FaCD Online Syndrome Fact Sheet

Last updated: 16 Jan 2008

Name: Naso-/Oropharyngeal/Laryngeal Cancer, Familial Clustering of

Synonym: incl.: Familial Head and Neck Cancer

Mode of Inheritance: multifact?/ AR?

OMIM number: 161550

Genes

ADH3, mapped to 4q22
CYP2E1, mapped to 10q24.3-qter
GSTM1, mapped to 1p13.3
HLA-A, mapped to 6p21.3
NAT2, mapped to 8p21.3-23.1
TNF, mapped to 6p21.1-p21.3

Tumor features

laryngeal cancer
lung/bronchial cancer
nasopharyngeal cancer
oropharyngeal cancer

Tumor features (possible)

breast cancer
melanoma, cutaneous

Non-tumor features

mutagen sensitivity, increased

Comment

A family history of head and neck aero-digestive tract squamous cell carcinomas (SCC) increases the risk to develop these tumors, especially if multiple primary tumors have occurred[1]. Relative risks (RR's) for first degree relatives of patients with these tumors have been estimated ranging from 3.5 (affected first-degree relatives in general) to 14.6 (siblings) [2-5]. The risk is especially elevated in relatives of patients with multiple primary head and neck tumors[3]. Morita et al.[6] reported that a family history of upper aerodigestive tract cancer appears to be associated with the occurrence of multiple upper aerodigestive tract cancer as well as the development of hypopharyngeal or upper esophageal cancer. Relatives of lung cancer patients are at an increased risk to develop laryngeal carcinoma and vice versa[2;4;7]. A study by Mork et al.[8] of cancer occurring in first-degree relatives of patients with head and neck SCC diagnosed before the age of 45 suggested sex asymmetry for these familial risk factors. A RR of 4.3 to develop cancer of the respiratory or upper digestive tract was calculated for relatives of female patients, whereas risk for relatives of male patients was not increased. An excess mortality from cancers of the larynx has been documented in first-degree relatives of breast cancer and melanoma patients[9,10].

With respect to external risk modifiers, Caravello et al [10] showed that, compared to subjects without family history, nonsmokers, and non or moderate drinkers, the OR for oropharyngeal cancer was 42.6 for current smokers, heavy drinkers with family history. Further support of the notion of hereditary predisposition to head and neck cancer was given by a segregation analyses of nasopharyngeal carcinoma in Taiwan. A Mendelian recessive model with a disease allele frequency of 0.18 best explained the familial clustering observed in this study[12]. Andrade et al.[13] performed a similar analysis, which estimated that heterozygotes for a postulated squamous cell head and neck cancer predisposition gene who smoke and drink have a risk of 14% by age 70 to develop such a tumor, whereas the risk for non-smoking/drinking carriers of this gene is close to zero.

Increased mutagen sensitivity may act as a marker for familial head and neck cancer[13-16]. This appears to be more pronounced in patients with laryngeal and oropharyngeal cancer than in nasopharyngeal cancer patients[18]. Cloos et al.[19] estimated the heritability of bleomycin induced chromatid breaks in lymphocytes, studied in a population of healthy volunteers with or without a first-degree relative with head and neck cancer to be 75%. Cheng et al.[18] and Wei et al.[20] observed a reduced DNA repair capacity, respectively a low expression of DNA mismatch repair genes, in peripheral blood lymphocytes of head and neck cancer patients.

In a Japanese study[21], certain HLA-A alleles were associated with an increased risk to develop oral SSC, whereas there was no such association at other head and neck SCC sites. Glutathione s-transferase M1 (null genotype) and n-acetyl transferase (NAT) polymorphisms have been shown to act as risk factors for (smoking associated) laryngeal carcinoma[22-24]. Oude Ophuis et al.[25] could not demonstrate an association between GSTM1or T1 polymorphisms and head and neck cancer. Slow NAT2 activity was shown to be a risk factor for smoking associated head and neck cancer[25]. Specific genotype combinations of glutathione s-transferase and alcohol dehydrogenase 3 are associated with a 80 % greater risk of developing laryngeal and oropharyngeal cancer in alcoholics[27]. Harty et al. calculated RR’s of up to 40 for oral cancer in heavy drinkers (at least 57 alcoholic drinks per week) carrying specific alcohol dehydrogenase 3 genotypes[28]. Non-smoking Taiwanese individuals homozygous for the (cytochrome P450) enzyme CYP2E1 c2 allele have been found to have a RR of developing nasopharyngeal cancer of 9.3[29]. Matthias et al.[30] demonstrated that polymorphisms at the TNF locus were associated with the risk to develop laryngeal squamous cell cancer (b3 allele homozygosity, RR 5.3).

References