cancers, yet the field was not yet advanced enough to definitively make this conclusion. After years of gene discovery and characterization as well as the expansion of FAMMM families, we have been given the opportunity to perform a more comprehensive analysis of one of the genes that contribute to the syndrome and assess its phenotypic heterogeneity. The objective of this study was to describe a wealth of information that has been revealed through the statistical analyses of these families and has guided the suggestion to expand surveillance to include that of cancers outside of the known FAMMM-related cancers in carriers.

We first reviewed the patterns of inheritance of FAMMM-related cancers and other cancers, from which we made a few important observations. First, in addition to family members exhibiting high rates of melanoma and pancreatic cancer, we also see that some of these individuals give rise to carrier offspring who exhibit only “other” cancers. Furthermore, in carriers who exhibit multiple primary cancers, which is a hallmark of inherited cancers, we see a combination of FAMMM-related cancers and other cancers. These suggest that the familial mutation likely contributed to each independent primary at different time points in an individual's life. Another visible pattern is the occurrence of dysplastic nevi and melanoma as the first primary followed by various combinations of other cancers. It is known that there is an environmental contribution to melanoma with sun ultraviolet (UV) rays being a strong factor in cancer initiation (25). It is likely that melanoma is the initial cancer to occur in a series of cancer occurrences as the result of a CDKN2A mutation tumor-driving effect paired with almost unavoidable UV light exposure, which is a common and abundant environmental cancer risk factor that directly affects skin. The additional cancer primaries that occurred in these individuals are likely the result of other acquired somatic mutations and/or environmental exposures that have latent effects in the tissue where these other cancers occurred.

Our examination of FAMMM-related cancer incidence rates as a function of time in the form of survival plots indicates that carriers show a strong age effect in cancer occurrence, which is another hallmark of familial cancers. We indeed expected this result because it is well known that melanomas occur at a younger age in CDKN2A carriers than in non-carriers. As we expected the FAMMM-related cancer group to display a strong age effect, this plot serves as a control and models the pattern we expected to see in the other cancers group if they indeed were the result of familial mutations. Just as with the FAMMM-related group, we see a sharp drop in cancer-free survival probability in carriers after the age of 25 with the 50% survival probability occurring around age 55 for the “other” cancer group. For both groups, the noncarriers have little to no incidence of cancer by this age providing strong evidence that the age effect seen in both FAMMM-related and other cancers analyses is due to CDKN2A familial mutations. Our analysis of lung and breast cancer, which both have been shown to have suggestive associations with FAMMM syndrome, supports previous findings. However, there were only eight cancer events in the analysis so this replication analysis was not conclusive. A larger dataset is needed to definitively state that this relationship exists.

The Cox regression analysis reflected what was seen in the survival plots. Individual who are carriers are 100 times more likely to develop a FAMMM-related cancer than those who are noncarriers (P = 7.15E−20). The effect of CDKN2A mutations on other cancers was also strong, albeit less so, with carriers being 20 times more likely than noncarriers to develop these other cancers (P = 5.00E−13). Despite the difference in magnitude of the effect between these groups, the HRs and their CI greatly overlap. This difference is possibly due to differences in sample size, resulting in the other cancers group having a wider CI. An additional explanation is that the stronger age effect in the FAMMM-related cancers may be driven by the melanoma events, which tend to occur at younger ages than other cancers. Finally, it is also possible that these mutations produce a stronger increase in the risk of FAMMM-related cancers than for the other cancers. Our assessment of ascertainment bias by examining only bloodline family members bolsters our survival analysis results and suggest that they are not due to flaws in participant recruitment design. They also suggest that the significant age effect and increased rate of other cancers is specific to carriers and not simply familial. Follow-up studies with larger sample sizes of known CDKN2A mutation carriers and known noncarriers within large families should perform similar analyses stratified by cancer type to further refine this age effect. In addition, larger studies may also examine the effects of the various mutations in CDKN2A since each may have different functional consequences and effects on cancer development. Those that were identified in this study were scattered across the gene and could not be grouped in a meaningful way (Supplementary Fig. S5).

Finally, it also appears that several cancers, especially nonmelanoma, non-sebaceous skin cancer, are observed more frequently in mutation carriers than noncarriers in this dataset (Supplementary Table S9). Thus, there may be greater susceptibility for these particular cancers (nonmelanoma skin cancer, colon, nervous system, soft tissue, bone, esophageal, ovarian, and testis cancers) in carriers when compared with other cancers. There are not enough samples in this dataset to suggest this is a feature of FAMMM syndrome in general, but distinguishing between other cancers that occur more frequently in mutation carriers will be important for future studies. We showed that the significant excess of additional cancers in CDKN2A carriers was not due solely to non-melanoma skin cancers since the analysis excluding these nonmelanoma skin cancers still showed highly significant increased risk for other cancers in the carriers compared with noncarriers (HR 0.02 95% CI, 0.02−0.13 P = 3.8E−10). This gives strong support to the clinical implication that carriers of these mutations should also be carefully screened at early ages for additional types of cancer.

These findings support our hypothesis that the high frequency of other cancers observed in these FAMMM syndrome families manifest due to familial mutations in the CDKN2A gene. These mutations cause an excess of other cancers and FAMMM-related cancers, thereby strongly arguing for much broader cancer screening recommendations in these families for not only the FAMMM-related but now the additional cancer types. Doing so may allow for earlier detection of these additional cancers and lower mortality rates due to earlier treatments.

Our findings emphasize the importance of performing carrier detection among more distant relatives of known carriers and earlier screening guidelines for both FAMMM-related and other cancers in the carriers of CDKN2A mutations. Our results also have implications for strategies of detecting germline mutations in individuals with a family history of cancer or with multiple primary cancers. It is most common for a cancer patient to have germline and tumor sequencing performed on a set of known cancer-predisposition genes based on the tumor type of the patient. Our results suggest that a broader set of cancer predisposition genes should be sequenced because a patient with one of the other cancers here might not be screened for CDKN2A at present. Support for this idea also comes from a recent study of adults with multiple primary cancers, which used whole genome sequencing (26). This study found that by sequencing all known cancer predisposing genes, rather than those targeted by cancer types in the patient, they could detect a deleterious variant in about a third of individuals and that of those with a pathogenic or likely pathogenic mutation, over 40% had a tumor type that appeared unrelated to the mutated gene.

Rapidly evolving genomic technologies are influencing cancer control through the diagnosis of hereditary cancer syndromes. A comprehensive cancer family history that includes cancers of all anatomic sites, paired with optimum cancer education and targeted therapy will enhance personalized medicine initiatives.