ATM Mutations in Patients with Hereditary Pancreatic Cancer

DOI: 10.1158/2159-8290.CD-11-0194 Published January 2012

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Figure 1.
Pedigrees of familial pancreatic cancer families FPC-A and FPC-B. A, family FPC-A. Patients were interrogated with whole-genome sequencing; those with an ATM mutation are indicated by K2756X. B, family FPC-B. Patients were interrogated with whole-exome sequencing; those with an ATM mutation are indicated by W57X.
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Figure 2.
Chromatograms from IV-1 of family FPC-A. A, PBLs of IV-1 demonstrating heterozygosity for the ATM inactivating mutant c.8266A>AT; p.K2756X. B, laser capture microdissected pancreatic tumor of IV-1 showing LOH with retention of the ATM inactivating mutant c.8266A>T; p.K2756X.

Table 1.

Summary data for familial pancreatic cancer families with inactivating ATM variants

Type	Family	Individual	Read length	Bases mapped to genome	Bases mapped to exome	Exome bases with ≥ 10 reads	Average raw coverage	Effective coverage	Total number of variants	Variants in SNP database
Whole-genome sequencing	FPC-A	1	100	115,388,854,300	1,294,030,427	34,681,602	35	95.1%	6,024,866	3,758,900
		2	100	110,742,763,000	1,219,892,546	34,328,889	33	94,7%	6,181,369	3,793,150
		3	100	112,771,643,500	1,271,909,140	34,656,841	34	95.1%	6,190,892	3,783,971
Whole-exome sequencing	FPC-B	1	75	8,110,266,675	4,118,378,295	36,458,593	109	97.9%	35,674	19,573
		2	75	7,597,985,850	4,076,171,309	36,560,365	108	98.0%	35,724	19,605
		3	75	5,649,542,100	2,815,928,672	36,067,752	74	97.6%	34,923	19,554

Table 2.

Summary of heterozygous deleterious ATM variants found in patients with pancreatic cancer

Variant	Pancreatic cancer type	Nucleotide (genomic)^{^a}	Nucleotide (cDNA)^{^b}	Amino acid (protein)^{^c}	Type	Number of affected individuals sequenced
1	Familial^{^d}	g.chr11:107711896A>T	c.8266A>T	p.K2756X	Nonsense	3
2	Familial^{^e}	g.chr11:107603810G>A	c.170G>A	p.W57X	Nonsense	3
3	Familial	g.chr11:107648719G>T	c.3214G>T	p.E1072X	Nonsense	1
4	Familial	g.chr11:107691848G>A	c.6095G>A	p.R2032K	Missense	1
5	Familial	g.chr11:107693309G>T	IVS41-1G>T	sp	Splice site	1
6	Familial	g.chr11:107660218delG	c.3801delG	fs	INDEL	1

↵^a Genomic positions are coordinates in the March 2006, hg1836.1 UCSC release of the human genome. Genomic coordinates and sequences of mutations are on the coding strand. All changes are heterozygous. g., genomic sequence; c., cDNA sequence; p., protein sequence; del, deletion.
↵^b Mutations in non-coding sequences are annotated by intron number preceded by “IVS”, with positive numbers starting from the G of the GT splice donor site and negative numbers starting from the G of the AG splice acceptor site.
↵^c fs, frameshift mutation; sp, splice site mutation.
↵^d Family FPC-A.
↵^e Family FPC-B.